The MASCC Textbook of Cancer Supportive Care and Survivorship

The MASCC Textbook of Cancer Supportive Care and Survivorship

Ian N. Olver Editor

The MASCC Textbook of Cancer Supportive Care and Survivorship

Editor Ian N. Olver MD PhD Clinical Professor University of Sydney Medical School Chief Executive Officer Cancer Council Australia Surry Hills, Sydney NSW 2010 Australia [email protected]

ISBN 978-1-4419-1224-4 e-ISBN 978-1-4419-1225-1 DOI 10.1007/978-1-4419-1225-1 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2010935191 © Multinational Association for Supportive Care in Cancer Society 2011 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Preface

The Multinational Association of Supportive Care in Cancer (MASCC) has as its underlying principle that “Supportive Care Makes Excellent Cancer Care Possible.” This international group attracts a multidisciplinary group of support care practitioners and researchers to its annual symposia. Over the years it has expanded to having 17 study groups led by key professionals in their fields. More recent developments have seen a focus on survivorship. The groups have not only provided education, networking and the promotion of research but have produced guidelines and research and teaching tools. With all of that expertise across the world, what better organisation could there be to produce a book on supportive care and survivorship, which spans the management of symptoms and the control of the side effects of treatment? The result is a textbook with authorship by experts from 17 countries. The authors are MASCC members and their colleagues, all of whom have volunteered their time and expertise to produce this comprehensive text. The topics range from management of broad general symptoms such as pain and fatigue to the very specific details of toxicities affecting the eye. Special consideration is given to children and the elderly, to rehabilitation and to palliative care. The ongoing issues of survivorship embrace the physical, the psychosocial and the spiritual. As such this book will be a resource for people from a broad range of disciplines. I am most grateful to the Board of MASCC for giving me the opportunity of participating in this exciting project and to work with so many talented experts across the world. Surry Hills NSW, Australia

Ian N. Olver

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Contents

Preface................................................................................................................................

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Contributors......................................................................................................................

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Part I: Introduction   1. Cancer Symptoms and Side Effects of Treatment................................................. Ian N. Olver

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Part II: General Symptoms   2. Cancer Pain............................................................................................................... 11 Mellar P. Davis   3. Cancer-Related Fatigue............................................................................................ 23 Barbara F. Piper, Karin Olson, and Carina Lundh Hagelin   4. Palliative Care: End-of-Life Symptoms.................................................................. 33 Paul Glare, Tanya Nikolova, and Nessa Coyle   5. Supportive Care in Elderly Cancer Patients.......................................................... 45 Matti S. Aapro   6. Supportive Care in Paediatric Oncology................................................................ 49 Marianne D. van de Wetering and Wim J. E. Tissing   7. Quality-of-Life Assessment: The Challenge of Incorporating Quality-of-Life and Patient-Reported Outcomes into Investigative Trials and Clinical Practice........................................................ 63 Richard J. Gralla and Patricia J. Hollen Part III: Cardiovascular   8. Cardiac Toxicities of Cancer Therapies: Challenges for Patients and Survivors of Cancer........................................................................................... 73 Winson Y. Cheung   9. Malignant Pericardial Effusion and Cardiac Tamponade (Cardiac and Pericardial Symptoms)...................................................................... 83 Marek Svoboda 10. The Vena Cava Syndrome........................................................................................ 93 Mario Dicato and Vincent Lens

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Part IV: Respiratory 11. Pulmonary Toxicity of Therapy............................................................................... 99 Andriani G. Charpidou and Kostas K. Syrigos 12. Management of Respiratory Symptoms in People with Cancer........................... 107 David C. Currow and Amy P. Abernethy Part V: Endocrine and Metabolic 13. Endocrine and Metabolic Symptoms of Cancer and Its Treatment..................... 117 Rony Dev Part VI: Reproductive 14. Sexual Problems in Patients with Cancer............................................................... 127 Andreas Meißner, Charalampos Mamoulakis, Grada J. Veldink, and Jean J. M. C. H. de la Rosette 15. Sterility, Infertility, and Teratogenicity................................................................... 133 Hele Everaus 16. Menopause Symptoms.............................................................................................. 145 Debra L. Barton and Sherry L. Wolf Part VII: Hematological and Cardiac 17. Preserving Cardiac Health in the Breast Cancer Patient Treated with Anthracyclines.................................................................................... 161 Neville Davidson 18. Thrombosis and Bleeding in Cancer Patients........................................................ 171 Wolfgang Korte 19. Lymphedema Care.................................................................................................... 179 Andrea M. Steely and Patricia O’Brien Part VIII: Infections in Cancer 20. Infections and Cancer............................................................................................... 195 Bernardo L. Rapoport and Ronald Feld Part IX: Gastrointestinal 21. Cancer Cachexia and Anorexia............................................................................... 205 Neil MacDonald and Vickie Baracos 22. Xerostomia and Dental Problems in the Head and Neck Radiation Patient...................................................................................................... 213 Arjan Vissink, Fred K. L. Spijkervert, and Michael T. Brennan 23. Dysphagia, Reflux, and Hiccups.............................................................................. 223 Amy A. Shorthouse and Rebecca K. S. Wong 24. Nausea and Vomiting................................................................................................ 231 Ian N. Olver 25. Mucositis (Oral and Gastrointestinal).................................................................... 241 Rajesh V. Lalla and Dorothy M. K. Keefe

Contents

Contents

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26. Diarrhea, Constipation, and Obstruction in Cancer Management...................... 249 Lowell B. Anthony 27. Ascites......................................................................................................................... 261 Rohit Joshi 28. Hepatotoxicity and Hepatic Dysfunction................................................................ 267 Ahmet Taner Sümbül and Özgür Özyilkan Part X: Urogenital 29. Urological Symptoms and Side Effects of Treatment............................................ 281 Ehtesham Abdi 30. Gynecological Symptoms.......................................................................................... 301 Stefan Starup Jeppesen and Jørn Herrstedt Part XI: Neurologic and Muscular 31. Central Nervous System Symptoms: Headache, Seizures, Encephalopathy, and Memory Impairment........................................................... 313 Roxana S. Dronca, Charles L. Loprinzi, and Daniel H. Lachance 32. Neuromuscular Disease and Spinal Cord Compression........................................ 321 Roxana S. Dronca, Charles L. Loprinzi, and Daniel H. Lachance 33. Eye Symptoms and Toxicities of Systemic Chemotherapy.................................... 333 April Teitelbaum Part XII: Skin 34. Extravasation............................................................................................................. 351 Lisa Schulmeister 35. Dermatologic Toxicities............................................................................................ 361 Eugene Balagula and Mario E. Lacouture 36. Chemotherapy-Induced Alopecia: Overview and Methodology for Characterizing Hair Changes and Regrowth.................... 381 Elise A. Olsen Part XIII: Rehabilitation 37. Rehabilitation in Cancer.......................................................................................... 389 Martin R. Chasen and Paul B. Jacobsen Part XIV: Survivorship 38. Oral Health and Survivorship: Late Effects of Cancer and Cancer Therapy................................................................................................. 399 Joel B. Epstein and Barbara E. Murphy 39. Survivorship: Psychosocial, Physical Issues, and Insomnia.................................. 407 Melissa Y. Carpentier, Tammy Weitzmann, Ziv Amir, Grace E. Dean, and Ian N. Olver 40. Spiritual Issues in Supportive Cancer Care........................................................... 419 Antonella Surbone, Tatsuya Konishi, and Lea Baider Index................................................................................................................................... 427

Contributors

Matti S. Aapro, MD Clinique de Genolier, Multidisciplinary Oncology Institute, 1 route du Muids, 1272, Genolier, Switzerland Ehtesham Abdi, MBBS, FRACP, FACP Department of Medical Oncology, Cancer and Aged Care, Griffith University, The Tweed Hospital, Tweed Heads, NSW, 2485, Australia Amy P. Abernethy, MD Associate Professor of Medicine, Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Director, Duke Cancer Care Research Program, Durham, NC 27710, USA Ziv Amir, PhD, MSc, BSc Director, MacMillan Research Unit, University of Manchester, School of Nursing, Midwifery and Social Work, Oxford Road, M13 9PL, Manchester, UK Lowell B. Anthony, MD, FACP LSUHSC New Orleans, Professor of Medicine, Department of Medicine, Ochsner Kenner Medical Center, 200 West Esplanade, Ste 200, Kenner, LA 70065, USA Lea Baider, PhD Professor, Director, Department of Psycho-oncology, Sharett Institute of Oncology and Radiotherapy, Hadassah University Hospital, 91120 Jerusalem, Israel Eugene Balagula, MD Clinical Research Fellow, Department of Dermatology, Memorial Sloan Kettering Cancer Center, New York, NY 10022, USA Vicki Baracos, BSc, PhD Professor, Department of Oncology, University of Alberta, Cross Cancer Instutute, Edmonton, AB, 7Y1C2, Canada Debra L. Barton, RN, PhD, AOCN, FAAN Department of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Michael T. Brennan, DDs, MHS Associate Chairman, Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC 28203, USA Melissa Y. Carpentier, PhD Department of Oral Medicine Pediatrics, Indiana University School of Medicine, 401 West 10th St., Suite 1001, Indianapolis, IN 46202, USA

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Andriani G. Charpidou, MD Chest Physician, Clinical Research Fellow, Oncology Unit, GPP, University of Athens Medical School, Athens, 11527 Greece Martin R. Chasen, MBChB, FCP(SA), MPhil(Pall Med) Division of Palliative Care, University of Ottawa; Palliative Rehabilitation, Élisabeth Bruyère Hospital, Ottawa, ON, Canada Winson Y. Cheung, MD, MPH, FRCPC British Columbia Cancer Agency, Division of Medical Oncology, 600 W. 10th Avenue, 4th Floor, Vancouver, BC, Canada V5Z 4E6 Nessa Coyle, MP, PhD Nurse Practitioner, Memorial Sloan Kettering Cancer Center, New York, NY 15021, USA David C. Currow, MPH, FRACP Palliative and Supportive Services, Flinders University, Adelaide 5041, South Australia Neville Davidson, FRCP, FRCR Department of Oncology Research, Broomfield Hospital, Ground Floor, West Wing 2, Court Road, Chelmsford CM1 7ET, Essex, UK Mellar P. Davis, MD, FCCP The Cleveland Clinic, 9500 Euclid Avenue R35, Cleveland, OH 44195, USA Grace E. Dean, PhD, RN Assistant Professor, University of Buffalo, School of Nursing, Buffalo, NY 14214, USA Rony Dev, DO Department of Palliative Care and Rehabilitation Medicine, University of Texas MD Anderson Cancer Center, Symptom Control and Palliative Medicine, Houston, TX 77030, USA Mario Dicato, MD Cancer Research Foundation – Luxembourg, Centre Hospitalier de Luxembourg, 1, rue Wieseck, L-8269, Mamer, Luxembourg Roxana S. Dronca, MD Department of Oncology/Hematology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55901, USA Joel B. Epstein, DMD, MSD, FRCD, FDS RCS(Ed) Department of Oral Medicine and Diagnostic Sciences, College of Dentistry and Head and Neck Surgery/Otolaryngology, 801 S. Paulina St, Chicago, 60612, IL, USA Hele Everaus, MD, PhD Department of Hematology-Oncology, Tartu University Hospital, Tartu 51014, Estonia Ronald Feld, BSc, Phm MD, FRCPC, FACP Professor of Medicine, University of Toronto; Staff Physician, Division of Hematology and Oncology, Princess Margaret Hospital, Toronto, M5G 2M9 Ontario, Canada Paul Glare, MBBS, FRACP, FACP Pain & Palliative Care Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA Richard J. Gralla, MD Division of Medical Oncology and Hematology, Hofstra North Shore-LIJ School of Medicine, Lake Success, NY 11042, USA

Contributors

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Contributors

Carina Lundh Hagelin, RN, PhD Department of Oncology and Pathology, Division of Clinical Cancer Epidemiology, Karolinska Institutet and Sophiahemmet University College, Stockholm, 114 86, Sweden Jørn Herrstedt, MD Department of Oncology, Odense University Hospital, DK-5000 Odense C, Denmark Patricia J. Hollen, PhD, RN, FAAN Professor of Oncology Nursing, Boyd School of Nursing, Professor of Pediatrics, School of Medicine, Charlottesville, VA 22903, USA Paul B. Jacobsen, PhD Professor and Chair, Department of Health Outcomes & Behavior, Moffitt Cancer Center & Research Institution, Tampa, FL 33612, USA Stefan Starup Jeppesen, MD Department of Oncology, Odense University Hospital, DK-5000 Odense, Denmark Rohit Joshi, MD Medical Oncology, Christian Medical College & Hospital, Ludhiana 141012, Punjab, India Dorothy M. K. Keefe, MBBS, MD Cancer Council Professor of Cancer Medicine, University of Adelaide; Clinical Director, CNAHC and Royal Adelaide Hospital Cancer Services, Royal Adelaide Cancer Centre, Adelaide 5000, Australia Tatsuya Konishi Director of Spiritual Care, Higashi Sapporo Hospital, Sapporo, Hokkaido 060-003, Japan Wolfgang Korte, MD, PhD Institute for Clinical Chemistry and Hematology, Kantonsspital St. Gallen, St. Gallen and University of Bern, Bern, Switzerland Daniel H. Lachance, MD Consultant and Assistant Professor of Neurology, Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA Mario E. Lacouture, MD Department of Dermatology, Memorial Sloan Kettering Cancer Center, 160 East 53rd Street, New York 10022, USA Rajesh V. Lalla, DDS, PhD, CCRP Section of Oral Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA Vincent Lens, MD Department of Radiology, Centre Hospitalier de Luxembourg, L- 1210, Luxembourg Charles L. Loprinzi, MD Director, North Central Cancer Center, Treatment Group Cancer Control Program, Co-Director, Mayo Cancer Center, Cancer Prevention and Control Program, Rochester, MN 55905, USA Neil MacDonald, CM, MD, FRCP(Can), FRCP(Edin) Department of Oncology, McGill University, Montreal, QC, Canada H2W 1S6 Andreas Meißner, MD Academic Medical Center, Department of Urology, University of Amsterdam, Amsterdam, 1105 AZ, The Netherlands

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Charalampos Mamoilakis, MD, PhD, MSc Academic Medical Center, University of Amsterdam, Department of Urology, Amsterdam, 1105 AZ, The Netherlands Barbara E. Murphy, MD Associate Professor, Department of Internal Medicine, Vanderbilt University, Nashville, TN 37232, USA Barbara F. Piper, DNSc, RN, AOCN, FAAN Scottsdale Healthcare/University of Arizona, 10684 N. 113th Street, 85259-4034 Scottsdale, AZ, USA Patricia O’Brien, MD, PT Clinical Associate Professor, Fletcher Allen Health Care, Department of Hematology/ Oncology, Burlington, VT 05405, USA Elise A. Olsen, MD Duke University Medical Center, Box 3294, Durham, NC 27710, USA Karin Olson, BScN, MHSc, PhD University of Alberta, Edmonton, AB, T6G 2G3, Canada Ian N. Olver, MD PhD Clinical Professor, University of Sydney Medical School, Chief Executive Officer, Cancer Council Australia, Surry Hills, Sydney NSW 2010, Australia Özgür Özyilkan, MD Professor, Department of Medical Oncology, Baskent University School of Medicine, Adana, 01120, Turkey Tanya Nikolova, MD Pain & Pallative Care Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065 USA Bernardo L. Rapoport, MD Department of Medical Oncology, The Medical Oncology Centre of Rosebank, Johannesburg 2196, South Africa Jean J. M. C. H. de la Rosette, MD, PhD Academic Medical Center, University of Amsterdam, Department of Urology, Amsterdam, 1105 AZ, The Netherlands Lisa Schulmeister, RN, MN, APRN-BC, OCN, FAAN 282 Orchard Road, River Ridge, LA 70123, USA Amy A. Shorthouse, B.Med(Hons), BSc, FRANZCR Radiation Medicine Program, Princess Margaret Hospital, Toronto, ON, Canada M5G2M9 Fred K. L. Spijkervert, DDS, PhD Associate Professor of Oral and Maxillofacial Surgery and Vice Program Chair, Department of Oral and Maxillofacial Surgery, University Medical Center Gronigen, Gronigen, 9700 RB, The Netherlands Andrea M. Steely, BA, MA Department of Hematology and Oncology, University of Vermont College of Medicine, 89 Beaumont Ave., Burlington, VT 05405, USA Ahmet Taner Sümbül, MD Department of Medical Oncology, Baskent University School of Medicine, Baskent Universitesi Adana Hastanesi Kisla Yerleskesi Tibbi Onkoloji BD Kazim Karabekir cadYuregir, Adana, 01120, Turkey

Contributors

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Contributors

Antonella Surbone, MD, PhD, FACP Department of Medicine, Division of Medical Oncology, New York University Medical School, 550 First Ave BCD 556 New York, NY 10016 USA Marek Svoboda, PhD, MD Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Center, Zluty kopec 7, Brno 65653, Czech Republic Kostas K. Syrigos, MD, PhD Sotiria General Hospital, Oncology Unit, GPP, Athens School of Medicine, Athens 11527, Greece April Teitelbaum, MD, MS AHT BioPharma Advisory Services, 3525A Del Mar Heights #312, San Diego, CA 92130, USA Wim J. E. Tissing MD, PhD Pediatric Oncologist, University Medical Center Groningen, Department of Pediatric Oncology/Hematology, Groningen 9700 RB, The Netherlands Grada J. Veldink Academic Medical Center, University of Amsterdam, Department of Policlinic Surgery and Urology, Amsterdam 1105 AZ, The Netherlands Arjan Vissink, DDS, MD, PhD Department of Oral and Maxillofacial Surgery, University Medical Center Groningen, Groningen, 9700 RB, The Netherlands Tammy Weitzman, LICSW Clinical Social Worker, Bone Marow Transplant Program, Dana Farber/Brigham and Women’s Cancer Center, Boston, MA 02115, USA Marianne D. van de Wetering, PhD, FCP(SA), MMed(SA) Department of Pediatric Oncology, Emma Children’s Hospital/Academic Medical Center, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands Sherry L. Wolf, RN, MS, AOCNS Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA Rebecca K. S. Wong, MBChB, MSc, FRCP Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario M5G2M9, Canada

Part I

Introduction

Chapter 1

Cancer Symptoms and Side Effects of Treatment Ian N. Olver

This is a book to cover the management of the symptoms of cancer and side effects of cancer treatment. The symptoms discussed range from general symptoms to organ-specific symptoms and cover all stages of cancer from the presenting symptoms of the cancer to symptoms that arise in the terminal phase of the illness which require palliation, or symptoms and late effects of treatment which persist post-treatment into the survivorship phase. The authors discuss the management of symptoms which apply to both adults and children. One unique aspect of this handbook is that it covers the whole patient journey including survivorship. This includes both the late effects of treatment and the psychosocial issues to be managed post-treatment. There is also specifically a section on rehabilitation and another on palliative care. The authors are members of MASCC (Multinational Association for Supportive Care in Cancer), a multidisciplinary international organisation whose focus is on supportive care and whose membership includes many of the world leaders in that field. The organisation regularly publishes guidelines in symptom control in order to encourage evidencebased practice. The target audience is the health professional who manages cancer. This includes those from the primary specialties of surgery, radiation oncology, medical oncology, palliative care and rehabilitation medicine as well as from allied disciplines of psychology, social work, physiotherapy, occupational therapy and pharmacy as well as specialist and general nurses. General practitioners who manage many of the symptoms and side effects after treatment will find it a useful reference. The book will also be a helpful resource for medical and allied health students. Finally, with the increasing sophistication of consumers, some will benefit from the greater detail provided in this book if they wish to research beyond traditional resources for patients and carers. I.N. Olver (*) University of Sydney Medical School, Sydney, NSW, Australia and Cancer Council Australia, GPO Box 4708, Level 1, 120 Chalmers Street, Surry Hills NSW 2010, Sydney, NSW 2001, Australia e-mail: [email protected]

The Symptoms of Cancer It is important to become familiar with the symptoms of ­cancer when it presents and when it recurs, to aid in prompt diagnosis, but also to know when the symptoms are not ­typical of cancer and other diagnoses must be considered (Table 1.1). The differential diagnosis of the symptoms of cancer includes the side effects of treatment, which can occur at the time of treatment or later, other drugs given to patients including those for symptom control and unrelated illnesses. Symptoms also have both a physical and psychological dimension and so cannot be isolated from the other experiences of the patient with a diagnosis of cancer. A common feature of cancer-related symptoms is persistence [1]. In the absence of treatment, a cancer-related symptom will persist and often worsen as the cancer progresses. For example, a pain due to an acute back injury or a cough due to an infection would be expected to improve over time because the underlying problem may improve, but that is not the pattern expected if the same symptoms are due to cancer. Some of the physical symptoms of cancer are general and so this book contains chapters which describe symptoms such as fatigue, insomnia, anorexia, cachexia, delirium, fever and pruritus. Some common symptoms such as pain can be associated with multiple organ systems. There are many symptoms specific to organ systems when the cancer directly affects them either as the site of the primary or due to secondary spread. All the major organ systems, cardiovascular, respiratory, gastrointestinal, urogenital and neurological are associated with specific symptoms. For example, the headache associated with primary or secondary cerebral malignancy is usually due to raised intracranial pressure and so is worst in the morning and progresses over several weeks [2]. Paraneoplastic symptoms are distant effects associated with cancer but not directly due to local pressure from the primary or from metastatic disease. They can be associated with any organ system but are commonly endocrine, neurological, haematological, renal or dermatological. Sometimes a rash, for example, may be the initial manifestation of an

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_1, © Multinational Association for Supportive Care in Cancer Society 2011

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I.N. Olver Table 1.1  How cancers present Found by screening or incidentally when asymptomatic Local presentations   Lump   Bleeding   Organ specific, e.g. pain, cough Systemic symptoms   Weight loss   Fatigue   Fever and sweats Medical emergency   Spinal cord compression   Superior vena caval obstruction   Bowel obstruction   Hypercalcaemia

internal malignancy [3]. Unfortunately, the paraneoplastic symptom may not resolve with successful treatment of the underlying malignancy. More generally, the symptoms due to the damage done by a tumour, for example nerve compression, may not reverse if the cancer is treated because the cancer may have caused irreversible cell death. Rehabilitation of the patient with cancer then parallels that which would be employed following other causes of the symptoms in the above example, that is vascular accidents or trauma [4]. Cancers often have predictable patterns of spread which will direct where to look for secondary spread, but will also predict from where symptoms are likely to arise. For example, breast cancer spreads first to the liver, lung, bones and brain [5]. Lung cancer spreads to the liver, brain and bones while colorectal cancer secondaries are most likely to be found in the liver and lungs [6, 7]. Prostate cancer will often cause most of its metastatic symptoms by spreading to the bones, but a subset of prostate cancers spread to soft tissues, often initially to lymph nodes [8]. Conversely, symptoms presenting because of secondaries can provide clues as to the primary sites of the cancer. For example, secondaries in the bone are most likely from prostate, breast, lung, thyroid, adrenal, and renal cancers or myeloma.

The Side Effects of Treatment It is perhaps easiest to group the side effects of cancer treatment depending on their temporal relationship to the treatment. With surgery, chemotherapy and radiotherapy side effects can be acute at the time of the treatment or late, coming sometimes years after the therapy. This can be illustrated by considering chemotherapy toxicities. The immediate toxicities of chemotherapy would include extravasation injury as it is being administered or an acute hypersensitivity reaction [9, 10]. A few hours later side

effects like emesis can occur, but even that has an acute phase spanning the first 24 h and a delayed phase which starts at the end of the first day and can continue for a week [11]. Furthermore, uncontrolled emesis following chemotherapy can establish a learned response where anticipatory emesis can occur prior to subsequent cycles of therapy. In 10–15 days after chemotherapy, in tissues with constant turnover such as the bone marrow, the mucosa or the hair follicles, the dividing cells that were meant to replace mature cells which had completed their life cycle in those tissues do not do so, because they had been destroyed by the chemotherapy, and so myelosuppression, mucositis and alopecia results [12–14]. The stem cells will be stimulated to produce replacements eventually, but the patient needs the symptoms managed in the interim. Next come symptoms that are often delayed by weeks or months, and these are the organ toxicities. Often these are due to cumulative damage from each cycle of chemotherapy. These include cardiotoxicity, pulmonary toxicity, neurotoxicity, nephrotoxicity and hepatic toxicity [15–18]. A good example is the cardiotoxicity associated with the anthracylines [19]. Every dose damages the myocardium until finally sufficient damage is done to manifest itself as a reduction in the ejection fraction. This becomes more likely with cumulative doses in excess of 500  mg/m2, but this varies between patients and depends on factors such as whether there is underlying cardiac disease or whether other cardiotoxic drugs are being administered, including other anti-­ cancer agents such as the targeted therapy, trastuzumab. Toxicities such as this are detailed in the chapters on the side effects associated with various organs. Months to years after the chemotherapy come the late effects. These include organ damage such as encephalopathy, sterility, or the most unfortunate late effect of the treatment, a second cancer [20–22]. Similar temporal relationships between the treatment and side effects are described for radiation therapy. Here the acute effects within the radiation field are most often due to direct cell death which leaves depleted stem cells and progenitor cells and results in denuded tissue, which recovers over time [23]. More general effects such as somnolence and fatigue are due to the release of cytokines by radiation. Subacute effects, are exemplified by pneumonitis when the lung is irradiated, or L’Hermitte’s syndrome following radiation to the spine, and occur between 6 weeks and 3 months. Their aetiology is uncertain, but they recover [24]. Late effects which occur months or years after treatment in tissues such as the brain, do not recover. Stem cells are depleted and the microvasculature is damaged, but also collagen is deposited secondary to activation by the radiation of a series of cytokines, ultimately resulting in fibrosis [25]. With the increasing use of multimodality treatment the propensity for different treatments to interact and worsen the

1  Cancer Symptoms and Side Effects of Treatment

side effects in tissues, must be considered. Including the heart in a radiation field may increase the propensity for later cardiotoxic drugs to exacerbate the damage done. Some drugs, such as gemcitabine will also cause recall reactions of the radiation reaction in a previous field [26].

Differential Diagnoses The importance of knowing the symptoms of cancers and the side effects of therapy has a practical significance because they form part of the differential diagnosis of a symptom cluster in a patient. Consider, for example, a patient receiving chemotherapy for a metastatic cancer who develops a non-specific symptom, such as somnolence, and on examination is dehydrated. This could be due to progressive disease, perhaps with the development of cerebral secondaries or worsening hepatic disease where nausea may decrease the oral intake. Alternately a patient who becomes neutropenic on treatment may develop sepsis with a fever causing somnolence and dehydration. This requires immediate treatment with broad spectrum antibiotics to avoid septic shock. Other medication which a patient is ­taking should be scrutinised. The same symptoms of somnolence and dry mouth would fit with the side effects of morphine. Paraneoplastic syndromes may also need to be considered with particular malignancies. For example non-small cell lung cancer or squamous cell carcinoma of the head and neck may be associated with secretion of a parathyroid-like hormone causing hypercalcaemia which could manifest itself with both of these symptoms. Note also that the hypercalcaemia could be from progression of bone metastases. The importance of considering hypercalcaemia, for example, is that even if the underlying cause is difficult to treat, the symptoms may respond quickly to rehydration and bisphosphonates. It is also important that not every symptom reported by a patient with cancer is automatically considered as due to the cancer or its treatment. Patients may be more susceptible to infections spreading through a community, or can develop common conditions like acute appendicitis. Also, given that the majority of cancers occur in older people, underlying heart or renal problems may be the problem. Separate consideration is given to managing cancers in the elderly where the goals of treatment may be modified by the prognosis of an underlying illness. However, symptom control will always be foremost.

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Often, anti-cancer treatment is very good for palliating symptoms. When treated with full doses with curative intent, a partial response to radiotherapy or chemotherapy may not translate into a survival advantage but will often shrink a tumour enough to relieve symptoms by taking the pressure off a nerve root, or relieving the obstruction of a hollow viscus or duct. The use of anti-cancer treatment for palliation requires a balance between the likely efficacy and toxicity of the treatment and the possible duration of each. Reducing the toxicity of a therapy may mean reducing the dose or duration of therapy, to treat with palliative intent. Often, a single fraction of radiation can provide excellent relief from the pain of bone metastases, for example [27]. Substituting drug regimens can also alleviate side effects. An early example was the decrease in secondary leukaemia after the successful treatment of Hodgkin disease when ABVD (Doxorubicin, Bleomycin, Vinblastine, dacarbazine) was substituted for MOPP (Nitrogen Mustard, Vincristine, Procarbazine, Prednisone) [28]. More recently, the targeted therapies such as Trastuzumab, used in breast cancer, have a much improved toxicity profile as compared to conventional cytotoxic drugs because they spare normal tissues and therefore are better candidates for palliation [29]. The specialty of palliative care uses supportive care drugs to relieve symptoms. Near the end of life, for example, it is said that just four drugs, morphine, midazolam, haloperidol and atropine can alleviate the majority of symptoms. However, symptom control is also required during times when patients are being treated with anti-cancer therapy often since the effects of treatment may take weeks to manifest themselves. My ideal model of multidisciplinary care for symptom control is parallel care, where the palliative care physicians join oncologists on rounds to help with symptom control and also learn when anti-cancer therapies are best used to alleviate symptoms (Fig. 1.1). The other advantage of this model is that as anti-cancer treatment becomes less relevant, a gradual transition can be made to palliative care without an abrupt change. Patients will have been used to seeing the palliative care team during the time when the treatment was primarily directed at shrinking the cancer and the palliative care team will just become progressively more involved with the patients’ management as symptom control becomes the major focus of care.

Parallel Care Cancer is increasingly being treated by multidisciplinary teams because of the need for multimodality treatment.

Fig. 1.1  Parallel care

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Quality of Life and Spiritual Well-Being To achieve the optimum quality of life the balance between the efficacy and toxicity of a drug must be optimised, whether it is an anti-cancer or supportive care drug. Scales of measure­ ment of quality of life can range from simple measures of performance status, which equates to the ability to ­perform the tasks of daily living, to validated scales which measure many domains of life’s quality [30]. Often in deciding the balance, physical symptoms predominate but psychosocial issues are being increasingly recognised as having a major impact on well-being [31]. Spiritual well-being has also shown to impact independently on quality of life. In one study which compared spiritual well-being as measured by the FACIT-Sp scale to quality of life, a hierarchical multiple regression showed spiritual well-being to be a significant, unique contributor to quality of life beyond the core domains of physical, social/family, and emotional well-being [32].

Survivorship Survivorship has several definitions ranging from surviving from the time of diagnosis to survivorship beginning at the time that a complete remission has been achieved [33]. It encompasses issues of adjusting to life with the experience of cancer and its treatment. There may be physical sequelae of the cancer, or late effects of treatment, or distress with anxiety and depression. There may be constant underlying concerns about recurrence of the cancer, particularly after the cessation of active treatment and less frequent monitoring. This is a time of change and relationships can be under stress and previous employment not as satisfying as the patients’ priorities have changed. It is recognised that survivorship issues may require management by a multidisciplinary team of health professionals. Recognising the problems and providing ongoing information and support as well as managing physical symptoms and treating psychological problems may all be required.

Conclusions After the diagnosis of cancer, supportive care is an ongoing need. Symptoms will arise from the cancer or its recurrence and side effects will occur in relation to the treatments offered. Supportive care encompasses managing the ­physical, psychosocial and spiritual needs of patients at the time of

I.N. Olver

d­ iagnosis, through treatment and once the patients have ­survived the cancer, or at the time when the end of life is approaching. Children and the elderly have special supportive care needs. The carers and families of patients will also be impacted by a relative or close friend’s diagnosis of cancer and will require support as well. Symptoms can arise from a number of causes which constitute a differential diagnosis. Once the cause of symptoms has been identified a multidisciplinary team of oncologists, allied health practitioners and palliative care specialists will all work together within a patients’ social support structure to maximise the patient’s quality of life for as long as possible. This book encompasses the many facets of that support.

References 1. Ramos M, Arranz M, Taltavull M, March S, Cabeza E, Esteva M. Factors triggering medical consultation for symptoms of colorectal cancer and perceptions surrounding diagnosis. Eur J Cancer Care (Engl). 2010;19:192–199. 2. Dexter AJ, Cheong J. Neurosurgical involvement with cancer patients. In Robotin M, Olver I, Girgis A, eds. When Cancer Crosses Disciplines. London: Imperial College Press 2009:343–365. 3. Pipkin CA, Lio PA. Cutaneous manifestations of internal malignancies: An overview. Dermatol Clin. 2008;26:1–15. 4. Fattal C, Gault D, Leblond C et  al. Metastatic paraplegia: care ­management characteristics within a rehabilitation centre. Spinal Cord. 2009;47:115–121. 5. Park YH, Lee S, Cho EY et al. Patterns of relapse and metastatic spread in HER2-overexpressing breast cancer according to estrogen receptor status. Cancer Chemother Pharmacol. 2010;66:507–516. 6. Beckles MA, Spiro SG, Colice GL, Rudd RM. Initial evaluation of the patient with lung cancer: symptoms, signs, laboratory tests and paraneoplastic syndromes. Chest. 2003;123:97S–104S. 7. Giess CS, Schwartz LH, Bach AM, Gollub MJ, Panicek DM. Patterns of neoplastic spread in colorectal cancer: implications for surveillance CT studies. Am J Roentgenol. 1998;170:987–991. 8. Long MA, Husband JE. Features of unusual metastases form ­prostate cancer. Br J Radiol. 1999;72:933–941. 9. Goolsby TV, Lombardo FA. Extravasation of chemotherapeutic agents: prevention and treatment. Semin Oncol. 2006;33:139–143. 10. Lee C, Gianos M, Klaustermeyer WB. Diagnosis and management of hypersensitivity reactions related to common cancer chemo­ therapy agents. Ann Allergy Asthma Immunol. 2009;102:187–179. 11. Olver IN. Prevention of chemotherapy-induced nausea and ­vomiting: Focus on fosaprepitant. Ther Clin Risk Manag. 2008; 4(2):1–6. 12. Heuser M, Ganser A, Bokemeyer C. Neutropenia: Review of ­current guidelines. Semin Oncol. 2007;44:148–156. 13. Keefe DM, Schubert MM, Elting LS, Sonis ST et  al; Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer. 2007;109:820–831. 14. Lemieux J, Maunsell E, Provencher L. Chemotherapy-induced ­alopecia and effects on quality of life among women with breast cancer: a literature review. Psychooncology. 2008;17:317–328. 15. Vahid B, Marik PE. Pulmonary complications of novel antineoplastic agents for solid tumours. Chest. 2008;133:528–538.

1  Cancer Symptoms and Side Effects of Treatment 16. Windebank AJ, Grisold W. Chemotherapy-induced neuropathy. J Periph Nerv Syst. 2008;13:27–46. 17. Darmon M, Ciroldi M, Thiery G, Schlemmer B, Azoulay E. Clinical review: Specific aspects of acute renal failure in cancer patients. Crit Care. 2006;10:211 (doi:1186/cc4907). 18. King PD, Perry MC. Hepatotoxicity of chemotherapy. Oncologist. 2001;6:162–167. 19. Bird BR, Swain SM. Cardiac toxicity in breast cancer survivors: Review of potential cardiac problems. Clin Cancer Res. 2008;14:14–24. 20. Hildebrand J. Neurologic complications of cancer chemotherapy. Curr Opin Oncol. 2006;18:321–324. 21. Meirow D, Schiff E. Appraisal of chemotherapy effects on reproductive outcome according to animal studies and clinical data. J Natl Cancer Inst Monogr. 2005;34:21–25. 22. Travis B, Rabkin CS, Brown LM et al. Cancer survivorship-genetic susceptibility and second primary cancers: research strategies and recommendations. J Natl Cancer Inst. 2006;98:15–25. 23. Fiorino C, Rancati T, Valdaqni R. Predictive models of toxicity in external radiotherapy: dosimetric issues. Cancer. 2009;115: 3135–3140. 24. Kempster PA, Rollison RD. The Lhermitte phenomenon: variant forms and their significance. J Clin Neurosci. 2008;15:379–381. 25. Enami B, Lyman J, Brown A et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21:109–122. 26. Friedlander PA, Bansal R, Schwartz L, Wagman R, Posner P, Kemeny N. Gemcitabine-related radiation recall preferentially

7 involves internal tissue and organs. Cancer. 2004;100: 1793–1799. 27. Kaasa S, Brenne E, Lund JA et al. Prospective randomised multicentre trial on a single fraction radiotherapy (8Gy x 1) versus multiple fractions (3Gy x 10) in the treatment of painful bone metastases. Radiother Oncol. 2006;79:278–284. 28. Brusamolino E, Baio A, Orlandi E et al. Long-term events in adult patients with clinical stage 1A-11A nonbulky Hodgkin’s ­lymphoma treated with four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine and adjuvant radiotherapy: a single institution experience. Clin Cancer Res. 2006;12:6487–6493. 29. Brufsky A. Trastuzumab-based therapy for patients with ­HER2-positive breast cancer: form early scientific development to foundation care. Am J Clin Oncol. 2010;33:186–195. 30. Bailey LJ, Sanson-Fisher R, Aranda S, D’Este C, Sharkey K, Schofield P. Quality of life research: types of publication output over time for cancer patients, a systematic review. Eur J Cancer. 2009;Oct 14 [Epub ahead of print]. 31. Cimprich B, Janz NK, Northouse L, Wren PA, Given B, Given CW. Taking CHAGE: A self-management program for women following breast cancer treatment. Psychooncology. 2005;14:704–717. 32. Whitford HS, Olver IN, Peterson MJ. Spirituality as a core domain in the assessment of quality of life in oncology. Psychooncology. 2008;17:1121–1128. 33. Little M, Sayers EJ, Paul K, Jordens CFC. On surviving cancer. J R Soc Med. 2000;93:501–503.

Part II

General Symptoms

Chapter 2

Cancer Pain Mellar P. Davis

Introduction Cancer pain is a subjective sensation of tissue damage, which has an adverse influence on multiple domains in an ­individual’s life. Severe pain is associated with decreased function, increased interference with daily activities, depression, and anxiety. Pain is a major problem in 25–30% of individuals with newly diagnosed cancer and 70–80% with advanced cancer. Over 500,000 Americans die of cancer each year corres­ponding to 1,500 deaths per day [1]; therefore, cancer pain is a major problem that cancer specialists face. The lifetime probability of invasive cancer is 45% for men and 38% for women. Among men, prostate, lung, colon, and rectal cancers account for 50% of newly diagnosed cancers. Breast, lung, and colorectal cancers account for 50% of cancers in women. [1] As a result, bone and visceral pain are major pain subtypes clinicians need to manage. Over 20% of individuals who have cancer pain also have pains related to treatment [2]. Over 60% with chronic pain have breakthrough pain. Most chronic pain is moderate to severe (>7 on a numerical rating scale where 0 = no pain, 10 = severe pain). Many suffer pain for months. There are 22 commonly classified cancer pain syndromes. These syndromes involve bone and/or joint lesions in 41%, visceral metastases in 28%, soft tissue in 28%, and pain from peripheral nerve injury in 28% [2]. Individuals frequently experience two or more distinct cancer pain syndromes. Nociceptive pain accounts for 72%, visceral pain 35%, and neuropathic pain (mixed or purely neuropathic) is experienced by 48% of individuals [2]. Factors associated with the greatest chronic pain intensity are the presence of breakthrough pain, bone, and neuropathic pain. Individuals less than 60 years and

M.P. Davis (*) The Cleveland Clinic, 9500 Euclid Avenue R35, Cleveland, OH 44195, USA e-mail: [email protected]

those with poor performance score will experience severe pain more frequently [2].

Pain and Nociception Rene Descartes in the 1600s articulated the theory that pain is conveyed by special nerves to the brain [3]. Nerves carry information about tissue damage to the central nervous ­system (CNS). This is termed nociception, which involves transduction of the electrical signals to the dorsal horn of the spinal cord, transmission through the superficial layers of the dorsal horn, through the contralateral spinothalamic tract or the ipsilateral dorsal column (in case of visceral pain) to the cerebral pain matrix. Nociception is modulated or gated through the spinal cord, brainstem, and supraspinal sites. Individual genetic makeup, prior experiences, physiological status, appraisal of the meaning of pain, mood, and social cultural environment modulate the conversion of nociception to pain [4]. Nociceptive stimuli are capable of eliciting pain but are not equated with pain. Pain is defined as “sensory and emotional experience associated with actual or potential tissue damage” and not tissue damage per se. There is a poor correlation between the degree of tissue damage and pain severity [4]. Acute pain is of short duration and is associated with a high level of physical pathology. Chronic pain (by definition >3–6 months) has low physical pathology because chronic pain tends to be perpetuated by factors that are both pathogenetically and physically remote for the original cause [4]. The degree of tissue injury does not correlate well with the pain severity for two reasons: (1)  persistent pain alters the CNS, resulting in facilitatory pain transmission and modulation (neuroplasticity) [5, 6]; (2) affective and cognitive factors associated with unrelieved pain interact with tissue damage and contribute to persistent pain and illness behaviors [4]. Prolonged uncontrolled pain kills [7]. It is therefore important that clinicians manage cancer pain aggressively.

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_2, © Multinational Association for Supportive Care in Cancer Society 2011

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The Anatomy of Pain Vanilloid, Sodium Channels, Acid-Sensing Channels Both A-delta (lightly myelinated) and C nerve fibers (unmyelinated) are “pain fibers,” which slowly conduct impulses; they have high thresholds and are often “silent” except with noxious stimuli (Fig. 2.1). Transient receptor potential vanilloid receptor-1 (TRPV-1) respond to heat and capsaicin (found in peppers) (Fig. 2.1) [8]. TPRV-1 receptors are activated by various kinases (protein kinase A, protein kinase C, phosphatidylinosital-3-kinase). These kinases are, in turn, activated by inflammation [9]. Certain sodium channels are also activated or modulated by nerve injury (Na1.3, Na 1.8, Na 1.9), which facilitates nociception. Neuropathic injury increases certain sodium channel expression, channel trafficking in axons, and channel phosphorylation. As a result, surviving sensory nerves develop increasing responsiveness. Certain adjuvants (lidocaine, bupivicaine, tricylic antidepressants, topiramate, lamotrigine, and carbamazepine) block sodium channels and reduce neuropathic pain [10, 11]. Metastases are frequently hypoxic in the center, resulting in an acidic environment. Osteoclasts stimulated by metastatic cells within the bone trabeculae require an acidic environment (pH 4–5) for osteolysis. Both stimulate acid-sensing ion channels (ASIC), which increase sensory afferent depolarization [12].

Fig. 2.1  Anatomy of pain

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Bone Pain Bone pain has a unique spinal cord “signature,” which is a combination of neuropathic and inflammatory pain. Continuous pain in addition to activation of ASIC involves local production of prostaglandin and endothelin, which stimulates preand postsynaptic afferent nociceptors in marrow spaces. As tumor grows within marrow, it destroys medullary sensory afferents. TPRV-1 receptors are also activated. Bone destruction leads to mechanical instability and periosteum nerve impingement. In the dorsal horn, sensory neurons produce and express C-fos, and astrocytes around secondary sensory neurons are activated and multiple in numbers [12–14]. For this reason, nonsteroidal anti-inflammatory drugs (NSAIDS) and gabapentin (an anticonvulsant commonly used for ­neuropathic pain) reduce bone pain [15].

Other Allergic Medications Neurokinins such as substance P are released by peripheral and central sensory neurons and bind to NK-1 receptors. Substance P causes neurogenic inflammation, hyperalgesia, vascular changes (increased permeability and dilatation), and increases prostaglandin production. Bradykinin and certain cytokines (interleukin-1 and tumor necrosis factor alpha) induce hyperalgesia through production of

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prostaglandins [16]. Nerve growth factors maintain and stimulate sensory nerve regeneration and are avidly taken up by membrane receptors. It also stimulates production of substance P [16].

Calcium Channels, NMDA Receptors Several types of calcium channels are present in sensory afferents, which facilitate conduction, transmission, and modulation of pain. N-type calcium channels contain alpha2 delta subunits that are targeted by gabapentinoids. N-methyld-asparate (NMDA) receptors require glutamate (released presynaptically) and glycine to be activated. Activation results in removal of magnesium from the center of the channel, which then allows calcium to enter. NMDA receptors are largely responsible for maintaining pain through “wind up” from repetitive stimulation of wide dynamic range neurons by primary afferents [16]. Increasing intracellular calcium leads to depolarization. NMDA receptors are noncompetitively blocked by ketamine. A common pathway to pain is by way of prostaglandin (PGE2) production. PGE2 binds to multiple receptors (EP1–EP4) to activate neurons. PGE2 alone does not produce pain but is necessary for induction of pain by other mediators, such as histamine and bradykinin. PGE2 amplifies pain. Prostaglandins are not stored (which differs from other mediators of pain) but are synthesized at the time of depolarization by membrane-bound prostaglandin synthase and cyclooxygenase [17]. Prostaglandin synthesis uses arachidonic acid mobilized from membranes. PGE2 is released and binds to multiple EP receptors both pre- and postsynaptic. Cyclooxygenase 1 and 2 are the important enzymes in PGE2 production and are amplified peripherally and centrally within neurons and glia with inflammatory and neuropathic pain. Both NK-1 receptors and NMDA receptors increase cyclooxygenase transcription in the spinal cord [17]. Central nervous system cyclooxygenase is much more responsive than peripheral mechanisms to NSAIDS [17]. NSAID levels are measurable in the CNS within 15–30 min of administration. Certain NSAIDS (ibuprofen, indomethacin, and ketoprofen) have CNS levels that exceed plasma levels [17]. CNS nociceptive transmission inhibition is one of the more important components to NSAID analgesia [18]. Cyclooxygenase 2 is not the only enzyme to be targeted by NSAIDS. Cyclooxygenase 1 in the brainstem (periaqueductal gray) controls A-delta and C fiber-evoked spinal nociception. Cyclooxygenase 1 blockade within the periaqueductal gray (PAG) is important to analgesia [19]. Hence, broad, nonselective NSAIDs should be used to treat cancer pain as there are no trials of cyclooxygenase 2 selective inhibitors in ­cancer pain.

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Central Excitatory Mechanism Primary sensory afferents synapse on superficial laminae of the dorsal horn (lamina I and II). Secondary afferents cross over to the contralateral lateral funiculus and ascend as the spinothalamic tract. The spinothalamic tract projects to the brainstem, PAG, rostral ventromedial medullary (RVM), thalamus, nucleus tractus solitarius, and medullary reticular formation. These fibers contain substance P and NK-1 receptors [8]. In the deeper laminae of the dorsal horn reside wide dynamic range neurons that respond to a wide variety of painful stimuli. These secondary neurons are activated by repetitive release of substance P and glutamate from primary afferents. These neurons produce a prolonged amplified ­signal (wind-up) and increase synaptic transmission efficiency [8, 20]. Wide dynamic range neurons are blocked by inhibitory interneurons and monoamines (mainly norepinephrine) [9]. Wide dynamic range neurons also project to the thalamus by way of the spinothalamic tract. The gate control theory proposed by Melzack and Wall in 1965 involved a descending modulatory/facilitatory system that gated nociceptive transmission through the dorsal horn [21]. The descending limb of the spinobulbospinal loop arises from the PAG, and RVM modulate spinal cord neurotransmission. The locus coeruleus, which contains norepinephrine, is also involved in modulation along with the PAG and RVM. The descending limb facilitates or inhibits nociceptive traffic at the level of dorsal horn, and descends through the dorsal funiculus [9]. Descending facilitation leads to central hypersensitivity (allodynia) and hyperalgesia. This facilitation is mediated by a particular serotonin receptor (5HT3). This receptor is blocked by ondansetron. This may explain why selective serotonin reuptake inhibitors (SSRI’s) are less effective than tricyclic antidepressants (TCAs) and selective norepinephrine serotonin reuptake inhibitors (SNRIs) in treating central sensitization and neuropathic pain [9]. Paradoxically, 5HT3 receptors are needed for gabapentin to work optimally as an analgesic [5].

Cerebral Pain Matrix The cerebral cortex “pain matrix” consists of a cerebral ­cortex medial and lateral pain matrix system. The medial system (prefrontal cortex, insular cortex, cingulate gyrus, and amygdala) is involved in the affective and motivational response to pain. The lateral sensory cortex locates the site of pain. The medial system receives projections from the medial thalamus as well as ascending projections from the brain stem. The sensory cortex receives input from the ventrioposteriolateral thalamus. The spinothalamic tract

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projections are devoid of motor neuron projections, which can be interrupted by anterolateral cordotomy without producing motor deficits [16].

Visceral Pain Visceral sensory afferents travel with abdominal sympathetic afferents arising from internal organs and converge on the celiac plexus within the abdomen or thoracic paravertebral sympathetics in the chest. In the pelvis, the sensory afferents ascend with parasympathetics. Visceral afferents converge with somatic sensory afferent neurons on the dorsal horn. For this reason, somatic referral pain frequently occurs with severe visceral pain. Pain from pancreatic cancer, as an example, is referred to the abdomen, back, or shoulder. Lung cancer will refer pain to the ear, mediastinum, or back [16]. Visceral afferents terminate in lamina I, IV, and ventral horn. Secondary visceral sensory afferents ascend in the dorsal column of the spinal cord rather than the lateral funiculus. Celiac, hypogastric, or splanchnic blocks effectively reduce visceral pain, as does medial myelotomy at the level of the cervical cord (where the dorsal column projections cross over to the contralateral side) [16].

Opioid Receptors In 1973, morphine was found to bind to particular sites within the brain called “morphine receptors” [22, 23]. Two years later, endogenous opiate peptides were discovered. Three major receptors have been described and are located on peripheral afferents, within the dorsal horn, visceral afferents, within the brain stem, and cerebral pain matrix [22]. Mu receptors are divided into high affinity (mu1) and low affinity (mu2) receptors. Mu2 receptors produce respiratory depression, pruritus, prolactin release, physical dependence, anorexia, and sedation, whereas mu1 receptors produce analgesia, euphoria, and serenity. Kappa receptors produce ­analgesia sedation, dyspnea, dysphoria, and respiratory depression. Both mu and kappa produce constipation by binding to receptors on enteral neurons [23]. The actions of delta receptors are not well known but are upregulated when mu receptors are activated and may facilitate pain control. Separate genes are responsible for each of the major opioid receptors; receptor subtypes are produced by mRNA splicing. Opioid receptors are found on pre- and postsynaptic A-delta and C fibers [22]. Activation results in inhibition of calcium channels, reduction in adenyl cyclase, and stimulation of inward rectifying potassium channels [23]. These three mechanisms prevent neuron depolarization and release of substance P

M.P. Davis

and glutamate. Opioids inhibit gamma aminobutyric acid release by inter­neurons and increase dopaminergic neurotramission and prolactin release. Opioids reduce gonadotropin release from the hypothalamus. This leads to reduced libido and impotence. The rewarding effects of opioids. Are due to release of dopamine in the nucleus accumbens. There are three majors types of opioids used to treat ­cancer pain: phenanthrenes (represented by morphine), phenylpiperidines (represented by fentanyl), and diphenyl heptanes (represented by methadone). Tramadol resembles venlafaxine; however, the metabolite, 0-desmethyl tramadol, is a mu ­agonist. Each opioid binds to receptors with different affinity, producing a different conformation, resulting in a different set of G protein interactions. Some opioids internalize receptors. Morphine causes receptor inactivation without internalization [24]. Opioid receptor affinity and opioid receptor activation are two different properties of opioid ligands. A ligand may poorly activate the receptor (low intrinsic efficacy) but have a high affinity for the receptor [22]. Differences in opioid responses between individuals are determined mainly by differences in opioid receptor pharmacodynamics rather than individual differences in opioid metabolism and clearance (pharmacokinetics) [25]. Low intrinsic efficacy opioids require more opioid receptors to be bound for the same degree of analgesia relative to high intrinsic efficacy opioids. As a result, a “ceiling effect” to analgesia occurs with low intrinsic efficacy opioids at high doses or high pain intensities, which alter equianalgesic ratios. This is one reason why morphine–methadone equivalents change with morphine doses [22]. Opioids have a log linear response with dose; doses are generally limited by side effects, not analgesia [22].

Opioid Tolerance Chronic opioid exposure leads to an “antiopioid” response, which lasts longer than analgesia. This antiopioid response causes a withdrawal syndrome when opioids are suddenly stopped. Opioid receptors activate various kinases, which in turn phosphorylate NMDA receptors rendering them active. Opioid receptor phosphorylation leads to receptor inactivation and internalization [24]. Go/i proteins switch to Gz ­proteins with analgesic tolerance causing activation of neurons. Receptor activation is curtailed through phosphorylation of certain regulatory proteins (RGS) [24, 26]. A change in opioids (opioid rotation) may reverse opioid tolerance and enhance pain control. In rare cases, opioid ligands facilitate pain that becomes neuropathic in character. Opioid dose titration will cause increasing pain. Dose reduction in this situation paradoxically reduces pain. The use of certain adjuvant drugs such as ketamine blocks opioid tolerance and facilitates pain control [5, 16, 26, 27].

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Cancer Pain Assessment Pain is a multidimensional experience though most experts believe pain intensity is most important [28] (Table  2.1). Multidimensional pain questionnaires most frequently measure pain intensity, location, and relief; temporal pattern is often not included [28]. Paradoxically, temporal pattern is most important to opioid dosing strategies [29, 30]. Worst pain and average pain severity over 24  h correlates with interference with daily activities. Breakthrough pain episodes are also critical to assessment. Numerical rating scales (0 = no pain, 10 = severe pain) are preferred to 10 cm. visual analog scales. Verbal rating scales or even observations for pain behaviors are helpful in assessing the cognitively impaired and in those suffering from dementia [31]. Pain qualities are reported to be helpful in determining pain mechanisms. “Numbness,” “pins and needles,” and “burning” pain occurring within an area of sensory or motor deficit is usually neuropathic pain. Bone pain has an achelike quality and is worsened with movement. Hyperalgesia (increased sensitivity to touch) occurs with inflammatory, bone, or neuropathic pain [31]. Pain qualities contribute to pain interference independent of severity. Deep pain, sharp pain, sensitive, or itchiness qualities interfere with daily activity [32]. Multidimensional scales provide a more comprehensive pain assessment. However, certain tools such as the Brief Pain Inventory may not be sensitive to changes in pain over time. Unidimensional pain intensity scales are validated and sensitive to changes in pain [33]. Pain interference may improve before severity. Pain relief may be experienced while pain intensity is still moderate or severe [31]. Asking “do you think your analgesics need to be increased (or decreased)” allows patients to find their personal acceptable relief as they judge benefits and risks of opioids. Recall fades with time; pain diaries, which include intensity and opioid doses, recorded several times during the day are helpful between clinic visits [31] (Table 2.2).

Table 2.2  Five axes for classifying pain into syndromes I. Anatomical Region II. Organ system that is producing pain III. Temporal characteristics IV. Pain intensity and pain onset V. Proposed pain etiology Source: Data from refs. [28, 31, 33]

In those with cancer and reduced cognition a questionnaire with 13 or more items in a multidimensional scale will have a significant number of items left blank by individuals [34]. The Brief Pain Inventory is completed by <60%, whereas a 9–10 item scale has a completion rate of 84% [35]. Verbal scales are better for those on palliative wards, but this reduces the possibility of detecting small but perhaps important differences in pain with treatment [34]. Individuals with a Mini Mental State Examination Score of <24 (0–30) have poor completion rates for multidimensional questionnaires [34]. Pain trials use the sum of pain intensity differences over time (SPID), total pain relief (TOTPAR), side effects, and patient global medication performance (satisfaction, preference) as outcomes [36]. Pain intensity differences of 33% are clinically meaningful [36, 37]. Two types of methods have been used to test analgesics. An anchor method uses the percentage of responders (the number with a 33–50% reduction in pain intensity or 2 point decrease in an 11-point numerical scale) and compares responders in terms of numbers needed to treat NNT. The numbers needed to treat and numbers need to harm (NNH) gauge analgesic efficacy [38]. The second method uses changes in mean intensity of the entire group. These trials can be powered to show differences in group mean intensity scores yet have little clinical relevance. Changes in mean intensity scores can reflect a large response in a few individuals or a small, perhaps clinically insignificant response, in a large number of ­individuals [38].

Imaging Pain Table 2.1  Dimension of pain Intensity Affect Interference Temporal Pattern Location Referral Quality Duration Beliefs (attitude/coping) Pain history (diffuse noxious inhibitory control) Treatment (worsening/relieving factors)

Skeletal Metastases Plain radiographs of painful bone sites are recommended for screening purposes. Over 50% of bone cortex has to be destroyed before lesions are visualized by plain radiographs [3]. Bone fracture is unlikely if <50% of the cortex is lost, whereas fracture should be anticipated if >75% of the cortex is lost. Surgeons use plain radiographs to determine the need for surgical intervention for this reason. Bone radiographs are preferred in myeloma over bone scans since

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osteolytic lesions are poorly visualized on bone scans [39]. One of the first signs of vertebral metastases visualized by plain radiographs is the “winking” owl sign due to the loss of a pedicle arising from tumor extension from the posterior vertebral body [40]. Skeletal metastases almost exclusively arise from hema­ togenous spread to red marrow. Bone is more frequently a site of metastases than anticipated based on percent of cardiac output and blood supply [3]. The distribution based on bone scans are: 39% vertebral, 38% ribs and sternum, 12% pelvis, and 10% long bones [3]. Pain is experienced in only a minority of bone metastases. Painful symptomatic vertebral metastases and spinal cord compression occur more often with thoracic spine metastases (70%) than lumbar (20%) or cervical spine (10%) [40]. Bone scan positivity is due to reactive osteoblastic activity around metastases, which does not occur with osteolytic metastases. Nearly 25% of positive bone scan uptake is related to nonmalignant causes. Bone scans have a high sensitivity, but low specificity and should not be interpreted without clinically relevant data. Metastases, if present diffusely in the red marrow, will cause the red marrow to expand, resulting in diffuse juxtarticular uptake and absence of the kidney shadows (super scan). This may be mistaken for a normal bone scan [3]. Bone scans will worsen as patients respond to treatment (flare). Osteolytic lesions regress, and osteoblasts fill in with healing bone. Computer tomography scanning (CT scans) is cumbersome when imaging bone and has limited views of the bone structures relative to magnetic resonance imaging (MRI). However, CT scans are more sensitive in detecting bone metastases than plan radiographs and can clarify bone scan positive painful and suspicious lesions in individuals unable or intolerant of MRI scanning [39]. CT scans will detect marrow metastases before bone destruction by differences of >20 Hounsfield units relative to normal fat containing ­marrow [39]. MRI skeletal metastases have low signals on T1 weighted images (marrow has high intensity). Fat suppression T1 images separate local fatty deposits from metastases. T2 weighted images demonstrate enhancement relative to marrow signals. This is due to the high water content of metastases. A rim of bright T2 enhancement can occur around metastases (halo sign) [39]. MRI is particularly suitable for vertebral lesions and, in addition, will image epidural metastases and spinal cord compression. Gadoliniumenhanced images better define epidural spaces and spinal soft tissues but are not needed for imaging bone. T1 sequences can be used to differentiate benign from malignant vertebral fractures [40]. Malignant rather than benign vertebral compression fractures are evidenced by pedicle, posterior vertebral element involvement, or the presence of epidural or paravertebral masses. MRI is also able to image

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marrow and has been used to stage malignancies such as multiple myeloma for this reason [39].

Liver and Abdominal Imaging Liver imaging has size limitations when used to screen for cancer. Metastases less than 1 cm are difficult to visualize or classify. For each metastatic lesion found, one to four cannot or will not be visualized due to size [41]. Edge definition is most important for visualizing liver metastases. Cysts have greater edge definition than metastases and hence are better visualized. Liver ultrasounds are relatively inexpensive, do not involve radiation, and are portable but are operator-­ dependent [41]. Ultrasound images are limited by the acoustic window. Intervening gas and obesity limit image capability. High-frequency transducers increase lesion detection. Doppler ultrasounds may detect liver metastases by edge definition and by increased hepatic artery blood flow to metastases. Iodine contrast is needed for liver CT scans to provide optimal imaging. Manipulation of arterial and portal contrast phase sequences help define metastases. Early enhancement during the arterial phase is common with breast and renal cancer, melanoma, and sarcoma [41]. Hypovascular tumors are better seen in the portal phase. CT portography bypasses the hepatic artery; the liver will be enhanced, while cancer remains unenhanced [41]. T2 weighted enhancement on an MRI is characteristic of liver metastases. Contrast or dynamic scans using gadolinium are generally not helpful. However, certain agents (Mn-DPDP, Gd-BGPTA) are selectively taken up by hepatocytes or reticuloendothelial cells and will give a better edge definition to liver metastases [41].

Lung Imaging Contrast enhanced CT scans of the lung should extend to the level of adrenals and liver in order to detect metastases [42]. CT scans better define metastases seen on screening chest radiographs and will detect lesions not seen by a standard anterioposterior chest x-ray. However, lesions less than 1 cm are difficult to define. CT scans have 61% sensitivity and 79% specificity for mediastinal involvement [43]. Positron emission tomography (PET) scanning combined with chest CT scanning better define lung lesions as malignant or benign and mediastinal node involvement. Whole-body PET scanning will detect distant metastases. Because the brain avidly takes up glucose,

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either a CT scan or MRI of the brain will be needed to detect brain metastases [44].

Cancer Pain Management The World Health Organization defined three levels of treatment based on pain severity: for mild pain, a nonopioid analgesic (NSAID or acetaminophen) plus an adjuvant; for moderate pain, a weak opioid (tramadol, codeine) plus adjuvant; and for severe pain, a potent opioid plus adjuvant [45–48]. An adjuvant analgesic is, by definition, a drug whose primary indication is for another reason but is analgesic in certain painful conditions. Tricyclic antidepressants, duloxetine, venlafaxine, and gabapentin are adjuvant analgesics. There are five essential principles to chronic pain management: (1) oral administration is preferred; (2) drugs should be given proactively around the clock to prevent pain from recurring rather than on an “as needed” basis; (3) drug administration should conform to the 3-step analgesic ladder; (4) administration must be individualized due to wide interindividual variability in opioid requirements; and (5) attention to details is needed in order to sculpt opioid administration to temporal pain pattern and repeat assessment at intervals consistent with opioid half-life and pain characteristics (acute or chronic) should follow the dosing strategy [48]. The treatment strategy should be explained and written down for the patient. Most will experience breakthrough pain and not infrequently experience-opioid side effects. Most individuals will require an around-theclock opioid plus an immediate release potent opioid for breakthrough pain [30]. The use of two sustained release opioids for chronic pain or two immediate release opioids for breakthrough pain should be avoided [48]. Most individuals with cancer pain require less than 200 mg of oral morphine (or morphine equivalents) per day [49]. The majority of individuals (80%) will experience relief from cancer pain by using the 3-step analgesic ladder and five basic principles [46]. Morphine remains the opioid of choice since no potent opioid is a better analgesic than morphine. Morphine is readily available in many countries, versatile as to its route of administration, relatively inexpensive, and has the greatest published experience [46, 50]. There is no difference in pain relief using sustained release morphine at 12- or 24-h intervals compared to immediate release morphine at 4-h intervals. Initial doses are 15 mg every 12 h of sustained release or 5 mg every 4 h of immediate release morphine in the opioid naïve. Low doses of potent opioids can be substituted for “weak” opioids on step 2 of the analgesic ladder [30, 45, 46]. Doses should be titrated to pain relief. The 4  h morphine

requirements can range from 5 to ³250 mg [45]. In place of morphine, oxycodone 5 mg every 4 h, hydromorphone 1 mg every 4 h, or fentanyl 12 mcg/h transdermal patch replaced every 3 days may be used [30]. Fentanyl patches are best used when chronic pain is well controlled by intravenous or subcutaneous fentanyl. The conversion to a patch is 1 to 1 relative to transdermal fentanyl but with wide differences among individuals in absorption from the transdermal patch. The around-the-clock dose should not be changed until steady state. Individuals on 4 h morphine should have doses adjusted daily if necessary (the same is true for oxycodone and hydromorphone) [51]. Individuals on sustained release morphine should not have around-the-clock doses adjusted sooner than 48 h – the same is true for transdermal fentanyl. Pain flares and unsatisfactory control should be managed by adjusting rescue doses in the interim.

Breakthough Pain Breakthrough pain includes several clinically distinct pains. The term “breakthrough” is problematic linguistically since literal translations do not exist in all languages [52]. “Episodic” or “transient” pain may be a better universal term. Episodic pain may be “incident” – or movement-related, which is either voluntary or involuntary (with hiccup or colic). Episodes may be spontaneous or occur at the time when the next opioid dose is due (end of dose failure) [52]. Transient pain is usually rapid in onset and short in duration. The offset of pain (30 min) is the average time to analgesia with oral immediate-release opioids [52]. Hence, oral immediate-release opioids may not be effective for this reason. The standard approach to the management of incident and breakthrough (spontaneous) pain is to give 10–20% of the total daily oral morphine dose as a rescue dose [30, 46, 52]. This may be repeated during a 4 h time period [46]. End of dose failure is due to suboptimal around-the-clock opioid doses and should be managed by increasing the sustained release opioid dose (or immediate release 4  h doses) before considering a shortened interval between doses; 8 h for sustained release morphine, 60–48 h for transdermal fentanyl, 3 h for immediate release morphine [30]. Several opioid preparations are available for incident or breakthrough pain: oral transmucosal fentanyl citrate and fentanyl buccal tablets [52]. Sublingual methadone also has a rapid onset to pain relief and parenteral morphine or hydromorphone using 1/6 of the total daily dose converted to parenteral equivalents have also been effective [52]. Both transmucosal and transbuccal fentanyl will need to be titrated to relief independent of the chronic opioid dose. Rescue doses should be added to the chronic opioid doses if the transient pain is spontaneous. This should be done at

18

steady state. If pain remains poorly relieved and the patient is not experiencing dose-limiting toxicity (myoclonus, cognitive failure, nausea and vomiting, hallucinations), the total opioid dose (chronic plus rescue doses) should be increased 30% and rescue doses adjusted [30]. Rescue doses for incident should not be added to chronic doses if the baseline pain is under control [30]. Doses for incident pain should be increased independent of the around-theclock doses if incident pain is poorly relieved. Doses should be increased 100% if <50% response and 50% if >50% response [30]. Rescue doses should also be increased if pain is relieved but rapidly returns before the next rescue dose [30].

Pain Control with Opioid Side Effects Mild nausea and sedation from opioids usually improves over several days. Doses usually do not need to be adjusted. However, tolerance does not develop to constipation. All who are started on potent opioids should be started on laxatives and stool softeners [30]. In those with pain control but excessive opioid side effects, the chronic opioid dose should be reduced 30% and the rescue dose maintained. Reducing

M.P. Davis

the chronic opioid dose may lead to resurgence of pain, and the rescue dose will be needed to control pain [51].

Uncontrolled Pain with Opioid Side Effects Opioid dose titration is limited by side effects (Table 2.3). Strategies for managing pain include opioid rotation, route conversion or the addition of an adjuvant analgesic followed by opioid dose reduction [30, 45, 47–49, 53, 54]. These strategies have not been compared: opioid rotation; route conversion; or the addition of an adjuvant with opioid dose reduction are largely based on clinical experience and circumstances. Route conversion, which may be from oral to parenteral opioids, alters the ratio of morphine to metabolites, and thus reduces side effects. However, most route conversions for poorly controlled pain are to spinal opioids. Parental route conversions are usually done for other reasons: where oral administration is impossible due to nausea, dysphagia, mucositis, or bowel obstruction; for poor drug absorption due to dysfunctional or ischemic bowel, short gut syndrome, or fistula; to reduce the number of tablets; as a means of gaining rapid control of acute pain [29, 48].

Table 2.3  Guidelines for opioid rotations   1. Calculate equianalgesic dose then – Reduce 50% if rotation is primarily for side effects in the elderly frail, those experiencing side effects on high opioid doses or in those with compromised organ function – Reduce 30% in those who are relatively healthy on low or standard opioid doses and normal organ function who are experiencing side effects – Use the equianalgesic dose if rotations is predominantly for pain   2. Adjust doses based on comedications, which interfere or alter with opioid clearance   3. Methadone equianalgesic doses should be reduced 75–90%, or a different dosing strategy should be used, which involves an every 3 h as needed dose using 10% of the total daily morphine equivalents. Alternatively a linear equivalent dose can be given every 8 h based on the following equianalgesic scale (morphine to methadone ratio)   4:1 <90 mg morphine/day   8:1 <300 and >90 mg morphine/day 12:1 >300 and <1,200 mg morphine/day 15:1 >1,200 and <2,000 mg morphine/day 20:1 >2,000 mg morphine/day Methadone should be prescribed by those with experience of using methadone   4. Provide a rescue dose preferably using the same opioid. The initial dose should be 10–20% of the total daily opioid dose   5. Do not adjust the chronic around the clock opioid dose until reaching steady state. Opioid rotation before reaching steady state is meaningless and dangerous   6. Frequently assess pain response and toxicity. Opioid toxicity may persist for several days. Rapid opioid rotations on a daily basis are dangerous. Methadone responses may not be seen for 1–2 days and steady state may not be reached for 3 days, so patients may experience pain for 1–2 days while rotating to methadone   7. Conservative equianalgesic ratios in one direction are not conservative when rotating back to the first opioid. There are bidirectional differences in opioid equivalents. Clinicians need to be aware that equivalents may not be “reversible” in direction   8. Add rescue doses to the around the clock dose then increase the total dose by 30–50% if baseline pain is uncontrolled at steady state   9. Add rescue doses (for nonincident pain) to the around the clock dose if pain is controlled at steady state and frequent rescue doses (>4) where needed in the last 24 h 10. Do not add adjuvants and rotate simultaneously. Do one at a time and assess analgesia before altering the strategy Source: Data from refs. [30, 46, 51]

19

2  Cancer Pain Table 2.4  Equianalgesia Opioid

Oral

Morphine 30 Hydromorphone 6 Oxycodone 20–30 Fentanyl 1:70 Methadone See Table 2.3 Buprenorphine Conversion similar to fentanyl Source: Data from refs. [49–51, 55, 56, 62]

Parenteral 10 2–3

Equianalgesia and Opioid Rotation Opioid route conversion and opioid switch is needed in 40% of individuals with advanced cancer at some time during the course of their illness [55] (Table  2.4). Equianalgesia is the ratio of doses for two opioids, which result in the same degree of pain relief. This should be determined at steady state; however, most equianalgesic tables use single dose comparisons (nonsteady state) and summed pain intensity differences. The study design for equivalents is usually crossover or parallel with intraindividual (crossover) or interindividual (parallel) comparisons [56]. Most individuals in rotation studies are relatively opioid naïve and not highly opioid tolerant, which is not the usual case when rotations are done for cancer pain. Populations from whom equivalents are determined differ from populations in whom opioid rotations are performed. There are large variations in equivalents between individuals such that published equivalents have large confidence intervals but are reported as single ratios. Factors that significantly alter equivalents are age, polypharmacy, organ function, and opioid tolerance [56]. Opioid rotations utilize equianalgesia, but tables for the purpose of improving analgesia and/or reducing side effects [49, 57]. Almost all rotations involve a “StopStart” strategy where the first opioid is discontinued and the second is started. A “partial” opioid rotation where another opioid as an “added on” has little clinical evidence and is likely to lead to dosing error and/or reduced patient compliance.

significantly reduces pain intensity, is then used as the 4 h dose by converting to oral morphine (parenteral dose ­multiply by 3) or continuous parental ­morphine by dividing the effective dose by 3 to 4 and using this dose as the hourly continuous dose. If individuals are on around-the-clock morphine, this will need to be added to the maintenance dose.

Patient-Controlled Analgesia In the 1960s, analgesic responses to small intravenous doses of morphine by patient demand was found to be superior to intramuscular opioids given at a fixed dose as needed [58]. The experience with patient-controlled analgesia (PCA) taught us: (1) small increases in opioid serum levels can dramatically reduce pain; (2) there is a minimally effective analgesic concentration, which varied considerably among ­individuals; (3) there is no single effective analgesic serum concentration of morphine. Two prerequisites are needed for effective PCA: (1) individualized titration to pain relief and (2) maintenance of plasma opioid concentrations by demand only (opioid naïve) or continuous plus demand (in opioid tolerant individuals) dosing. For PCA to be successful, the demand dose should produce appreciable analgesia with a single activation [58]. Demand doses too low frustrate patients and demand doses too high (or activation frequency or intervals too short) lead to delayed opioid toxicity. A large number of PCA strategies have been published; in the opioid naïve, 1–4 mg at a 5–60 min lockout interval, and in the opioid ­tolerant, continuous morphine plus 1–20 mg of morphine at 20–60 min intervals. Some strategies use 25–50% of the hourly morphine dose as the demand, or 10% of the total daily morphine dose converted to parenteral equivalents as the demand dose [59]. In general, lockout intervals are ­longer if continuous ­morphine infusion is used.

Acute Pain

Spinal Analgesia

Severe acute or crescendo pain usually arises from complications related to cancer (bone fracture, perforated bowel). Strategies for managing pain are distinct from those used to treat chronic pain [29]. Morphine 1–2 mg every 1–2 min, fentanyl 20  mcg/min or hydromorphone 0.2  mg/min intravenously until pain control is an effective titration strategy [29]. This requires bedside titration by physicians with assessment of pain intensity every 1–2 min and a respite every 10 min. Alternatively, 1.5 mg of morphine can be given every 10 min or 10–20  mg every 15  min. The goal is significant but not complete pain relief with titration. The morphine dose which

Intrathecal and epidural opioid analgesia are effective in ­managing continuous deep somatic pain unresponsive to ­systemic opioids or in individuals experiencing dose limiting toxicity from systemic opioids [54]. Cutaneous pain and pain from intestinal obstruction are not responsive to spinal ­opioids. Sixty to 80% will experience relief. Adjuvant analgesics such as bupivicaine, clonidine, or the calcium channel blocker ziconotide are frequently needed to improve pain control. Spinal opioid rotation (morphine to hydromorphone or fentanyl) may improve pain that is not responsive to morphine [54]. Epidural opioids are used in those with only a

20

few weeks to survive, whereas intrathecal opioids are preferred in those expected to survive months. In general, 1% or less of the oral morphine dose is needed for effective spinal analgesia. Certain side effects related to the opioid (nausea, ­vomiting, sedation); pruritus, urinary retention, hypogonadotropic hypogonadism are more frequent with spinal opioids than systemic opioids. Clonidine and ziconotide may produce orthostatic hypotension. Major motor weakness can develop from a hematoma at the catheter insertion site or with high doses of bupivicaine [54].

Opioid Overdose Respiratory depression occurs with opioid overdose. Tachypnea and dyspnea with sedation is usually not due to opioids. Overdose will reduce the respiratory rate and tidal volume leading to carbon dioxide retention. Opioid overdose is almost always accompanied by reduced consciousness and pupillary miosis. Dilated fixed pupils or unequal pupils are indications that the cause of reduced consciousness is the result of a stroke, hypoxia, or mass lesion rather than opioid. Individuals on stable doses of morphine for weeks may develop signs and symptoms of overdose from radiation induced pain response, progressive renal failure, drug interactions, or sepsis, which alters morphine or morphine 6-glucuronide clearance. To manage opioid overdose, dilute a 1 ml (0.4 mg) ampoule of naloxone to 10 mg of saline or glucose and give 1 ml intravenously every 2–3 min until the respiratory frequency increases to 10 per minute and sedation resolves. The goal is to reverse respiratory depression, not analgesia [38, 48]. The half-life of naloxone is 30 min, so repeat doses or continuous infusion may be necessary to reverse respiratory depression with methadone, transdermal fentanyl, or sustained release morphine.

M.P. Davis

choices. Sublingual methadone is relatively well absorbed and has a quicker onset to analgesia than oral morphine [52].

Adjuvant Analgesics NSAIDs are technically analgesics rather than adjuvant medications. The addition of NSAIDs to morphine improves analgesia, and may reduce side effects by reducing morphine requirements by 30% [60, 61]. Adjuvant analgesics are added to improve pain control or to allow for opioid dose reduction in those with inadequately controlled pain and opioid side effects (Table 2.5). This strategy is effective and an alternative to opioid rotation and route switch. A listing of adjuvant analgesics is provided on Table 2.5. Corticosteroids (dexamethasone 2–16  mg/day) reduce headaches from increased intracranial pressure, pain from soft tissue infiltration, nerve compression, or hepatomegaly [45]. Bisphosphonates (pamidronate 60–90  mg or zolendronate 4  mg monthly) relieve pain from bone metastases. Tricyclic antidepressants, gabapentin, pregabalin, duloxetine, and venlafaxine are equally effective in relieving neuropathic pain as determined by the NNT. However, the gabapentinoids are better tolerated and have fewer drug interactions. Two or three adjuvant analgesics may be needed for neuropathic pain [45]. Transdermal lidocaine is effective for mononeuropathies and postherpetic neuralgia. Transdermal lidocaine is not absorbed to any great extent, and is particularly safe in the elderly or for those on multiple psychotropic medications. Ketamine is a NMDA receptor antagonist, which is analgesic at subanesthetic doses [62]. Ketamine reverses morphine tolerance and can be used for breakthrough pain for those on systemic or spinal opioids. Oral doses are 25–50 mg three to four times daily or 0.1–0.5 mg/kg/h as a continuous infusion. Strontium-89 chloride and samarium-153 are absorbed in Table 2.5  Adjuvant analgesic and nonopioid analgesics

Pain Management in the Actively Dying Delirium occurs in 80% of those actively dying and so pain assessment will depend on non-verbal cues. Terminal restlessness is often related to delirium, fecal impaction, urinary retention, or poorly controlled pain. Opioid dosing should not be interrupted; rescue doses are used as a trial to see if restlessness improves, once sure that urinary retention or fecal impaction are not a problem. Oral intake may be a problem such that an alternative route  is frequently necessary. Conversion to rectal opioids (morphine, hydromorphone, oxycodone, and methadone) is 1  to 1. Sublingual morphine and oxycodone are poorly absorbed and have a delayed onset to action, so are not good

Drug Acetaminophen Ibuprofen Naproxen Ketorolac Etodolac Amitriptyline Nortriptyline Gabapentin Pregabalin Carbamazepine

Caution/side effects

Hepatotoxicity GI, renal toxicity GI, renal toxicity GI, renal toxicity GI, renal toxicity Sedation, cardiac Sedation Sedation Sedation Sedation, myelosuppression Duloxetine Headache, dizziness, sleepiness Venlafaxine Headache, dizziness, sleepiness Source: Data from ref. [50]

Maximum dose/day 4,000 mg 3 × 800 mg 3 × 500 mg 45 mg × 6 (sc/IV) 1,200 mg 50–225 mg 50–225 mg 3,600 mg 600 mg 1,600 mg 120 mg 225 mg

2  Cancer Pain

areas of high bone turnover and will reduce pain from diffuse bone metastases over several weeks to months. Delayed myelosuppression limits repeated dosing. Baclofen reduces muscle spasm pain secondary to spinal cord compression, as  does low doses of diazepam [63]. Methylphenidate improves opioid-induced somnolence as well as depression. Doses are 5–10 mg in the morning and at noon. Octreotide and anticholinergic medications reduce painful colic from malignant bowel obstruction [63].

Nondrug Treatment for Cancer Pain Transcutaneous electrical nerve stimulation, acupuncture, single fracture radiation, and vertebral kyphoplasty can relieve poorly controlled pain [45, 53]. Hypnoses reduce procedural pain and mucositis. Cordotomy or rhizotomy, celiac or splanchnic blocks reduce morphine requirements and pain in those whose pain is not responding to opioids or who develop dose-limiting opioid toxicity [53].

Conclusion Cancer pain is a composite of acute and chronic pain, which is tumor- or treatment-related in etiology. Individuals with cancer generally experience more than one pain during the course of their illness. Assessment is the key to effective management. The World Health Organization 3-step ladder and five principles form the foundation for medically managing cancer pain. Dosing strategies take into account pain intensity and temporal pattern to sculpt opioid doses to individual needs. Opioid rotation, route change, or the addition of adjuvant analgesics successfully relieves opioid poorly responsive pain.

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21 sensitization states in humans. Proc Natl Acad Sci USA 2005, 102(50):18195–200. 7. Liebeskind JC. Pain can kill. Pain 1991, 44(1):3–4. 8. Harvey VL, Dickenson AH. Mechanisms of pain in nonmalignant disease. Curr Opin Support Palliat Care 2008, 2:133–9. 9. D’Mello R, Dickenson AH. Spinal cord mechanisms of pain. Br J Anaesth 2008, 101:8–16. 10. Aurilio C, Pota V, Pace AC, et al. Ionic channels and neuropathic pain: physiopathology and applications. J Cell Physiol 2007, 215:8–14. 11. Rogers M, Tang L, Madge DJ, et al. The role of sodium channels in neuropathic pain. Semin Cell Dev Biol 2006, 17:571–81. 12. Luger NM, Mach DB, Sevcik MA, et al. Bone cancer pain: from model to mechanism to therapy. J Pain Symptom Manage 2005, 29(5S):S32–46. 13. Honore P, Rogers SD, Schwel MJ, et al. Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience 2000, 98(3):585–9. 14. Luger NM, Sabino MC, Schwei MJ, et  al. Efficacy of systemic ­morphine suggests a fundamental difference in the mechanisms that generate bone cancer vs inflammatory pain. Pain 2002, 99(3): 397–406. 15. Caraceni A, Zecca E, Martini C, et al. Gabapentin for breakthrough pain due to bone metastases. Palliat Med 2008, 22:392–3. 16. Regan JM, Peng P, Chan VWS. Neurophysiology of cancer pain: from the laboratory to the clinic. Curr Rev Pain 1999, 3:214–25. 17. Burian M, Geisslinger G. COX-dependent mechanisms involved in the antinociceptive action of NSAIDs at center and peripheral sites. Pharmacol Ther 2005, 107:139–54. 18. McCormack K. The spinal actions of nonsteroidal anti-­inflammatory drugs and the dissociation between their anti-inflammatory and analgesic effects. Drugs 1994, 47(5):28–45. 19. Leith JL, Wilson AW, Donaldson LF, et  al. Cyclooxygenase1-derived prostaglandins in the periaqueductal gray differentially controls C-versus A-fiber-evoked spinal nociception. J Neurosci 2007, 27(42):11296–305. 20. Murakami M, Kudo I. Prostaglandin E synthase: a novel drug target for inflammation and cancer. Curr Pharm Des 2006, 12:943–54. 21. Melzack R, Wall PD. Pain mechanisms. Science 1965, 150(699): 971–9. 22. Pasternak GW. Molecular biology of opioid analgesia. J Pain Symptom Manage 2005, 29(5S):S2–9. 23. Trescot AM, Datta S, Lee M, et  al. Opioid pharmacology. Pain Physician 2008, 11:S133–53. 24. Law PY, Loh HH. Regulation of opioid receptor activities. J Pharmacol Exp Ther 1999, 289:607–24. 25. Snyder SH. Opioid receptor revisited. Anesthesiology 2007, 107:659–61. 26. Garzon J, Rodriguez-Munoz M, Sanchez-Blazquez P. Do pharmaceutical approaches that prevent opioid tolerance target different elements in the same regulatory machinery? Curr Drug Abuse Rev 2008, 1:222–38. 27. Pelissier T, Laurido C, Kramer V, et al. Antinociceptive interactions of ketamine with morphine or methadone in mononeuropathic rats. Eur J Pharmacol 2003, 477:23–28. 28. Hermstad MJ, Gibbins J, Caraceni A, et al. Pain assessment tools in palliative care: an urgent need for consensus. Palliat Med 2008, 22:895–903. 29. Davis MP, Weissman DE, Arnold RM. Opioid dose titration for severe cancer pain: a systematic evidence-based review. J Palliat Med 2004, 7(3):462–8. 30. Walsh D, Rivera NI, Davis MP, et al. Strategies for pain management: Cleveland Clinic Foundation guidelines for opioid dosing for cancer pain. Support Cancer Ther 2004, 1(3):157–64. 31. Anderson KO. Assessment tools for the evaluation of pain in the oncology patient. Curr Pain Headache Rep 2007, 11:259–64.

22 32. Jensen MP, Dworkin RH, Gammaitoni AR, et al. Do pain qualities and spatial characteristics make independent contributions to interference with physical and emotional functioning? J Pain 2006, 7(9):644–53. 33. Caraceni A, Cherny N, Fainsinger R, et al. Pain measurement tools and methods in clinical research in palliative care: recommendations of an expert working group of the European Association of Palliative Care. J Pain Symptom Manage 2002, 23(3):239–55. 34. Radbruch L, Sabatowski R, Loick G, et al. Cognitive impairment and its influence on pain and symptom assessment in a palliative care unit: development of a minimal documentation system. Palliat Med 2000, 14:266–76. 35. Twycross R, Harcourt J, Bergl S. A survey of pain in patients with advanced cancer. J Pain Symptom Manage 1996, 12(5):273–82. 36. Farrar JT, Berlin JA, Strom BL. Clinically important changes in acute pain outcome measures: a validation study. J Pain Symptom Manage 2003, 25(5):406–11. 37. Turk DC, Dworkin RH, McDermott MP, et al. Analyzing multiple endpoints in clinical trials of pain treatments: IMMPACT recommendations. Pain 2008, 139:485–93. 38. Dworkin RH, Turk DC, Wyrwich KW, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain 2008, 9(2):105–121. 39. Rosenthal DI. Radiological diagnosis of bone metastases. Cancer 1997, 80:1595–607. 40. White AP, Kwon BK, Linskog DM, et al. Metastatic disease of the spine. J Am Acad Orthop Surg 2006, 14:587–8. 41. Mahfouz AE, Hamm B, Mathieu D. Imaging of metastases to the liver. Eur Radiol 1996, 6:607–14. 42. Pfister DG, Johnson DH, Azzoli C, et  al. American Society of Clinical Oncology treatment of nonresectable non-small-cell lung cancer guidelines: update 2003. J Clin Oncol 2004, 22(2): 330–53. 43. Gould MK, Kuschner WG, Rydzak CE, et al. Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: a metaanalysis. Ann Intern Med 2003, 139(11):879–92. 44. Silvestri GA, Gould MK, Margolis ML, et al. Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest 2007, 132(3 Suppl):178S–201 45. Fallon M, Hanks G, Cherny N. Principles of cancer pain. BMJ 2006, 332:1022–4. 46. Hanks GW, de Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 2001, 84(5):587–93.

M.P. Davis 47. Jost L. Management of cancer pain: ESMO clinical recommendations. Ann Oncol 2007, 18:92–94. 48. Krakowski I, Theobald S, Balp L, et  al. Summary version of the standards, options and recommendations for the use of analgesia for the treatment of nociceptive pain in adults with cancer (update 2002). Br J Cancer 2003, 89(Suppl 1):S67–72. 49. Mercandante S. Opioid rotation for cancer pain. Rationale and ­clinical aspects. Cancer 1999:86:1856–66. 50. Gralow I. Cancer pain: an update of pharmacological approaches in pain therapy. Curr Opin Anaesthesiol 2002, 15:555–61. 51. Davis MP, Lasheen W, Gamier P. Practical guide to opioids and their complications in managing cancer pain. What oncologists need to know. Oncology 2007, 21(10):1229–38. 52. Hagen NA, Biondo P, Stiles C. Assessment and management of breakthrough pain in cancer patients: current approaches and emerging research. Curr Pain Headache Rep 2008, 12:241–8. 53. Carr DB, Goudas LC, Balk EM, et al. Evidence report on the treatment of pain in cancer patients. Evidence report on the treatment of pain in cancer patients. J Natl Cancer Inst Monogr 2004, 32:23–31. 54. Newsome S, Frawley BK, Argoff CE. Intrathecal analgesia for refractory cancer pain. Curr Pain Headache Rep 2008, 12:249–56. 55. Shaheen PE, Walsh D, Lasheen W, et  al. Opioid equianalgesic tables: are they all equally dangerous? J Pain Symptom Manage 2009, 38(3):409–17. 56. Knotkova H, Fine PG, Portenoy RK. Opioid rotation: the science and limitations of the equianalgesic dose table. J Pain Symptom Manage 2009, 38(3):426–39. 57. Miller L, Shaw JS, Whiting EM. The contribution of intrinsic activity to the action of opioids in vitro. Br J Pharmac 1986, 87:595–601. 58. Grass JA. Patient-controlled analgesia. Anesth Analg 2005, 101: S44–61. 59. Davis MP. Patient-controlled analgesia chapter 24. Opioids in Cancer Pain, Oxford University Press, (Oxford UK) 2009, 367–84. 60. Elia N, Lysakowski C, Tramer MR. Does multimodal analgesia with acetaminophen, nonsteroidal anti-inflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Anesthesiology 2005, 103:1296–304. 61. Marret E, Kurdi O, Zufferey P, et al. Effects of nonsteroidal antiinflammatory drugs on patient-controlled analgesia morphine side effects. Anesthesiology 2005, 102:1249–60. 62. Grond S, Radbruch L, Lehmann KA. Clinical pharmacokinetics of transdermal opioids. Clin Pharmacokinet 2000, 38(1):59–89. 63. Pharo GH, Zhou L. Controlling cancer pain with pharmacotherapy. J Am Osteopath Assoc 2007, 107(Suppl 7):ES22–32.

Chapter 3

Cancer-Related Fatigue Barbara F. Piper, Karin Olson, and Carina Lundh Hagelin

Introduction and Significance Cancer-related fatigue (CRF) is one of the most common and distressing symptoms experienced by cancer patients [1, 2] and often is more distressing than pain, nausea, or vomiting [3]. CRF may be dose-limiting, may compromise the timing and frequency of treatments [2], and may also affect treatment adherence and survival [4]. Despite its frequency and negative impact, CRF remains underreported, underdiagnosed, and undertreated [1].

Prevalence Rates Approximately 70–100% of cancer patients experience CRF at some time during diagnosis and treatment [1]. Prevalence rates vary from 25 to 99% [5, 6] depending on the type of treatment, dose and route of administration, type and stage of cancer, and the method and timing used to assess CRF [7]. In patients receiving chemotherapy (CT), 80–90% report CRF, and its prevalence rates and patterns over time may vary with the specific CT agent, its route of administration, and the frequency and density of treatment cycles. Less is known about CRF’s prevalence rates and patterns prediagnosis [2] and in patients receiving oral or targeted CT agents [7]. Few studies have examined fatigue in surgically treated or hospitalized cancer patients. One study reported an increase in

B.F. Piper () Scottsdale Healthcare/University of Arizona, 10684 N. 113th Street, 85259-4034 Scottsdale, AZ, USA e-mail: [email protected] K. Olson University of Alberta, Edmonton, AB, T6G 2G3, Canada C.L. Hagelin Department of Oncology and Pathology, Division of Clinical Cancer Epidemiology, Karolinska Institutet and Sophiahemmet University College, Stockholm, 114 86, Sweden

fatigue in cancer patients associated with a longer period of hospitalization [8]. During radiation therapy (RT), CRF is an almost universal occurrence with 70–100% of patients experiencing a gradually increasing, cumulative pattern of CRF over time that peaks and plateaus usually at 4–6 weeks and gradually declines thereafter over time. Patients need to be forewarned about the possibility of experiencing this type of CRF pattern, as they may feel that their disease is getting worse instead of better, and may fear that their treatment is not working [1, 7]. Increased CRF may be reported when different therapies such as RT and CT are used in combination [9]. In patients treated with biologic-response modifiers or biotherapy, such as interleukin-2 and interferon-a, CRF can be dose-limiting [7]. A prevalence rate of 70% is reported with interferon [10]. Fatigue in cancer patients receiving ­hormonal therapy has not been well studied [10, 11]. Increased levels of CRF are reported by patients with advanced malignancies [12, 13], and in those who have other illnesses or comorbidities [14]. In patients with metastatic disease, for example, fatigue prevalence rates may exceed 75% [1, 7].

Definition(s) Many definitions for CRF exist in the literature [7]. The most common definition used in practice settings, at least in the United States (US), is the National Comprehensive Cancer Network’s (NCCN) CRF definition: CRF is a distressing persistent subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity that interferes with usual functioning [1]. There is an emerging consensus for clinicians and researchers to begin to use a “case definition” for CRF to better enable comparisons across studies and populations to be made [7, 15]. For example, using a “cut score” of ³4 on a 0–10 numeric rating scale (NRS) during the past week where “0” = no fatigue, and “10” = worst fatigue, and using established

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_3, © Multinational Association for Supportive Care in Cancer Society 2011

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severity levels of 0 = none, 1–3 = mild, 4–6 = moderate, and 7–10 = severe [16, 17] is recommended by several investigators for clinical and research purposes [1, 18, 19]. In 1998, the first attempt to develop a case definition was proposed that included a set of diagnostic criteria for the syndrome of CRF [20]. These criteria were to be included in the United States version of the World Health Organization’s International Classification of Diseases-10 Clinical Modification (WHO ICD-10-CM) but were never submitted to the Center for Disease Control and Prevention (CDC) (D. Pickett, personal communication, December 8, 2008). At a recent international CRF consensus conference [21], it was acknowledged that these syndrome criteria unfortunately were not developed based on a broad range of evidence [7]. They were designed to classify CT “cases” who were receiving every 2 week dosing cycles of CT; and may have “set the bar too high” for a CRF case definition, as many patients with CRF did not fit these criteria. Thus, prevalence rates were far lower than expected. At that same CRF consensus conference, it was concluded that there were probably different phenotypes [22] or manifestations for CRF across the illness and treatment trajectories (i.e., active treatment, survivorship, and palliative end-of-life care) that require more study [7]. This conclusion was reached, in part, because symptoms such as weakness that can be reported as part of the CRF experience, may more commonly occur in palliative care patients with advanced or incurable malignancies [12], who also may be experiencing anorexia, weight loss, and the loss of muscle mass. Whereas, weakness is not a common occurrence or descriptor of CRF in earlier stage patients, such as women undergoing treatment for breast cancer, or men receiving hormonal ablation therapy [7, 23].

Underlying Mechanisms Despite the prevalence of CRF, little is known about CRF’s underlying mechanisms. Recently, two investigative teams working independently from one another have integrated a variety of seemingly disparate underlying mechanisms based on emerging evidence from several studies into over-arching integrated conceptual frameworks based on stressors, such as pain, cancer, its treatments, and other comorbidities including psychological stress, that activate inflammation [22, 24]. Cytokines released as part of the innate inflammatory immune response to these stressors, alter the sleep–wake cycle. This, in turn, contributes to the disruption in the neuroendocrine system especially in the HPA-axis and its related glucocorticoids [22]. This interaction results in unrestrained inflammation and increased release of proinflammatory cytokines, which interact with central nervous system (CNS) pathways that regulate behaviors. This leads to the pathophys-

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iological changes that underlie the behavioral manifestations of fatigue, depression, impaired sleep, and impaired cognitive function [22]. The model put forth by Olson et al. [24] also includes central and peripheral mechanisms for muscle fatigue. While more study is needed to validate these proposed models and their underlying assumptions and propositions, they both offer plausible explanations based on the evidence thus far about underlying mechanisms for CRF [7]. Both these models [22, 24] can be used to guide future studies investigating how CRF is related to other symptoms and behavioral alterations such as pain, insomnia, depression, and cognition [7, 25].

Assessment Barriers Despite the prevalence of CRF and the availability of guidelines such as the NCCN Evidence-Based Guidelines for CRF assessment and management [1] used in the US (www.nccn. org) and elsewhere, assessment is still not routinely performed in many institutions and oncology practice settings [18, 26, 27]. Numerous patient-, provider-, and systemrelated barriers hinder the translation of these guidelines into practice settings [18, 26]. In one study, the most frequent patient-related barrier was the patient’s belief that the physician would ask about CRF if it was important, followed by the patient’s desire to play the “good patient role” and not bring the subject up for discussion unless the physician did. Provider-and systems-related barriers included the lack of documentation in the medical record for guideline adherence and lack of supportive care referrals [7]. When the intervention phase of this study was implemented that included educational materials and teaching sessions for both patients and their providers [18], many of the patient-related barriers including the severity of CRF decreased over time compared to the usual care (control) group [18]. This suggests that many of the patient-related barriers to the assessment and management of CRF including its severity can be reduced by patient and provider education.

Screening The NCCN CRF Guidelines state that all patients must be assessed for the presence or absence of CRF at their first visit and at each subsequent visit. If CRF is present, the guidelines recommend that a simple 0–10 numeric rating scale (NRS) be used to assess CRF intensity (0 = no fatigue; 10 = worst fatigue you can imagine). Patients can be asked directly: “How would you rate your fatigue on a scale of

3  Cancer-Related Fatigue

0–10 over the past 7 days?” Mild fatigue is indicated by a 1–3 score, moderate fatigue by a 4–6 score, and severe fatigue by a 7–10 score [1]. For patients who are unable to assign a number to their fatigue, using the words “none, mild, moderate, and severe” is recommended [1]. As baseline CRF severity levels have been shown to be predictive of severity levels over time in patients undergoing treatment [28], it is important to assess and document these levels before patients begin treatment and to repeat and compare these screening assessments periodically over time during treatment [7]. Because CRF can persist for months, even years following treatment cessation, repeated assessments posttreatment are recommended [1, 2]. These assessments can be supplemented by having patients’ complete daily diaries prior to their next clinical visit [7].

Focused Workup For patients who are experiencing moderate to severe levels of CRF (4–10 on the 0–10 NRS), further assessment of CRF and its possible underlying causes is indicated. The NCCN guidelines recommend that this focused workup includes a more in-depth CRF symptom history [7]. Also included is an assessment of the patient’s current disease status, the type and length of cancer treatment planned as well as its potential to cause CRF [1]. It is important to evaluate whether CRF is due to disease recurrence or progression as treatment planning may be affected [7]. A review of systems is important as it serves to direct the physical examination and diagnostic testing.

Differential Diagnosis In making the differential diagnosis of CRF, it is important to distinguish CRF from other diagnoses such as depression [29] as the treatments may vary. It is essential to assess the presence of common contributing and treatable factors of CRF [1, 27]. These factors include anemia, comorbidities and medication side effects, activity levels and deconditioning, emotional distress (depression and/or anxiety), nutrition, pain, and sleep disturbance [1, 7].

Management

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41% were not at all familiar with them [30]. In another survey conducted by the NCCN nationally of more than 1,000 oncology clinicians, roughly one third were not aware of the CRF guidelines, and 34% of oncology specialist physicians (N = 293/863) were unaware of the guidelines, compared to 17% of advanced practitioners and nurses (N = 27/157) [31]. These findings indicate that health-care providers might benefit from more information about the existence of these CRF evidence-based guidelines and assistance in how to translate and implement them in their practice settings. Patient and Family Education Patients and family members need to receive education about CRF before they even start treatment to better prepare them for how to manage it, should they experience it. There are now several studies that have evaluated nurse-led educational programs focused on CRF during treatment [18, 32–38]. All but one [36] demonstrated decreased fatigue in the experimental groups receiving the educational intervention [7]. The small sample size in this study may have affected its conflicting results [36, 39]. In two of these studies [18, 37, 40], the intervention effect on fatigue was maintained during the follow-up period [39]. Each of these studies used short educational interventions, consisting of three to four individual patient sessions lasting 10–60 min [39], and to a large extent, the same elements, such as information about CRF, self-care or coping skills, and activity management, such as learning how to balance activities and rest [39]. Patients need to be “coached” to treat CRF as the 6th vital sign (after temperature, pulse, respirations, blood pressure, and pain) [22, 27] and to bring up the subject of CRF for discussion themselves to their health-care provider, even if the provider does not do so on their own [7]. Energy Conservation and Distraction The NCCN Guidelines suggest that general educational strategies to manage CRF need to be included as well, such as energy conservation techniques [40] and distraction techniques such as games, music, reading, and socializing [1]. Energy conservation techniques use a common sense approach to help patients prioritize and pace activities, and to delegate less essential activities [1, 40]. Daily or weekly diaries can inform the patient about peak energy periods allowing them to plan their activities accordingly [1].

Provider Education Provider education about CRF is essential to effective CRF management. At one national meeting held in the US, approximately 50% of health-care providers (mostly nurses), were only somewhat familiar with the NCCN CRF Guidelines, and

General Treatment Principles Treatment must always be tailored to the patient [1], taking into account the patient’s disease and treatment status and

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goals of treatment [7]. Treatment planning also takes into account what is most likely the primary underlying cause of CRF and whether referrals to other health-care providers or supportive care disciplines are needed [1]. Treatment should be first directed to one or more of the common contributing and treatable factors associated with CRF [7]. By the time patients realize that the fatigue has become unusual for them, CRF most likely is multicausal, and will probably require multimodal combination therapies and referrals [7]. If none of these common contributing and treatable factors is present or the patient continues to have moderate to severe fatigue despite treatment, additional workup and treatment planning must occur [1]. Each of these common contributing factors is discussed in more depth in the following sections [7].

While more studies are clearly indicated in this area, there are a few studies in cancer that are beginning to report consistent and significant findings about how specific comorbidities such as arthritis [44] and an increase in the actual total number of comorbidities a patient has, can increase CRF severity [45]. The CRF guidelines recommend that each comorbidity be reviewed to determine whether any changes in the management of the comorbidity or its medications need to be made within the context of the patient’s CRF [1]. Referral to an internist or specialist, and/or consultation with a clinical pharmacist often is helpful [7]. Patients need to receive education that comorbidities and medications are one of the common contributing and treatable factors associated with CRF.

Anemia

Activity and Deconditioning

Decreased hematocrit [41] and hemoglobin levels are associated with CRF [41]. In one study, the degree of anemia (mild, moderate, severe) predicted fatigue severity (p < 0.001) [42]. The NCCN CRF Guidelines [1] identify anemia as one of CRF’s common contributing and treatable factors. In many instances, however, anemia may be only a partial contributing factor, as the level of fatigue in cancer patients without anemia is greater than that reported for the general population at large [7, 42]. Since CRF and anemia can both be multifactorial, the NCCN guidelines for cancer- and chemotherapyrelated anemia [43] recommend assessing both subjective and objective symptoms associated with each, to better identify the underlying causes and to tailor treatment accordingly [43]. Patients need to be educated about the relationship between CRF and anemia [7]. They need to receive information about the possible underlying causes of anemia and how treatment may vary depending on a number of factors, including the underlying cause of their anemia, the indications and rationale for the various types of anemia treatments including iron supplements, and their risks, benefits, and associated sideeffects [1, 7, 43]. Correction of anemia within the context of CRF will depend upon whether the anemia is cancer-related (nontreatment-related), treatment-related due to the myelosuppressive effects of CT, or due to other causes [43]. Anemia treatment will also depend on the goals of CT treatment (curative versus noncurative), how rapidly the anemia must be corrected, and the presence of comorbidities [7].

In cancer patients, cancer and treatment side effects, such as CRF, often result in decreased activity patterns and reductions in physical performance. As a consequence, deconditioning is common and is identified as one of the common contributing and treatable CRF factors [1]. Cancer patients need to have their activity levels assessed at baseline when they are first diagnosed and before treatment begins [7]. Thereafter, they need to be periodically reassessed over time to identify changes in their exercise or activity patterns and to identify if there is any evidence that deconditioning is present due to their malignancy, CRF, other comorbidities, treatments, or other symptoms such as pain [7]. Patients need to be educated about the high risk for developing deconditioning, the multiple causes of deconditioning that can occur, and how it can lead to a downward spiral of secondary fatigue as a consequence. Based on the strength of the evidence for exercise, patients need to be educated about the need to engage in moderate levels of physical activity during and following treatment [1]. Despite this teaching, however, in one study [18], one of the more persistent patient-related barriers was the belief that they should rest more when they were fatigued, and that exercise would increase rather than decrease their CRF despite the evidence to the contrary [7]. Being diagnosed with cancer constitutes a “teachable” moment [46]. Patients need to be educated not only about the barriers to exercise (patient-, provider-, and systems-related) [7] but also about the benefits of exercise that include the prevention of disease recurrence, the prevention and treatment of comorbidities such as diabetes, hypertension, and obesity, the positive effects on sleep disturbance, depression and cognition, and the strength of the evidence in reducing CRF in cancer patients (Level 1) [1]. For patients not currently exercising, progression needs to occur slowly over time as they are taught how to monitor their own progress along with being closely monitored by trained professionals [7].

Comorbidities Despite the fact that comorbidity is identified as one of the common contributing and treatable factors to CRF [1], specific types of comorbidities and their medications have not received much investigation for their CRF association [7].

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Providers may be hesitant to prescribe an exercise program for cancer patients without having evidence-based guidelines specific to cancer to follow [7]. Fewer than 20% of medical oncologists recommend exercise to their patients [46, 47]. Providers may be unaware of just how powerful their recommendations for exercise prescriptions can be [7]. Maintaining or enhancing activity and exercise patterns in cancer patients has the highest level of evidence associated with decreasing CRF as do psychosocial interventions [1]. In a recent systematic and meta-analytic review of 57 nonpharmacologic randomized clinical trials (RCTs) [15] of exercise (physical activity, walking, yoga) and psychosocial interventions (counseling, stress management and coping strategies), both interventions were equally and moderately effective in reducing CRF [7]. This review suggested that multimodal therapy that combines these two types of interventions into an integrative intervention trial could potentially be more likely to reduce CRF and improve vigor and vitality [15]. While more study is needed in this area, walking and multimodal exercise programs appear to have the greatest potential for reducing CRF and enhancing vigor and vitality [15]. Based on these findings, it seems reasonable to encourage all patients to engage in a moderate level of physical activity during and following treatment cessation [1, 15]. For patients who are severely deconditioned, who are not currently exercising, or have comorbidities (i.e., arthritis, COPD), recent surgery or functional or anatomical issues, referral to health-care providers or exercise specialists such as physical therapy, physical medicine, or rehabilitation should be considered [1]. There is some evidence that exercise may be beneficial in maintaining activity patterns and reducing or at least stabilizing CRF in patients with advanced disease at end of life as well [1]. Caution is needed in tailoring an exercise prescription in patients who have bone metastases, fever or infection, anemia, thrombocytopenia, neutropenia, or immunosuppression [1].

Emotional Distress The NCCN Distress Guidelines [48], use the term “distress” in their definition because it is believed to be less stigmatizing than other terms that can be used to describe psychosocial problems like anxiety and depression [7]. In cancer patients, prevalence rates for depression range between 25 and 33% [48] and anxiety can occur at all times and in all cancer patients [7]. Emotional distress (i.e., anxiety and depression) is one of the common contributing factors of CRF [1]. While CRF and depression are common concurrent symptoms in cancer patients [1], one study in RT patients concluded that CRF and depression were independent conditions with different patterns over time [49]. The distress guidelines recommend asking cancer patients about how their distress is the past week including today

on a 0–10 distress thermometer where ³4 scores indicate clinical significant distress [48] that indicates further workup and referrals may be needed. In addition, there is a checklist for common problems that cancer patients can experience such as practical, family, emotional, spiritual/ religious, physical (symptoms), and memory/concentration that patients can self-complete. This screening assessment is recommended to be done initially at baseline before treatment is initiated and be repeated periodically over time during and following treatment [7]. Patients need to be taught about how CRF may be related to emotional distress and that emotional distress is one of the common contributing and treatable factors of CRF. They need to be counseled about stress management techniques, and methods and resources that can help not only reduce anxiety and depression and but also CRF associated with emotional distress [7]. Several nonpharmacologic, randomized clinical trials using psychosocial interventions, such as participation in support groups, individual counseling sessions, cognitivebehavioral training (identification and correction of inaccurate thoughts associated with depressed feelings using relaxation and enhancing problem-solving skills, stress management training, using a comprehensive coping strategy, and a tailored behavioral intervention), have consistently shown that not only can emotional distress be reduced but also CRF can be reduced when associated with depression or anxiety [15]. Level 1 evidence exists for using these psychosocial interventions in cancer patients experiencing CRF due to emotional distress [1, 48]. Supportive care referrals to other disciplines including Nursing, Social Services, Psychology and Chaplaincy/Pastoral Services often are indicated and can be very beneficial [7]. A variety of pharmacologic interventions to treat emotional distress exist including anxiolytics and antidepressants [7]. In one antidepressant study, depression was decreased, but the treatment had no effect on CRF [50]. For further information, please refer to the NCCN distress guidelines [48], the NCI’s PDQ websites for anxiety [51] and depression [52], and the review by Breitbart and Alici [53].

Nutrition In cancer patients, nutritional problems are common [1, 7, 54, 55]. It is estimated that 20–80% of cancer patients develop malnutrition during the course of their illness [56]. While nutritional problems are one of the common contributing and treatable factors of CRF in cancer patients [1], their relationships to CRF have not received much study [7]. There are only two studies in cancer patients that examined these relationships, and both found no relationship between nutritional status and CRF [57, 58].

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Nutritional assessment within the context of CRF includes determining the presence of any unintentional weight gain or loss, and the extent to which the patient is experiencing nutritional problems such as fluid and electrolyte disturbances [1]. The degree to which CRF may be limiting the patient’s ability to shop and prepare food needs to be assessed [7]. Frequently, patients alter their dietary patterns when they receive a cancer diagnosis, disease recurrence, or during survivorship following treatment cessation [46]. They may take numerous over-the-counter supplements, vitamins, and other herbal remedies that may affect not only their nutritional status and treatments but also CRF. The relationship between CRF and these over-the-counter supplements, vitamins, and other herbal remedies has not received much study. All cancer patients need to be taught that nutritional problems are common in cancer and its treatments, and while not well studied, nutritional problems are one of the common contributable and treatable factors associated with CRF. Because of the lack of studies investigating the relationships among nutritional status, nutritional problems, and CRF, counseling patients about general nutritional guidelines such as eating a balanced diet low in fat and high in vegetables and fruits as appropriate to their condition and goals of their treatment seems a reasonable approach to include [5, 46, 59, 60]. When indicated by the patient’s condition and goals of treatment, both pharmacologic and nonpharmacologic therapies may be considered to improve nutritional status [7] including referring the patient for a nutritional consultation [1].

Pain Pain is one of the common contributing and treatable factors of CRF [1, 61]. Pain commonly co-occurs with CRF, but may be more common in certain subgroups of patients. [7] For example, one study in 841 patients age ³65 years diagnosed breast, colon, lung, or prostate cancer found that women (versus men), patients with late stage cancer versus early stage), patients with lung cancer (versus other solid tumors), and those with three or more comorbidities were more likely to experience pain and fatigue concurrently [14]. In another study, when the control or usual care (Phase 1: N = 83) and intervention groups (Phase 2: N = 104) were combined for analysis (N = 187), 10.7% (N = 20) had pain only; 56.2% (N = 105) had fatigue only; and 33.2% (N = 62) had both symptoms [18]. Of importance, the higher the baseline pain intensity, the higher it was 3 months later (b = 0.268, p = 0.012). Again, this finding emphasizes the importance of assessing symptoms like pain at baseline before treatment is started, and perhaps intervening earlier to prevent or lesson these symptom intensities over time [7]. More study is

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needed to determine actual prevalence rates and risk factors for pain and CRF co-occurring, and how treatment of one symptom or combining therapy to treat both together affects this symptom cluster. See the symptom cluster discussion that follows this section [7]. For pain assessment and management, refer to the NCCN pain guidelines [62]. In addition to education about pain, its causes, treatments, associated side effects and their management, patients need to be taught that pain is a common contributing and treatable factor for CRF [1]. They also need to be taught about barriers to effective pain assessment and management [7]. In a recent review of pain studies, patient education improved knowledge and attitudes about pain, and reduced average and worst pain intensity scores [63]. Similarly, in another study, patients in the education intervention group demonstrated significantly more improvements in pain knowledge scores and fewer patient-related barriers at 1 and 3 months after the intervention compared to the control group (Phase 1) [18]. This suggests that these changes were sustained over time. Two persistent areas of lack of knowledge in the intervention group however, was the belief that cancer pain can only be treated with medication, and that pain medication can be stopped abruptly (i.e., instead of being titrated downward over time) if no longer needed [7]. For guidance on how to treat pain, please refer to the NCCN Pain Guidelines [62].

Symptom Clusters Fatigue is thought to rarely occur by itself. More commonly, it is thought to co-occur with other symptoms such as pain, depression (i.e., emotional distress) [61], and insomnia [8, 64–66]. It’s proposed that these symptom clusters may share a common underlying pathway or mechanism [25, 41, 67, 68]. Thus, the treatment of one or more of these symptoms might beneficially affect the other symptoms [68] including CRF [1]. There is also some evidence that the relationships among symptoms may change over time [69]. Nevertheless, the cumulative burden of these symptoms is thought to also contribute to or exacerbate CRF [70]. In one study that focused on pain and fatigue, more patients experienced CRF alone (³4 on a 0–10 NRS), followed by pain and fatigue (³4) co-occurring together, followed by pain alone (³4) [7, 18]. Another study investigated women, newly diagnosed with stage I–III breast cancer receiving at least four cycles of adjuvant or neoadjuvant anthracycline-based CT) who had a symptom cluster that included sleep disturbance, fatigue, and depression [71]. These women before the start of their CT were subdivided into three groups based on the number of symptoms (achieving symptom scores above the cut scores for standard fatigue, sleep, and depression scales) (i.e., no cut scores exceeded, 1–2 cut scores exceeded, and all three cut scores exceeded), and a symptom cluster index

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(SCI) was computed for each group. In this study, the prevalence rates for these subgroups were: 19.7% (SCI 0 group; N = 15/76), 56.6% (SCI 1–2 group; N = 43), and 23.7% (SCI 3 group; N = 18) [71]. These women were then followed over time. Before CT, 66% of the women reported poor sleep, 63% reported fatigue, and 25% reported depressive symptoms, and each of these symptoms were significantly correlated with one another. All women regardless of subgroup experienced worse sleep, more fatigue and more depression during treatment compared to baseline. However, the baseline group differences remained consistent overtime. Thus, the women in group 3 at baseline continued to report higher levels of symptoms than those women in group 1–2; the women in group 1–2 continued to report higher levels of symptoms than the women group 1. Thus, these baseline group differences were maintained during treatment [7, 71]. This is another study that indicates that pretreatment or baseline assessment of CRF and these and other symptoms is critical as pretreatment severity levels can identify the risk for the severity of symptoms over time during CT. Whether symptom management strategies started earlier at baseline proactively versus reactively by waiting for the symptom severity to worsen, can prevent or ameliorate the severity of these symptoms over time needs to be studied [7].

Cognitive Impairment Another problem that cancer patients can frequently experience particularly when undergoing treatment is cognitive impairment [72]. Signs and symptoms include forgetfulness, lack of mental clarity, and impaired concentration [7]. While relationships between CRF and cognitive impairment have not been well studied, attentional fatigue, the decreased capacity to concentrate or to direct attention, is considered one aspect of sensory CRF [1]. Use of attention-restoring interventions in women with breast cancer has positively affected concentration, problem-solving, and the ability to direct attention on neurocognitive tests [1]. Bird watching and sitting in a park are examples of attention-restoring activities in natural environments [73].

Sleep–Wake Disturbances Sleep–wake disturbance is a general term used to describe perceived or actual alterations in nighttime sleep with concomitant daytime impairment [74]. This term is used when a specific diagnosis of a sleep disorder has not been made [75]. While a variety of sleep disturbances can occur in healthy adults and adults with cancer, insomnia is the most common disorder that occurs in cancer patients [76]. Common descriptors of insomnia include problems in fall-

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ing asleep, staying asleep, early-morning awakenings, an inability to fall back to sleep, and sleep described as being nonrestorative, nonrefreshing, with some form of daytime impairment [74]. Insomnia is a serious issue in cancer patients as it is associated with other symptoms such as CRF and pain during and following treatment. In one study, the co-occurrence of the symptom cluster of pain, fatigue, and insomnia in elderly cancer patients was associated with an increased risk of death during the first year following the diagnosis [77]. While most studies have assessed the relationship between CRF and sleep disturbances in women with breast cancer receiving CT, correlations also are reported in patients undergoing RT and surgery, and in patients with other malignancies. Reviews of some of these studies are available [7, 78]. Approximately 30–75% of cancer patients have sleep disturbances. As a consequence, sleep disturbances are identified as one of the common, contributing, and treatable factors of CRF [1]. Treating sleep disturbances with cognitive-behavioral strategies is thought to reduce the incidence and prevalence of CRF [5, 78, 79]. Patients need to be asked at diagnosis and periodically over time, whether they are experiencing any sleep disturbances [74]. Patients need education about how common sleep disturbances are in cancer patients and that sleep disturbances are one of the common contributing and treatable factors of CRF [1]. Patients need to be taught to report disturbances to their providers and how to use some of the more common cognitive and behavioral therapies (CBT) available to treat insomnia. These include stimulus control, such as going to bed when sleepy, sleep restriction, such as limiting the total time in bed [80], relaxation training, including complementary therapies, and sleep hygiene methods, such as avoiding caffeine after noontime [1]. Patients also need to be taught about other interventions that can enhance sleep patterns such as exercise, sleep medications, controlling other symptoms such as pain, and using complementary therapies to enhance relaxation before bedtime [1]. Nonpharmacological therapies to manage sleep disturbances include the CBTs, complementary therapies, and exercise mentioned above. There is some evidence that these same therapies may also improve CRF [1, 81] but more study is needed. There also are a wide variety of pharmacologic options available, including the sedatives–hypnotics, but there is little evidence of their use in cancer patients or how they may affect CRF [74]. These medications are not without their own side effects, and concerns have been raised about drug to drug interactions when taken with tamoxifen or selective serotonin reuptake inhibitors [1, 74, 76]. For further information about these sleep enhancing medications, please see the National Cancer Institute’s PDQ website on sleep disorders [82]. Consultation and referral to a sleep specialist may be indicated in some patients [7].

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When indicated in medically-induced fatigue such as opioid-induced sedation for pain and when treating depression or cognitive impairment, psychostimulants can be considered [53]. The NCCN CRF guidelines state that pharmacological interventions for CRF remain investigational, but there is more evidence for methylphenidate [83] than modafinil at present. These agents need to be used cautiously and optimal dosing and schedules have not been established [1].

Summary and Future Directions Cancer-related fatigue (CRF) is a complex, multicausal, and multidimensional sensation [27]. Both the intensity of CRF and its impact need to be assessed and measured in practice and research settings. It is suggested that different phenotypes or manifestations of CRF exist and may vary by stage of disease and treatment trajectory (i.e., active treatment, survivorship [off treatment without evidence of disease], and palliative end-of-life care) [21]. Thus, for future studies, it is preferable to include homogeneous samples whenever possible. It is also important to remember that the words patients use to describe CRF may vary by language and culture [84] and that the words energy, vigor, and vitality are not interchangeable with the terms tiredness, fatigue, and exhaustion [15]. When CRF becomes unusual for patients, compared to the usual tiredness they experienced when healthy, it most likely has become chronic and is due to multiple causes. As a consequence, it most likely will require multimodal combination therapies directed toward alleviating it directly [39] More study is needed using sophisticated statistical procedures to longitudinally follow other symptoms that cluster with CRF at baseline; to monitor changes in these symptom clusters and CRF and their patterns over time; and how changes in these symptoms and CRF respond to different treatments. Provider and patientfamily educational programs and supportive care referrals to other disciplines related to the NCCN CRF Guidelines are essential for effective assessment and management. More research is warranted to determine how to best to translate and implement these educational programs and guidelines in practice and evaluate their impact on patient, provider, and setting outcomes [26]. Providers also need to appreciate the significant impact that their prescriptions and referrals have on patients making behavioral lifestyle changes such as diet and exercise [60]. Lastly, more research is needed to identify underlying mechanisms of CRF so that treatments can be targeted and tailored accordingly.

References 1. Berger AM, Barsevick AM, Cimprich B, Jacobsen PB, Ligibel JA, Murphy BA, et al. National comprehensive cancer network (NCCN) clinical practice guidelines in oncology: Cancer-related fatigue,

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31 40. Barsevick AM, Dudley W, Beck S, Sweeney C, Whitmer K, Nail L. A randomized clinical trial of energy conservation for patients with cancer-related fatigue. Cancer. 2004;100(6):1302–10. 41. Payne J, Piper BF, Rabinowitz I, Zimmerman B. Biomarkers, fatigue, sleep, and depressive symptoms in women with breast cancer: A pilot study. Oncol Nurs Forum. 2006 [cited January 28, 2008]; 33(4):775–83. 42. Cella D, Lai JS, Chang CH, Peterman A, Slavin M. Fatigue in cancer patients compared with fatigue in the general united states population. Cancer. 2002;94(2):528–38. 43. Rodgers GM, Bennett CL, Djulbegovic B, Gilreath JA, Kraut EH, Matulonis U, et al. NCCN clinical practice guidelines in oncology: Cancer and chemotherapy induced anemia. J Natl Compr Cancer Netw. 2008;6(6):536–64. 44. Belza BL. Comparison of self-reported fatigue in rheumatoid arthritis and controls. J Rheumatol. 1995;22(4):639–43. 45. Given B, Given C, Sikorskii A, You M. When compared with information interventions, are cognitive behavioral models more effective in assisting patients to manage symptoms? Oncol Nurs Forum. 2009;36(1):IV. 46. Demark-Wahnefried W, Aziz NM, Rowland JH, Pinto BM. Riding the crest of the teachable moment: Promoting long-term health after the diagnosis of cancer. J Clin Oncol. 2005;23(24):5814–30. 47. Blanchard CM, Stein KD, Baker F, Dent MF, Denniston MM, Courneya KS, et al. Association between current lifestyle behaviors and health-related quality of life in breast, colorectal, and prostate cancer survivors. Psychol Health. 2004;19:1–13. 48. National comprehensive cancer network (NCCN) clinical practice guidelines in oncology: Distress management [homepage on the Internet]. v.2. 2009. June 18, 2009. Available from: http://www. nccn.org/professionals/physician_gls/PDF/distress.pdf. 49. Smets EM, Visser MR, Willems-Groot AF, Garssen B, SchusterUitterhoeve AL, de Haes JC. Fatigue and radiotherapy: (B) experience in patients 9 months following treatment. Br J Cancer. 1998; 78(7):907–12. 50. Roscoe JA, Morrow GR, Hickok JT, Mustian KM, Griggs JJ, Matteson SE, et  al. Effect of paroxetine hydrochloride (paxil) on fatigue and depression in breast cancer patients receiving chemotherapy. Breast Cancer Res Treat. 2005;89(3):243–9. 51. Anxiety disorder – National Cancer Institute [homepage on the Internet]. [Cited September 30, 2009]. Available from: http://www. cancer.gov/cancertopics/pdq/supportivecare/anxiety/health professional. 52. Depression – National Cancer Institute [homepage on the Internet]. [Cited September 30, 2009]. Available from: http://www.cancer. gov/cancertopics/pdq/supportivecare/depression/health professional. 53. Breitbart W, Alici Y. Pharmacologic treatment options for cancerrelated fatigue: Current state of clinical research. Clin J Oncol Nurs. 2008;12(5 Suppl):27–36. 54. Fatigue (PDQ) health professional version [homepage on the Internet]. 2009. Available from: http://www.cancer.gov/cancertopics/pdq/supportivecare/fatigue/HealthProfessional. 55. Graziano F, Bisonni R, Catalano V, Silva R, Rovidati S, Mencarini E, et al. Potential role of levocarnitine supplementation for the treatment of chemotherapy-induced fatigue in non-anaemic cancer patients. Br J Cancer. 2002;86(12):1854–7. 56. Kubrak C, Jensen L. Critical evaluation of nutrition screening tools recommended for oncology patients. Cancer Nurs. 2007;30(5):E1–6. 57. Beach P, Siebeneck B, Buderer NF, Ferner T. Relationship between fatigue and nutritional status in patients receiving radiation therapy to treat lung cancer. Oncol Nurs Forum. 2001;28(6):1027–31. 58. Porock D, Beshears B, Hinton P, Anderson C. Nutritional, functional, and emotional characteristics related to fatigue in patients during and after biochemotherapy. Oncol Nurs Forum. 2005;32(3):661–7. 59. Brown JK, Byers T, Doyle C, Courneya KS, Demark-Wahnefried W, Kushi LH, et al. Nutrition and physical activity during and after

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Chapter 4

Palliative Care: End-of-Life Symptoms Paul Glare, Tanya Nikolova, and Nessa Coyle

Introduction The goal of modern palliative care may be the relief of suffering due to life-threatening illness irrespective of the stage of disease [1], but ensuring and maintaining comfort and dignity throughout the last hours of life will always be its core competency. Despite the increases in cancer survivorship and improvements in mortality rates for many cancers achieved in the past two decades, there are still more than seven million cancer-related deaths annually worldwide. Consequently, care of the actively dying remains part of the everyday practice of comprehensive cancer care. As with any other aspect of supportive care and survivorship, high-quality care of the dying requires the application of three clinical skills: diagnosis, therapy, and prognosis. Dying of cancer is not usually catastrophic and sudden, yet the first task – diagnosing the patient is now dying – is not always easy [2]. In patients at home or in a palliative care unit (PCU), the signs often associated with the dying phase are: • The patient becomes bedbound. • The patient is able to take only sips of fluid and is no longer able to take oral drugs. • The patient is semicomatose. In the hospital, diagnosing dying is often a more complex process. In one English hospital, the approach of death was not identified until the final 24 h in >50% cases and >72 h beforehand in <15% cases [3]. The hospital culture is often focused on “cure,” with continuation of invasive procedures, investigations, and death-delaying treatments being pursued, often at the expense of the comfort of the patient [4]. The second clinical task – therapy of dying – is discussed in detail in the remainder of this chapter. Before making the pharmacological and nonpharmacological interventions P. Glare () Pain & Palliative Care Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA e-mail: [email protected]

described here, the therapeutic task in the dying first involves clarifying with the patient and family the preferences for end-of-life care [5]. In most cases, this means de-escalating or at least capping the care: • Canceling routine blood work and any invasive tests • Ceasing unnecessary medications – either no longer clinically relevant or having a long half-life • Eliciting and documenting a do-not-resuscitate order In an attempt to improve access to good end-of-life care outside the hospice, integrated care pathways and order sets for generalists to use are being developed [6–8]. The final task in the care of the actively dying – prognosis – requires the clinician to make a numerical estimate of the short-term survival and then be prepared to communicate this to the patient and family if asked. Various tools are available for estimating survival [9]. Factors indicating a patient with cancer is unlikely to survive hospital admission include emergency admission, short duration of illness, poor performance status, low hemoglobin, and high LDH [10]. Data from studies of the Palliative Prognostic Score indicate the typical time course once the patient has entered the dying phase as follows: the patient becomes totally bedbound approximately 1 week before death; he/she is only able to take sips of fluid in the last 48 h; he/she is semicomatose and only having mouth care in the final 24 h [11]. In hospitals, there is often a reluctance to make the diagnosis of dying and discuss the prognosis if any hope of improvement exists and even more so if no definitive diagnosis has been made. When recovery is uncertain, it is better to discuss this rather than giving false hope to the patient and the family. This is generally perceived as a strength in the doctor–patient relationship and helps to build trust [4].

Common Symptoms at the End of Life Autopsy studies from the 1970s were undertaken to determine the proximate cause of death in cancer patients [12]. Massive dissemination was observed most often in breast

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and ovarian carcinomas, while hematologic malignancies led to death through extensive organ infiltration in about onethird of the cases. Organ invasion and/or failure were most often due to massive hepatic metastases, biliary obstruction, and cardiac failure, while pelvic tumors had caused fatal ureteral compression. Death due to infection occurred most frequently in cases of hemotologic, urogenital, and gastro­ intestinal malignancies, and in patients dying after cancer surgery. Death due to hemorrhage originated from peptic ulceration, vascular invasion by head and neck tumors, or chemotherapy-induced thrombocytopenia. A summary of clinical studies that have surveyed symptom prevalence as death approaches is shown in Table  4.1 [13–20]. The common symptoms of the terminal phase that cause discomfort and which need to be addressed include pain, nausea, agitation/restlessness, retained respiratory secretions, and breathlessness. Anorexia and fatigue are very common but not included in this list as they are accepted as an unavoidable part of the dying process and not usually treated. Less commonly, dysphagia, constipation, urinary retention, decubitus ulcers, fevers, hemorrhage, seizures, and choking/suffocation can also occur in the last hours/days of life and can impact on care. Some of these develop suddenly and need to be treated emergently. Fortunately, all these symptoms usually can be controlled by a handful of medications, which can be given safely either subcutaneously or intravenously (see Table 4.2).

Table 4.1  Symptom prevalence at end of life Author Fainsinger [16] Conill [18] % with symptoms, time before death Pain Agitation or delirium Retained secretions Dyspnea Hemorrhage Seizures a Background pain (incident pain 47%) b Moderate or stronger

1 week 99 39 – 46 – –

1 week 30 68 – 47 12 –

Table 4.2  Drugs used in USA for terminal symptoms Drug Initial dose, p.r.n

Management of Common Symptoms in Dying Patients Pain Pain is one of the commonest symptoms in terminal patients with cancer, with a prevalence approaching 100%. Fortunately, complete control of pain is not accomplished in less than 10% of patients in the last few days of life. To achieve this outcome, the four basic principles of pain control need to be followed, adapted for the circumstances • • • •

Identify and if possible reverse the noxious stimulus Identify and if possible reverse any “pain threshold” issues If indicated, use opioids correctly If appropriate, use coanalgesic medication

Identifying the cause of the pain is challenging at the end in view of the limited history. The focused physical examination becomes even more important. In nonverbal patients, information about appetite as well as observing posture, interactivity, vocalization, and facial expressions can be helpful. Pain in cancer patients can be due to the disease, a side effect of its treatment, debility, or unrelated causes. Examples of debility pains, which are more prevalent at the terminal stage, include muscle spasm, myofascial pain, capsulitis of the shoulder, and constipation. It is important to remain cognizant of the

Nauck [20] Lichter [13] Ellershaw [19] Goncalves [14] Grond [17] 72 h 26 55 45 25 – –

48 h 51 42 56 22 – –

48 h 46 52 45 – – –

48 h   9a 49 46 36 15  2

24 h 13b 25 – 17 – –

Symptoms

Morphinea 5–10 mg IV q2h Pain, dyspnea Hydromorphonea 1–2 mg IV q2h Pain, dyspnea Lorazepam 1–2 mg IV q1h Agitation, delirium, nausea, seizures, hemorrhage, refractory other symptoms Haloperidol 2–5 mg IV q1h Agitation, delirium, nausea, seizures, hemorrhage, refractory other symptoms Chlorpromazine 10–25 mg IV q4–6h Agitation, nausea, delirium, seizures, hemorrhage, refractory other symptoms Scopolamine/hyoscine hydrobromide 1 patch topically q72h Rattly secretions, nausea Glycopyrrolate 0.2–0.4 mg SC q2h Rattly secretions a Dose if opioid-naïve; increase by 50% if already on opioids and symptomatic

4  Palliative Care: End-of-Life Symptoms

psychosocial dimensions of cancer pain, which will serve to lower the “pain threshold,” and address them where possible [21]. In nonverbal terminal phase patients, pain aggravated by anguish may present as restlessness/agitation. Adequate treatment of moderate to severe pain usually demands that opioids be prescribed. When considering the use of opioids in the dying, there are three scenarios, depending on whether or not patients have uncontrolled pain and are opioid-naïve. 1. Controlled pain in a patient on chronic opioid therapy: Initially, the current management is continued, and if necessary, conversion to the intravenous or subcutaneous route is prescribed. Steady delivery of the medication can be achieved via continuous infusion or patient-controlled analgesia (PCA). The rescue dose for breakthrough pain is 10–20% of the total 24-h oral opioid dose or 50–150% of the hourly intravenous rate. 2. Uncontrolled pain in the opioid-naïve patient: The usual starting dose for moderate to severe pain is morphine 2–4 mg intravenously (or 2.5–5 mg subcutaneously) every 2 h as needed. Use of other opioids, like hydromorphone at equianalgesic doses, is appropriate as well. 3. Uncontrolled pain in a patient already on chronic opioid therapy: This usually constitutes a complex pain problem related to ineffective analgesia or rapidly escalating pain. Therapeutic options include switching opioids, dose escalation and, less frequently, adding adjuvant agents. For better control of mild to moderate pain, the suggested increase in opioid dose is 25–50%. For severe pain, the increase needs to be in the range 50–100%. It is not usually recommended to start long-acting opioid preparations for new pain in the last few days of life because of variable absorption and the difficulty in rapid titration. It is reasonable to continue the fentanyl patch or oral longacting opioid while the oral route is available and the pain is controlled. Fentanyl patches make the transdermal route an effective alternative to parenteral oral therapy in terminally ill patients with controlled pain who become unable to swallow. If pain escalates on the fentanyl patch, it is preferable to continue the patch and use morphine or hydromorphone as needed in the first 24 h. Once the requirement is established, changing this to a continuous morphine or a hydromorphone infusion would achieve even better pain control. Continuing the patch does not compromise pain control in the last few days and may be associated with fewer episodes of uncontrolled pain and fewer breakthrough doses [22]. The opioid side effects like sedation, nausea, and constipation should continue to be anticipated and prevented/ treated [23]. Sedation usually is a short-lived side effect of the initiation of treatment with opioids but if needed can be

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effectively treated with methylphenidate. Use of antiemetics in the first few days of the opioid therapy may be effective in preventing nausea in patients with increased risk. Patients at their terminal stage usually have minimal oral intake of solids, which can diminish the discomfort associated with opioidinduced constipation. It is important to maintain as regular as possible bowel movements to keep the patient comfortable. For severe cases of constipation resistant to usual pharma­ cological therapies, opioid dose reduction, opioid rotation, or treatment with methylnaltrexone may be indicated [24]. Neuroexcitatory side effects (myoclonus, allodynia, hyperalgesia, hallucinations, agitation, delirium, and even seizures) are more common in dying patients, as the dose often has to be titrated up to control rapidly escalating pain. The incidence of opioid-induced myoclonus ranges from 2.7 to 87% [25]. Predisposing factors to development of myoclonus are: high opioid doses, prolonged opioid use, recent rapid dose escalation, renal failure, dehydration, advanced age, and the use of other psychoactive agents. Myoclonus in terminally ill patients can be a consequence of factors unrelated to opioid use; the differential diagnosis is long and includes electrolyte abnormalities, hypoglycemia, uremic or hepatic encephalopathy, hypoxia or hypercarbia, sepsis, terminal delirium, and other drugs. When myoclonus is clearly related to opioids, the main therapy includes hydration and rotation to another opioid. Naloxone is not likely to be effective [26]. Another common therapeutic option especially in patients nearing death is administering medications that counteract the neuroexcitatory effect of opioids. Benzodiazepines such as clonazepam, diazepam, and midazolam are preferred [27], with baclofen and dantrolene as second-line agents. Patient education to promote adherence to therapy is an important part of the correct use of opioids at any stage of the disease, but when patients are actively dying, the use of opioids often raises serious concerns in the patient’s family about the possible hastening of death. Clinicians treating pain correctly at the end of life use safe doses to achieve analgesia and rarely encounter a scenario of the unintended side effect of opioid-related death. Large prospective cohort studies have demonstrated that the timing of death in patients with advanced illness is associated with multiple variables including cancer diagnosis, unresponsiveness, and pain of <5 on a 0–10 pain scale, not just high opioid doses. Opioid dosing is associated with time until death, but this factor alone explains very little of the variation in survival [28]. In the case of palliative sedation, the doctrine of double effect describes the difference between what the physician intends by prescribing opioids and benzodiazepines and what is accepted as an unintended side effect, [29]and may not hasten death anyway [30]. Undertreatment of pain is a much more serious problem than overtreatment, driven by an overrated concern of the potential for serious opioid-induced toxicity [31].

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The last step in basic pain management is the use of coanalgesic drugs for components of the pain that are not very opioid-responsive. Their use is often prevented in the actively dying owing to the patient’s inability to swallow and the drugs’ slow onsets of action. As nonsteroidal ­anti-inflammatory drugs and steroids are very effective for bone pain, options include parenteral ketorolac or dexamethasone, rectal naproxen or acetaminophen, and topical diclofenac. Anticonvulsants and antidepressants for neuropathic pain are very useful adjunct therapies but frequently are omitted in the last days of life because of their long half-life, especially in the context of renal and liver impairment. Options in the last hours of life include topical lidocaine, parenteral ketamine, and escalating the opioid dose.

Delirium Delirium is a multifactorial syndrome of alterations of consciousness, attention, and cognition, which occur abruptly and have a fluctuating course. Delirium affects up to 88% of patients in the last weeks of life [32]. Three clinical forms of delirium have been described – hyperactive, hypoactive, and mixed. Patients with hyperactive delirium present with agitation, restlessness, and hallucinations. Hypoactive delirium is commonly confused with depression or medication-related sedation and is the most frequently observed subtype of delirium. Delirium during the dying phase is a sad and distressing problem. Delirium is associated with dissolution of autonomy and dignity, stigma of mental illness, and evaporation of the quality of the remaining life. The diagnosis of delirium should demand quick and aggressive management [33]. As with pain and other symptoms, the cause of delirium needs to be identified, and reversed if possible, although the etiology remains unclear in 50% of the cases. The most common causes of delirium are infection, organ failure, drug toxicity (including opioid neurotoxicity), dehydration, and electrolyte abnormalities. If a reversible cause is identified it should be removed if possible. In opioid-induced delirium, opioid rotation is a therapeutic option although the assessment of clinical response may be difficult in a short time frame. In the right clinical setting, withdrawal from alcohol and benzodiazepines needs to be considered and appropriately treated. Bladder distention in a setting of urinary retention is very distressing and insertion of a Foley catheter is very effective. Similarly, treatment of severe constipation can alleviate delirium. Uncontrolled pain should always be considered as a possible cause of delirium. Pharmacological treatment of delirium is provided by typical antipsychotics, atypical antipsychotics, and benzodiazepines. For intractable delirium, palliative sedation may be the only effective therapeutic intervention. The mainstay of

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the treatment of delirium remains typical antipsychotics with haloperidol being the drug of choice. Haloperidol has proven efficacy and a relatively safe profile. It is available for administration by different routes. Studies have shown that the typical antipsychotics are underutilized and only 17% of terminally ill patients with delirium receive them [32]. Starting doses of haloperidol are in the range of 0.5–5  mg given orally, intravenously, or subcutaneously with total daily doses rarely exceeding 20  mg. In severe cases of agitated delirium, haloperidol is used in conjunction with lorazepam, providing sedation and counteracting any extrapyramidal side effects of haloperidol. Chlorpromazine may also be used, administered as a singular agent or in combination with lorazepam [34, 35]. Haloperidol, though, has superior side-effect profile. An emerging alternative to the typical antipsychotics is a group of drugs named atypical antipsychotics like risperidone, quetiapine, olanzapine, and ziprasidone. They are reported to have less extrapyramidal side effects, although it is only at doses of more than 4.5 mg/day that haloperidol causes more side effects than the newer agents. Atypical antipsychotics can be used in severe cases refractory to typical antipsychotics, but well-designed studies confirming their superiority remain to be conducted. Benzodiazepines are considered to be first-line agents for treatment of delirium associated with seizures and alcohol withdrawal. They are frequently used in conjunction with haloperidol in agitated patients. The sedative properties of benzodiazepines can be used in refractory cases requiring sedation. Studies report that up to 30% of terminally ill patients have delirium resistant to treatment with antipsychotics [36]. Short-acting benzodiazepines like midazolam have been used as first-line agents for palliative sedation. The use of barbiturates and general anesthetics for the treatment of delirium is less common. They can be prescribed as a second-line agent for palliative sedation.

Dyspnea Like pain, dyspnea is a subjective experience involving both the physical and psychosocial domains. As the patient enters the terminal phase, it may not be possible or practical to address all of these factors. The aim of treatment changes to focus on the perception of breathlessness and associated anxiety, ensuring that the patient remains comfortable. Quickly reversible causes should be treated specifically. For example, bronchospasm and bronchial inflammation may abate with nebulized albuterol and oral or injectable corticosteroids. Performing a thoracentesis for a massive pleural effusion can provide quick and definitive relief, but the burden–benefit ratio must be weighed up. However, if death is imminent or a

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definitive treatment for the cause of dyspnea is not available, proper symptomatic treatment assures patients that they will be comfortable, regardless of the cause. Pharmacological intervention forms the mainstay of treatment although nondrug measures such as cool-air blowing on the face or a calming hand may still have a role [37]. Typical pharmacological regimens involve opioids, benzodiazepines, and oxygen [38]. Consideration may also be given to anticholinergic drugs when there are retained secretions contributing, and phenothiazines if very distressed. As the patient becomes progressively weaker, oral administration of medication may no longer be possible, and drugs are commonly given via the intravenous or subcutaneous route. The rectal route can be used, although suitable preparations do not exist for all drugs. Oxygen may be used for hypoxic patients, although the evidence of its efficacy is weak [39]. If the patient is unconscious, consideration to discontinue it can be made. As patients with dyspnea typically experience tachypnea and anxiety, it is believed that by reducing the respiratory rate and addressing the associated anxiety, the perception of breathlessness will also be reduced. Opioids act in variety of ways; essentially they can reduce the respiratory rate and reduce the level of anxiety. Morphine (or diamorphine in Britain) is used and is administered by intravenous or subcutaneous injection or infusion. The dose used depends on the previous oral requirements, although for an opioid-naïve patient, a suitable starting dose would be 10 mg morphine total dose daily. If the patient has been receiving opioids for pain, the dose can be increased to achieve the necessary reduction in the respiratory rate, to a level of 15 breaths per minute. This may require a dose increase of up to 50%. Nebulized morphine has been used in the palliative treatment of dyspnea with varying results. Until more positive evidence is forthcoming, this route of administration is not recommended. Benzodiazepines are useful when dyspnea is associated with anxiety or fear of suffocating. Lorazepam or midazolam via intravenous or subcutaneous injection/infusion are the drugs of choice. If using midazolam, starting doses of 5–10  mg may be given stat, followed by continuous infusions of 10–30  mg/24  h. Occasionally, lorazepam is given sublingually at a dose of 0.5–1 mg up to 4 times a day. The phenothiazine levomepromazine is anxiolytic and can be used for treating dyspnea associated with anxiety or agitation. A suitable starting dose would be 12.5 mg daily – subcutaneous intermittent doses or via subcutaneous continuous infusion (CSCI). It is not available in USA, where chlorpromazine could be used. No patient should die believing that they will suffer from uncontrollable dyspnea. Although opioid and sedatives are employed, the aim of treatment is to reduce the level of anxiety and improve the sensation of breathlessness whilst maintaining the patient’s level of consciousness. However, this may

not always be possible; indeed, as the patient becomes weaker, drowsiness may become more apparent. This should be explained clearly to the patients and their relatives/caregivers.

Retained Respiratory Secretions Patients approaching the terminal stages of life are often unable to clear their upper respiratory tract secretions, which lead to a condition known as “death rattle.” In clinical practice, this is a common symptom, occurring in up to 92% of dying patients. Clinical experience would suggest that most patients are unconscious when the death rattle is present, and it is, therefore, not possible to evaluate the benefit to the patient of the alleviation of this. However, it is has been suggested that terminal secretions may contribute to the development of dyspnea and terminal restlessness. No association has been demonstrated between the level of hydration and terminal secretions. The most apparent benefit of control of respiratory secretions is to minimize the distress of relatives and caregivers. The treatment of this condition can involve positional changes and pharmacological intervention. Difficult cases may require suction. Not all patients will be suitable for positional changes, which involve moving to positions to facilitate secretion drainage. Suction may be unpleasant and the patient may require a subcutaneous dose of midazolam 2.5–5 mg prior to the procedure. Nebulized saline and acetylcysteine may help patients with viscous secretions. The main treatment of terminal secretions involves the antimuscarinic drugs. One important point to remember about these agents is that in general, they will not control or diminish secretions that are well established; treatment must be started as soon as the symptoms become apparent. In the US, the agents used include topical scopolamine (patches q72h, or gel 0.25–0.5 mg q8–12h, applied to the skin behind the ear or on the chest), hyoscyamine 0.125 mg sublingually q8h, and diphenhydramine 10–50 mg IM q4–6h p.r.n. In the UK and Australia, scopolamine is known as hyoscine hydrobromide, while other agents include hyoscine butylbromide and glycopyrrolate. It is somewhat surprising, given the prevalence of retained secretions, that there is a paucity of evidence to support the superiority of any of these drugs. One small study concluded that there was no difference between the three [40]; however, glycopyrrolate is almost 1.5 times more potent than hyoscine/scopolamine in preventing salivary secretions, a component of terminal secretions, and was superior in a subsequent study [41]. As hyoscine/scopolamine and glycopyrrolate are both quaternary ammonium compounds, neither crosses the blood brain barrier easily and so they are devoid of the sedative (or antiemetic) effects associated with hyoscine butylbromide. All three may be administered subcutaneously by injection or via CSCI.

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Seizures Seizures sometimes occur in the terminal phase. They are usually a consequence of an intracerebral mass. From all patients with primary brain tumors, 20–45% present with seizures and another 15–30% suffer from seizures during the progression of the tumor. The rate of seizures in patients with brain metastasis is around 30%, and among patients with leptomeningeal carcinomatosis, the prevalence of seizure is 15%. Other causes of seizure include metabolic disarrangement (e.g., hypercalcemia, hypoglycemia), hypoxia, CNS infection, withdrawal from medication, drugs of abuse or alcohol, and medication side effects. For patients on chronic antiseizure therapy who are at the end of life, careful evaluation of the necessity to continue anticonvulsant use is required. In cases of anticonvulsants used strictly for seizure prophylaxis, discontinuation of those drugs when the patient loses the capacity to swallow is recommended. When it is clinically indicated to continue anticonvulsant use, the physician may need to consider using different medication in addition to changing the route of administration. Although the rectal absorption varies highly from one person to another, the rectal route of administration is the preferred route for anticonvulsants when the patient cannot swallow. Valproic acid, carbamazepine, and phenobarbital can be continued but given as rectal preparations. There is no good evidence to support the rectal administration of phenytoin and in most circumstances it will have to be substituted with a rectal preparation of valproic acid or carbamazepine. For seizures or status epilepticus in terminal patients, the treatment of choice is diazepam administered rectally as a rapidly absorbed gel at doses of 10, 15, or 20 mg [42]. Lorazepam can be used as well, but because of its limited bioavailability, rectal doses need to be 2–4 times higher than the intravenous doses. Midazolam and phenobarbital via continuous intravenous or subcutaneous infusion can be used in refractory cases, while propofol may even be needed occasionally.

Hemorrhage Terminal hemorrhage does not occur commonly, but it is one of the most distressing end-of-life complications for the patients and their families. Risk factors for major terminal hemorrhage are: thrombocytopenia, large head and neck tumors, large centrally located lung cancers, hematological malignancies, metastatic liver disease with insufficient coagulation, and patients on anticoagulants. Hemorrhage in patients with advanced cancer most frequently occurs at the site of malignancy, with carotid artery, femoral artery, and pulmonary vessels being most often affected. Gastrointestinal hemorrhage is also frequent. Specific risk factors for carotid

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artery rupture in patients with head and neck tumors have been identified. They include radiation therapy to neck, surgery (radical neck dissection), poor postoperative healing, visible arterial pulsation, pharyngocutaneous fistulae, and fungating tumor surfaces. Besides identifying the patients at high risk for terminal hemorrhage, it is important to assess the quality of life and prognosis of each patient. In some cases, general resuscitative measures with fluid and blood product transfusion may be appropriate. Selected patients with several months life expectancy are frequently treated with prophylactic interventions like surgical ligation of the artery, local radiotherapy, or stenting. In patients with persistent minor bleeds, fibrinolytic inhibitors such as tranexamic acid have been used both orally and topically [43], although should be avoided in renal tract hemorrhage because of possible “clot colic.” In catastrophic bleeds, the measures at the last few days of life are more palliative in nature. The appropriate actions include: apply pressure to external bleeding if possible, use of dark towels, placement of the patient in lateral position, use suctioning if possible, for hospitalized patients, ensure close nursing-staff observation, and provide psychological support for patient and their family [44]. Owing to the severely distressing nature of having a massive external bleed, palliative sedation is often considered. The aim of this treatment is to alleviate suffering and enormous emotional distress when they are present, and not to hasten death. Literature supports the use of benzodiazepines [44], with reports of midazolam being preferred over the rest of benzodiazepines. IV morphine may also have a role [45], especially if there is acute pain or other symptoms not controlled with benzodiazepines. It may also help to relieve the panic as the patient dies, and by dropping the blood pressure, it may also reduce the rate of bleeding.

Parenteral Administration of Drugs As the condition of a patient with far advanced cancer deteriorates, parenteral administration of medications becomes necessary in many cases. Reasons include persistent nausea and vomiting, severe dysphagia (including head and neck or esophageal cancer), patient too weak for oral drugs, reduced conscious level, and poor alimentary absorption due to intestinal obstruction. It may also be considered when there are doubts about or problems with compliance. The route that is used depends on the setting. At MSKCC in New York, approximately 25% of the cancer deaths occur each year while patients are being treated in Memorial Hospital. Most have a Mediport or other vascular access device so that the IV route is easy to use. In Britain and Australia, the culture is to generally avoid the intravenous route at the end of life,

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4  Palliative Care: End-of-Life Symptoms

and parenteral medications are given either by intermittent subcutaneous injection or via continuous subcutaneous infusion (CSCI). An audit of PCU in the UK found that approximately 30 drugs were being given subcutaneously. CSCI via syringe driver has advantages over regularly scheduled intermittent injections, of increased patient comfort and convenience and maintaining steady plasma levels. CSCI is particularly convenient for patients at home, delivered by a syringe driver that is refilled each day by a visiting nurse. Syringe drivers are quite inexpensive, costing around half the price of a CADD PCA pump. It is also common practice to use syringe drivers in inpatient PCUs so much that recently it was commented that they are overused, like some palliative care “last rite” [46]. Other alternatives to IV and SC include transdermal, although only a handful of drugs can be given this way (fentanyl, diclofenac, lidocaine, scopolamine), and rectal, although it is not always available or acceptable and absorption may be unreliable. Intramuscular injections should be avoided because they are painful especially in cachectic patients. Like any technology, using a syringe driver raises practical issues and staff need to be trained in setting up a driver and troubleshooting. Compatibility of drugs mixed together and pharmaceutical issues relating to the stability of solutions are other issues. The mixing of drugs prior to administration, unless specifically mentioned in the product license, constitutes “off-label” prescribing. The possibility exists for two drugs chemically interacting to form a new, potentially toxic compound, so is not recommended by the authors.1 The Palliative Care Matters site recommends that no more than three drugs be combined in the same driver and that a compatibility database or chart needs to be consulted. As a result, more than one driver may be needed in some cases. Potential pharmaceutical problems include degradation of the drug(s) and therefore reduced efficacy and precipitation and/or crystallization. The degradation rate may be increased by other drugs which alter the pH of the mixture. Crystallization can occur either through formation of an insoluble product of drug interaction or because a drug alters the pH of the solution rendering a second drug insoluble. The more drugs mixed, the greater is the potential for interaction. Drugs that have a high or low pH in solution are more likely to interact with others. Data from compatibility studies are only available for a few combinations [47]. Turbidometers detect crystallization or precipitation by optical means. HPLC methods determine drug stability as, for example, the percentage of original drug present after 24 h. Simple visual inspection of a

 For clinicians wishing to mix drugs in syringe drivers, there is a searchable database of drug mixtures for syringe drivers at the website of Palliative Care Matters, http://www.pallcare.info (accessed 15/11/09).

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mixture before and during administration will detect most problems of crystallization or precipitation, although fine particles may not be visible to the naked eye. However, some combinations have been shown to interact without any visible change, e.g., dexamethasone, which inactivates glycopyrronium without causing precipitation. It is important to note that neither turbidometry nor HPLC will detect toxic compounds, and therefore are not tests of safety.

Nursing Aspects of End-of-Life Symptoms When someone is dying, nursing care involves not only attention to the needs of the patient but also attention to the needs of the family. How well a patient’s symptoms are controlled in the last few days or hours of life is what the family will remember. Inadequate control of symptoms invariably leaves them feeling angry, frustrated, and guilty [48]. Similar feelings can be experienced by the staff with the added burden of responsibility of not having done enough [49]. Most of us who have cared for dying patients over time remember at least one or two situations where symptoms were not adequately managed. Those patients are not forgotten. I failed to care for him properly because I was ­ignorant – you cannot practice what you do not know There are several areas of importance when caring for the dying all of which are integral to the nursing aspects of symptom management at end of life [50]. They include: 1. Clinical competence – adequate training and experience of the nurse in the assessment and management of pain, dyspnea, excess secretions, delirium, nausea, and other symptoms prevalent at the end of life. 2. Compassion – demonstrating that what is happening to the patient is critically important not only to the patient and family but also to the nurse and others caring for him. 3. Comfort – working with the team to identify and address the physical, psychosocial, spiritual, and existential issues of the patient are all part of the nurses role in symptom control at the end of life. 4. Communication – both verbal and nonverbal – identifying the patient’s needs and demonstrating to the patient and family care and concern. 5. Family cohesion and integration – facilitating the support of family members for one another so that the feeling of burden is lessened 6. Consistency and perseverance – dying patients can have a fear of abandonment especially when their symptoms are difficult to control; they have a prolonged dying phase, and/or they feel their family is being burdened by their ongoing existence. Nurses are a consistent figure whose presence is reassuring to the patient and family – they will

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be there – the symptoms will be managed – they are not on their own 7. Equanimity and “presence” – nurses who display composure in the presence of a dying patient convey reassurance to the patient and family. A nurses’ anxiety can undermine a patient’s sense of security. Self-awareness of one’s own emotional state is important – anxiety, when recognized, needs to be acknowledged and controlled before entering the patient’s room.

Symptom Assessment by the Nurse in those Close to Death Common physical symptoms experienced by people who are actively dying at the end of a prolonged and debilitating illness include – pain from illness and or/immobility, dyspnea, drowsiness, confusion, disorientation, agitation/restlessness/ delirium, weakness and fatigue, fever, dry mouth, noisy and moist breathing, gurgling sounds in the back of the throat from not being able to swallow saliva, incontinence, and skin breakdown due in part to poor nutrition and immobility. The nurse is responsible for identifying, reporting, and documenting symptoms that are causing distress to the patient or family, for implementing the prescribed treatment plan, and for the ongoing assessment and monitoring of the treatment plan’s effectiveness. In patients close to death, vigilance and speedy action on the nurses’ part to both prevent and relieve distress is critical. The nurse at the bedside has the responsibility of being the embodiment of the team in end-of-life care [51–53]. In addition, there are common psychosocial and spiritual symptoms, which occur in the person who is actively dying and increase their distress. Unless these symptoms are recognized and addressed, physical symptoms such as pain and dyspnea may be difficult to control at the end of life. These include – fear of the dying process, fear of abandonment either by God or their loved ones, fear of the unknown, regret for mistakes made, and fear of being forgotten – of not having left a meaningful “imprint” in the world. Some patients experience “visions” or talk to relatives long since dead. How these are interpreted – either as a derangement that needs treating pharmacologically or as a normal part of the dying process – varies. Other signs of the normal dying process frequently include loss of interest in eating and drinking, social withdrawal, decreased attention span, decreasing ability to concentrate, sometimes a surge of energy within 24-h of death, and a gradual loss of consciousness. It is the nurses’ responsibility to normalize this process for the patient and family and to intervene when evidence of distress is seen and to involve the appropriate team members, for example, chaplaincy or social work.

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When the patient is close to death and nonverbal, assessment of individual symptoms can be difficult. Symptomatic patients who are dying frequently have multiple symptoms further complicated by the high prevalence of delirium at the end of life. In dying nonverbal patients, behaviors that indicate distress include restlessness, moaning when moved, guarding, crying out, combativeness when touched, or a furrowed brow. Nursing assessment includes recognizing what symptoms have been present prior to the immediacy of the dying process, and what other factors might be contributing to the patient’s current signs of distress. If, for example, a patient did not previously have pain but appears now to be in pain, the nurse would rule out other possible causes of distress such as a full bladder, decubitus ulcers, and/or delirium. Once an assessment of the probable cause of the distress has been made, the nurse/physician team decides on interventions, which are then implemented, usually by the nurse. A time frame is given for the intervention to be effective and if not effective the assessment process starts again to try and identify what was missed in the initial assessment. Supporting and educating the family about what to expect as death draws near are essential nursing components of symptom management at end of life and in alleviating family distress. This is never more important than when the patient is being cared for at home. Signs and symptoms of imminent death such as decreased urine output, cold and mottled extremities, altered breathing pattern, respiratory congestion, noisy breathing with rattling secretions (“death rattle”) are explained and normalized for the family and interventions, both pharmacological and nonpharmacological, are implemented as needed. Reassurance and educating the family about what to expect, role modeling and comforting, paying attention to culture and religious beliefs are all part of supportive nursing interventions in managing symptoms at end of life. These interventions can make it easier for the family to remain by the bedside and be a comforting presence for the patient and for each other.

General Nursing Measures to Improve a Patient’s Comfort at End of Life Review the patient’s medication regimen with the physician or nurse practitioner, discontinuing nonessential medications for symptom management and using an alternate route of drug administration if a patient is no longer able to use the oral route or is excessively burdened by taking medication in pill or liquid form. Selecting the alternate route as appropriate for the patient’s site of care: Commonly used alternate routes include rectal, transdermal, intravenous, or subcutaneous infusions. Explain to the family why each change is being made. If familiar medications are discontinued without explanation, the family can see this as a lack of care and caring.

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Understanding family concerns about not feeding the patient or giving them artificial hydration is extremely important. Religious overtones may be present or the patient may have a past history of deprivation. Not addressing these concerns can result in major distress for the family and conflict with the medical team on what is “basic” and humane care at the end of life. Monitor the patient for parameters that make a difference to the dying – comfort without signs of distress. Discontinue monitoring parameters that are not important in an actively dying patient such as blood pressure and pulse. Explain to the family that you are monitoring the patient closely with a focus on what will make a difference – that is – patient comfort. Some families, however, need the vital signs to be taken – as a familiar parameter of what is happening and the patient’s closeness to death. Avoid oral suctioning, if at all possible, or keep to a minimum. Use pharmacologic agents to decrease secretions as previously described. Elevate the head of the bed if indicated. Such a position may lessen noisy breathing – of such distress to families. Provide oral care with soft applicators. This should be done frequently and is something that family members usually feel comfortable in doing and also comforted by the doing. A salt and soda solution can be used. Vaseline or other lubricants can be placed on the patient’s lips to prevent cracking and caking. If the patient gives evidence of any sign of distress if sponged or turned, medicate prior to the activity. Have the family participate in patient care with the nurse if they would like to. Use a turn sheet and have an adequate number of people present to turn the patient gently always focusing on comfort and watching for signs of distress. Perhaps turn the patient every 4-h instead of every 2 h as may have be an earlier part of their nursing care. Explain to the family why this change has been made. Without this explanation the family can see this as a sign of lack of care and caring. Pay attention to the patient’s skin especially the skin folds – keep clean and dry. The family is usually comforted when they see the patient being cared for with “respect and dignity.” The patient being clean and with fresh sheets is seen as a sign of respect by family members. Paying attention to the patient’s bowels and bladder is important if incontinent adult diapers can be used. Sometimes, a Foley catheter is indicated especially if the patient is being cared for at home to lessen caregiver burden. If a patient is febrile, administer prescribed acetaminophen suppositories on an around-the-clock basis for comfort. Other more general aspects of ongoing nursing assessment which contribute to symptom control and the comfort of dying patients include recognition that although earlier in the disease process a clear mind may take precedence for the patient over freedom from pain; as death draws near,

sedation may be welcomed, and the relief of pain and other symptoms assume prime importance. This is the patient’s choice. In addition, specific objects at the bedside can provide comfort to the patient (e.g., family photos; children’s drawings, special objects, loved ones sitting nearby) and decrease anxiety and the sense of aloneness. Having lighting at a level that the patient prefers, for example, a dim light on at night vs. darkness, can decrease anxiety and thus make a difference to comfort. Finally, certain sounds can comfort a patient at end of life (e.g., music, family chatting nearby, TV or radio in the background, someone reading aloud, silence).

Expecting the Unexpected: Contingency Planning in Care of the Dying As previously outlined, ongoing education of the family by the nurse about what is happening, what to expect as life draws to a close, and reinforcing goals of care are important nursing aspects of end-of-life care and symptom management. Anticipating situations that may develop during the dying process especially if a patient is being cared for at home can make the difference between a peaceful death and one that is filled with panic, guilt, and subsequent difficult bereavement for the family. With thought, most situations that can occur during a particular individual’s dying process can be anticipated. These include progressive dyspnea, escalating pain, delirium, nausea and vomiting, pulmonary congestion, noisy secretions, inability to take oral medication, and the loss of bowel and bladder function. Especially, when a patient is dying in the home, a plan needs to be in place in case these contingencies occur. For example, appropriate medications that can be given by a nonoral route should be available in the house to deal with agitated delirium, escalating pain, and dyspnea. Many home hospice programs provide what they call a “comfort pack,” which includes these medications so that they are readily available in case of patient need. Examples of medications included in the comfort pack are: liquid haloperidol, atropine drops, lorazepam tablets, liquid morphine, prochlorperazine suppositories, chlorpromazine suppositories, and acetaminophen suppositories. If the patient is at risk for having seizures, then lorazepam, phenytoin, or valium suppositories may be included. These comfort packs are usually sealed and placed in the refrigerator, the content only to be used when directed to do so by the nurse. A Foley catheter should also be available in the house, in case urinary retention becomes an issue or incontinence results in difficulty for the family caring for the patient. In summary, the role of nursing in relieving suffering in those close to death includes: providing effective pain and symptom management, addressing the psychosocial and spiritual needs of the patient and family, incorporating cultural

42

values and attitudes into the plan of care, supporting those who are experiencing loss, grief, and bereavement (patient, family, and staff), using therapeutic communication skills, and facilitating collaborative practice through team work.

References 1. Sepulveda C, Marlin A, Yoshida T, Ullrich A. Palliative Care: the World Health Organization’s global perspective. J Pain Symptom Manage 2002;24:91–6. 2. Higgs R. The diagnosis of dying. J R Coll Physicians Lond 1999;33:110–2. 3. Gibbins J, McCoubrie R, Alexander N, Kinzel C, Forbes K. Diagnosing dying in the acute hospital setting–are we too late? Clin Med 2009;9:116–9. 4. Ellershaw J, Ward C. Care of the dying patient: the last hours or days of life. BMJ 2003;326:30–4. 5. Quill TE, Arnold R, Back AL. Discussing treatment preferences with patients who want “everything”. Ann Intern Med 2009;151:345–9. 6. Ellershaw J. Care of the dying: what a difference an LCP makes! Palliat Med 2007;21:365–8. 7. Bookbinder M, Blank AE, Arney E, et  al. Improving end-of-life care: development and pilot-test of a clinical pathway. J Pain Symptom Manage 2005;29:529–43. 8. Jarabek BR, Jama AA, Cha SS, Ruegg SR, Moynihan TJ, McDonald FS. Use of a palliative care order set to improve resident comfort with symptom management in palliative care. Palliat Med 2008;22:343–9. 9. Glare PA, Sinclair CT. Palliative medicine review: prognostication. J Palliat Med 2008;11:84–103. 10. Bozcuk H, Koyuncu E, Yildiz M, et al. A simple and accurate prediction model to estimate the intrahospital mortality risk of hospitalised cancer patients. Int J Clin Pract 2004;58:1014–9. 11. Lau F, Downing GM, Lesperance M, Shaw J, Kuziemsky C. Use of palliative performance scale in end-of-life prognostication. J Palliat Med 2006;9:1066–75. 12. Inagaki J, Rodriguez V, Bodey GP. Proceedings: causes of death in cancer patients. Cancer 1974;33:568–73. 13. Lichter I, Hunt E. The last 48 hours of life. J Palliat Care 1990;6:7–15. 14. Goncalves JF, Alvarenga M, Silva A. The last forty-eight hours of life in a Portuguese palliative care unit: does it differ from elsewhere? J Palliat Med 2003;6:895–900. 15. Turner K, Chye R, Aggarwal G, Philip J, Skeels A, Lickiss JN. Dignity in dying: a preliminary study of patients in the last three days of life. J Palliat Care 1996;12:7–13. 16. Fainsinger R, Miller MJ, Bruera E, Hanson J, Maceachern T. Symptom control during the last week of life on a palliative care unit. J Palliat Care 1991;7:5–11. 17. Grond S, Zech D, Schug SA, Lynch J, Lehmann KA. Validation of World Health Organization guidelines for cancer pain relief during the last days and hours of life. J Pain Symptom Manage 1991;6:411–22. 18. Conill C, Verger E, Henriquez I, et al. Symptom prevalence in the last week of life. J Pain Symptom Manage 1997;14:328–31. 19. Ellershaw J, Smith C, Overill S, Walker SE, Aldridge J. Care of the dying: setting standards for symptom control in the last 48 hours of life. J Pain Symptom Manage 2001;21:12–7. 20. Nauck F, Klachik E, Ostgathe C. Symptom control during the last three days of life. Eur J Pall care 2001;10:81–4. 21. Lickiss JN. Approaching cancer pain relief. Eur J Pain 2001;5 Suppl A:5–14. 22. Ellershaw JE, Kinder C, Aldridge J, Allison M, Smith JC. Care of the dying: is pain control compromised or enhanced by continuation

P. Glare et al. of the fentanyl transdermal patch in the dying phase? J Pain Symptom Manage 2002;24:398–403. 23. Cherny N, Ripamonti C, Pereira J, et al. Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol 2001;19:2542–54. 24. Thomas J, Karver S, Cooney GA, et  al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med 2008;358:2332–43. 25. Mercadante S. Pathophysiology and treatment of opioid-related myoclonus in cancer patients. Pain 1998;74:5–9. 26. Daeninck PJ, Bruera E. Opioid use in cancer pain. Is a more liberal approach enhancing toxicity? Acta Anaesthesiol Scand 1999;43: 924–38. 27. Eisele JH, Jr., Grigsby EJ, Dea G. Clonazepam treatment of myoclonic contractions associated with high-dose opioids: case report. Pain 1992;49:231–2. 28. Portenoy RK, Sibirceva U, Smout R, et al. Opioid use and survival at the end of life: a survey of a hospice population. J Pain Symptom Manage 2006;32:532–40. 29. Sulmasy DP, Pellegrino ED. The rule of double effect: clearing up the double talk. Arch Intern Med 1999;159:545–50. 30. Mercadante S, Intravaia G, Villari P, Ferrera P, David F, Casuccio A. Controlled sedation for refractory symptoms in dying patients. J Pain Symptom Manage 2009;37:771–9. 31. Teno JM, Clarridge BR, Casey V, et  al. Family perspectives on end-of-life care at the last place of care. JAMA 2004;291:88–93. 32. Breitbart W, Alici Y. Agitation and delirium at the end of life: “we couldn’t manage him”. JAMA 2008;300:2898–910; E1. 33. Macleod AD. The management of delirum in hospice practice. Eur J Palliat Care 1997;4:116–20. 34. McIver B, Walsh D, Nelson K. The use of chlorpromazine for symptom control in dying cancer patients. J Pain Symptom Manage 1994;9:341–5. 35. Breitbart W, Marotta R, Platt MM, et  al. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 1996;153:231–7. 36. Rietjens JA, van Zuylen L, van Veluw H, van der Wijk L, van der Heide A, van der Rijt CC. Palliative sedation in a specialized unit for acute palliative care in a cancer hospital: comparing patients dying with and without palliative sedation. J Pain Symptom Manage 2008;36:228–34. 37. Ben-Aharon I, Gafter-Gvili A, Paul M, Leibovici L, Stemmer SM. Interventions for alleviating cancer-related dyspnea: a systematic review. J Clin Oncol 2008;26:2396–404. 38. Cuervo Pinna MA, Mota Vargas R, Redondo Moralo MJ, Correas MA. Pharmacologic intervention for cancer-related dyspnea. J Clin Oncol 2008;26:4225; author reply 6. 39. Currow DC, Agar M, Smith J, Abernethy AP. Does palliative home oxygen improve dyspnoea? A consecutive cohort study. Palliat Med 2009;23:309–16. 40. Hughes A, Wilcock A, Corcoran R, Lucas V, King A. Audit of three antimuscarinic drugs for managing retained secretions. Palliat Med 2000;14:221–2. 41. Hugel H, Ellershaw J, Gambles M. Respiratory tract secretions in the dying patient: a comparison between glycopyrronium and hyoscine hydrobromide. J Palliat Med 2006;9:279–84. 42. Dreifuss FE, Rosman NP, Cloyd JC, et al. A comparison of rectal diazepam gel and placebo for acute repetitive seizures. N Engl J Med 1998;338:1869–75. 43. Dean A, Tuffin P. Fibrinolytic inhibitors for cancer-associated bleeding problems. J Pain Symptom Manage 1997;13:20–4. 44. Nauck F, Alt-Epping B. Crises in palliative care–a comprehensive approach. Lancet Oncol 2008;9:1086–91. 45. Currow D, Clark K. Emergencies in palliative and supportive care. Oxford: Oxford University; 2006:50–2.

4  Palliative Care: End-of-Life Symptoms 46. O’Neill WM. Subcutaneous infusions–a medical last rite. Palliat Med 1994;8:91–3. 47. Grassby PF, Hutchings L. Drug combinations in syringe drivers: the compatibility and stability of diamorphine with cyclizine and haloperidol. Palliat Med 1997;11:217–24. 48. Coyle N. Suffering in the first person. In: Ferrell BR, ed. Suffering. Boston: Jones and Bartlett; 1996:44–54. 49. Ferrell BR, Coyle N, eds. The nature of suffering and the goals of nursing. Oxford: Oxford University; 2008. 50. Cassem NH. The dying patient. In: Cassem NH, Stern TA, Rosenbaum JF, Jellinek MS, eds. Massachusetts General Hospital handbook of

43 General Hospital Psychiatry. 4th ed. St Louis: Mosby-Year Book; 1997:605–36. 51. Speck P, ed. Teamwork in palliative care – fulfilling or frustrating. Oxford: Oxford University; 2006. 52. Ingham J, Coyle N. Teamwork in end-of-life care. In: Clark D, Hockley J, Ahmedzai S, eds. A nurse physician perspective on introducing physicians to palliative care concepts. New Themes in Palliative Care, Buckingham: Open University; 1997:255–74. 53. Coyle N. Introduction to palliative nursing. In: Ferrell BR, Coyle N, eds. Textbook of palliative nursing, 2nd ed. Oxford: Oxford University; 2006:7.

Chapter 5

Supportive Care in Elderly Cancer Patients Matti S. Aapro

There is not one precise definition of the age of “geriatric” patients, although it is widely accepted that after the age of 70, comorbidities become more frequent and organ function decreases. Thus, this is the age limit that is suggested to be used in future studies [1]. While cancer and cancer treatment are one of the prime causes of disability in older individuals, not only of mortality, the adverse outcomes of inadequate dosing and of lack of supportive care in both curative and palliative treatments have been demonstrated in a number of treatment settings [2]. The challenges of aging, comorbidities, and polypharmacy require special considerations for supportive care in the elderly, as outlined in this chapter.

Evaluation of the Elderly Patient The comprehensive geriatric assessment (CGA) developed by geriatricians is a multidisciplinary evaluation of the older patient encompassing a number of essential clinical domains (Table  1) [3], which is superior to simple assessments like performance status (PS) [4]. It can reliably identify patients with a short life expectancy, and it allows for the correction of one or many clinically relevant issues, thus forming an essential basis for adequate support of many elderly patients who will undergo cancer therapy (Table 5.1). However, as the CGA is a complex tool that is not ­reliably predictive of cancer treatment toxicity, ongoing studies are trying to define a screening tool and improve on its predictive value for the use of cytotoxic therapy in daily practice. It should nevertheless be emphasized that this tool, along with other evaluations, provides an important method to follow a patient who is to undergo a major surgical procedure. Poor health in relation to disability (assessed using the instrumental activities of daily living (IADL)), fatigue, and M.S. Aapro (*) Clinique de Genolier, Multidisciplinary Oncology Institute, 1 route du Muids, 1272, Genolier, Switzerland e-mail: [email protected]

PS were associated with a 50% increase in the relative risk of postoperative complications. Multivariate analysis identified moderate/severe fatigue, a dependent IADL, and an abnormal PS as the most important independent predictor of postsurgical complications. Disabilities assessed by the activities of daily living (ADL), IADL, and PS were associated with extended hospital stays [5].

Depression and the Elderly Cancer Patient Depressive disorders are frequent in cancer patients and in elderly people, but the specificities of depression in elderly cancer patients remain a largely unexplored field of research [6]. Depression, in the elderly as well as the younger cancer patients, is at risk of being underrecognized and untreated. As recently reviewed, in clinical practice, the assessment and treatment of depressive symptoms in elderly cancer patients are largely based on data obtained from the general medical population [7]. However, in spite of the paucity of randomized placebo-controlled trials, there is evidence that depressive disorders in cancer patients can be successfully treated with antidepressants when such drugs are needed [8]. Elderly cancer patients differ from younger ones in their tolerance to some of the side effects of antidepressant agents that need to be introduced with caution. Obviously, presently available data on some potentially important drug interactions, like that of some selective serotonin-reuptake inhibitors and tamoxifen need to be taken into account [9].

Pain Control in the Elderly The elderly population will often suffer from noncancerrelated pain due to comorbid conditions such as arthritis or osteoporotic fractures. This makes the evaluation of pain even more complex in the elderly than in younger patients. Not all tools for the assessment of pain are equally reliable in

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_5, © Multinational Association for Supportive Care in Cancer Society 2011

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M.S. Aapro

Table 5.1  Comprehensive geriatric assessment DOMAIN

Instrument to assess

Dependency Dependency

Activities of daily living (ADL) Instrumental activities of daily living (IADL) Geriatric Depression Scale (GDS) Mini-mental state examination (MMSE) Charlson Comorbidity Index (CCI) and Cumulative Illness Rating Scale-Geriatric (CIRS-G) Mini nutritional assessment (MNA) and Body Mass Index

Depression Cognition Comorbidity

Nutrition

Polypharmacy Geriatric syndromes Mobility/falls Timed-up-and-go-test / Tinetti test Source: modified from Extermann [3]

the elderly, and it is suggested that numerical rating scales, pictorial pain scales, and verbal descriptor scales are more reliable than visual analog scales [10]. Analgesics, as described in this book (Chap. 2), should be used with care in the elderly as the elderly are generally more susceptible to changes in doses, to drug side effects, and they receive many drugs that may affect the metabolism of some pain-relieving agents. However, this should not deter the use of analgesics, in particular opioids, in the treatment of elderly patients who suffer from cancer-related pain [11]. Particular attention should be paid to the use of nonsteroidal anti-inflammatory drugs that often decrease the renal function. Another issue is that somnolence, dizziness, cognitive function, and gait impairment are often seen in the elderly who started on analgesics, and this can lead to falls and fractures.

often receive abbreviated courses of daily G-CSF and consequently obtain a reduced level of febrile neutropenia protection. Prospective studies are, however, needed to validate the importance of delivering the full dose intensity of standard chemotherapy regimens, with G-CSF support where appropriate, across a range of settings. These studies should also incorporate the prospective evaluation of risk stratification for neutropenia and its complications, including patient’s age [14].

Undernutrition: A Cause of Unexpected Toxicities The clinical and biological factors of the elderly cancer patients that can lead to decreased treatment tolerance and increased need of support include nutritional aspects. Tumoral cachexia (molecular and physiological) and undernutrition are detailed elsewhere in this volume (Chap. 21). Malnutrition is observed in a third to two thirds of ­hospitalized or institutionalized elderly persons. A comprehensive screening tool for assessment of nutritional status is needed, but guidelines for the elderly are basically nonexistent [15]. If malnutrition is suggested by screening tests like the one included in the CGA, conventional nutritional assessment is recommended before treatment is planned [16]. The most important factor related to undernutrition is the albumin level of the patient, which is a determinant of toxicity for chemotherapy as well as for molecularly targeted agents, as volume of distribution of many drugs is highly dependent on its level [17, 18].

Neutropenia

Nausea and Vomiting

Guidelines on the use of white blood cell growth factors (Chap. 18) recognize older individuals above the age of 65 as a group at high risk [12], confirming a previous position paper of the European Organization for Research and Treatment of Cancer (EORTC) in which we concluded that increasing age is not, in itself, a contraindication to cancer chemotherapy [13]. However, the risk of development of febrile neutropenia may contribute to a reluctance to administer chemotherapy in the elderly patient population. Sufficient evidence allows us to affirm that prophylactic granulocyte colony-stimulating factor (G-CSF) reduces the incidence of chemotherapy-induced neutropenia, febrile neutropenia, and infections in elderly patients receiving myelotoxic chemotherapy for several tumor types. An agent of interest for the elderly population is pegfilgrastim, which is administered in a single injection, instead of repeated administrations like filgrastim or lenograstim. Accumulating data from “real-world” clinical practice settings indicate that patients

Elderly patients are somewhat less prone to nausea and vomiting related to cancer therapy but guidelines do not indicate that they can or should be treated preventatively in a different manner from younger patients as documented in this book (Chap. 24). Some specific problems related to these patients are an increased risk of toxicity from antiemetics due to an age-related decrease in organ function, use of polypharmacy with increased risk of drug–drug interactions and due to comorbidity (hypertension, cardiac issues (including the QTc interval on the electrocardiogram, a cause of concern for registration authorities), diabetes (which can be decompensated by corticosteroids given as antiemetics). Elderly patients have a higher risk of constipation and electrolyte disturbances than younger patients. Compliance needs to be carefully evaluated, particularly in patients with a high risk of noncompliance, such as the elderly with dementia and impaired vision [19].

5  Supportive Care in Elderly Cancer Patients

Osteopenia and Osteoporosis and Bone Metastases Osteopenia and osteoporosis are frequent in the elderly, both in females and males. By definition, osteoporosis is associated with an increased incidence of fractures, but osteopenic patients being the majority, the majority of fractures actually occur in such patients. Age-related osteoporotic fractures result not only in an increase in morbidity for elderly patients, but also in a decreased survival and an increase in the consumption of scarce health resources. In addition to the prevalent osteoporotic status, bone metastases cause considerable morbidity, particularly in the elderly population, including pain, impaired mobility, hypercalcemia, pathologic fractures, spinal cord or nerve root compression, and bone marrow infiltration. Besides exercise and use of calcium and ­vitamin  D, bisphosphonates are recommended for these patients, with or without osteoporosis. Several guidelines have been put forward [20, 21], and some address specifically the elderly cancer patient [22], and will need to be updated with the recent registration of denosumab for osteoporosis and in certain conditions for cancer patients [23, 24]. Besides their effect on delaying skeletal-related events in the setting of metastatic disease to the bones, zoledronic acid, ibandronate, and pamidronate can effectively contribute to relieving metastatic bone pain. Bisphosphonates have also been discussed as agents which might have an anticancer effect of their own, which would make them even more indicated for the elderly [25]. Creatinine clearance should be monitored in every patient receiving ibandronate or zoledronic acid. The assessment and optimization of hydration status is recommended especially in elderly patients who are often dehydrated. Due to the risk from osteonecrosis of the jaw, routine oral examination and treatment of dental ­problems by a dental team is recommended before use of bisphosphonates or denosumab.

Conclusion Supportive care in the elderly patient is based on the same principles as for younger patients. As older patients can have serious problems related to side effects that are considered of minor or modest importance in younger patients (like ­diarrhea or drowsiness), the use of any drug needs special precaution. A major topic of supportive care in the elderly, social support has not been addressed as it depends too much on specificities of the various health care systems.

47

References 1. Pallis AG, Fortpied C, Wedding U, et al. EORTC elderly task force position paper: approach to the older cancer patient. Eur J Cancer. 2010; 46:1502–1513. 2. Dixon DO, Neilan B, Jones S, et  al. Effect of age on therapeutic outcome in advanced diffuse histocytic lymphoma: the Southwest Oncology Group experience. J Clin Oncol. 1986; 4:295–305. 3. Extermann M, Aapro M, Bernabei R, et al. Task Force on CGA of the International Society of Geriatric Oncology. Use of comprehensive geriatric assessment in older cancer patients: recommendations from the task force on CGA of the International Society of Geriatric Oncology (SIOG). Crit Rev Oncol Hematol. 2005; 55:241–252. 4. Repetto L, Fratino L, Audisio RA, et  al. Comprehensive geriatric assessment adds information to Eastern Cooperative Oncology Group performance status in elderly cancer patients: an Italian Group for Geriatric Oncology Study. J Clin Oncol. 2002; 20:494–502. 5. PACE participants, Audisio RA, Pope D, Ramesh HS, et al. Shall we operate? Preoperative assessment in elderly cancer patients (PACE) can help. A SIOG surgical task force prospective study. Crit Rev Oncol Hematol. 2008; 65:156–163. 6. Spoletini I, Gianni W, Repetto L, et al. Depression and cancer: an unexplored and unresolved emergent issue in elderly patients. Crit Rev Oncol Hematol. 2008; 65:143–155. 7. Fisch M. Treatment of depression in cancer. J Natl Cancer Inst Monogr. 2004; 32:105–111. 8. Williams S, Dale J. The effectiveness of treatment for depression/ depressive symptoms in adults with cancer: a systematic review. Br J Cancer. 2006; 94:372–390. 9. Henry NL, Stearns V, Flockhart DA, et  al. Drug interactions and pharmacogenomics in the treatment of breast cancer and depression. Am J Psychiatry. 2008; 165:1251–1255. 10. Herr K, Garand L. Assessment and measurement of pain in older patients. Clin Geriatr Med. 2001; 17:457–478. 11. Urban D, Cherny N, Catane R. The management of cancer pain in the elderly. Crit Rev Oncol Hematol. 2010; 73:176–183. 12. Aapro MS, Cameron DA, Pettengell R, et al. EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the ­incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumors. Eur J Cancer. 2006; 42:2433–2453. 13. Repetto L, Biganzoli L, Koehne CH, et  al. EORTC Cancer in the Elderly Task Force guidelines for the use of colony-stimulating ­factors in elderly patients with cancer. Eur J Cancer. 2003; 39:2264–2272. 14. Aapro M, Crawford J, Kamioner D. Prophylaxis of chemotherapyinduced febrile neutropenia with granulocyte colony-stimulating factors: where are we now? Support Care Cancer. 2010; 18: 529–541. doi: 10.1007/s00520-010-0816-y. 15. Blanc-Bisson C, Fonck M, Rainfray M, Soubeyran P, BourdelMarchasson I. Undernutrition in elderly patients with cancer: target for diagnosis and intervention. Crit Rev Oncol Hematol. 2008; 67:243–254. 16. Vellas B, Lauque S, Andrieu S, et al. Nutritional assessment of the elderly. Curr Opin Clin Nutr Metabolic Care. 2001; 4(1):5–8. 17. John V, Mashru S, Lichtman S. Pharmacological factors influencing anticancer drug selection in the elderly. Drugs Aging. 2003; 20(10): 737–759. 18. Pond GR, Siu LL, Moore M, et al. Nomograms to predict serious adverse events in phase II clinical trials of molecularly targeted agents. J Clin Oncol. 2008; 26:1324–1330. 19. Jakobsen JN, Herrstedt J. Prevention of chemotherapy-induced nausea and vomiting in elderly cancer patients. Crit Rev Oncol Hematol. 2009; 71:214–221.

48 20. Hadji P, Body JJ, Aapro MS, et al. Practical guidance for the management of aromatase inhibitor-associated bone loss. Ann Oncol. 2008; 19:1407–1416. 21. Aapro M, Abrahamsson PA, Body JJ, et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol. 2008; 19:420–432. 22. Body JJ, Coleman R, Clezardin P, et  al. International society of geriatric oncology (SIOG) clinical practice recommendations for the use of bisphosphonates in elderly patients. Eur J Cancer. 2007; 43:852–858.

M.S. Aapro 23. Cummings SR, San Martin J, McClung MR, et al. FREEDOM Trial. Denosumab for prevention of fractures in postmeno­pausal women with osteoporosis. N Engl J Med. 2009; 361:756–765. 24. Smith MR, Egerdie B, Hernández Toriz N, et al. Denosumab HALT Prostate Cancer Study Group. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009; 361:745–755. 25. Santini D, Fratto ME, Galluzzo S, et al. Are bisphosphonates the suitable anticancer drugs for the elderly? Crit Rev Oncol Hematol. 2009; 69:83–94.

Chapter 6

Supportive Care in Paediatric Oncology Marianne D. van de Wetering and Wim J. E. Tissing

Introduction, Epidemiology and Incidence of Childhood Cancer Although childhood cancer represents about 1% of all cancer cases, it comprises worldwide around 250,000 children yearly. Globally, this gives an age-standardised incidence rate of 140 per million per year [1] (http://www-dep.iarc.fr/ accis.htm). Of these 250,000 children, 50,000 are diagnosed in the developed countries and 200,000 in middle or low income countries. Of the 50,000 children in the developed countries, around 80% survive. Of the 200,000 in middle and low income countries, only 25% survive. International collaboration is necessary to create possibilities to improve the care and cure of the paediatric cancer patient worldwide. The UICC (International Union Against Cancer) initiated a world cancer campaign in 2005 to increase awareness, improve care and coordinate training of professionals (www.uicc.org) [2, 3]. The types of childhood cancer (0–18 years) vary greatly from those seen in adults. The most common childhood ­cancers are leukaemia (30%, mainly acute lymphoblastic leukaemias) and brain tumours (mainly glioma’s and medullo­blastoma’s, 25%) (See Fig.  6.1). Together, they account for more than half of all new childhood cancer patients. The mixed group of solid tumours (45%) are tumours that mainly occur in children and sometimes in young adults, and are related to the growth and development of the organs. Children can tolerate far more intense therapy than adults, and over the years, with combination chemotherapy, surgery and/or radiotherapy, survival rates

M.D. van de Wetering (*) Department of Pediatric Oncology, Emma Children’s Hospital/ Academic Medical Center, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands e-mail: [email protected]

have improved (Fig.  6.2). Children in the high-income countries are mostly registered in trials and (international) collaborations within these trials have led to the success of reaching around 80% survival in these children. Important trial and registration groups are the COG (Children’s Oncology Group) and the SIOP (International Organization for Paediatric Oncology) [4]. Supportive care of the paediatric cancer patient has played an increasingly important role in the management of these critically ill patients. As intensity of primary treatment has escalated, so have the side-effects such as myelosuppression and infection [5]. Children who receive aggressive chemotherapy such as the induction phase of leukaemia or lymphoma treatment or patients with any stem cell transplant have a chance of around 40% of getting a febrile episode during neutropenia; this is one episode per 30 days at risk. Around 10–15% of patients will have a proven bacteraemia. Only 2% will present with invasive mycoses. Children with neutropenic fever more often present with fever of unknown origin (FUO) than adults. Therefore, guidelines from adults cannot easily be translated to guidelines for paediatric oncology patients [6]. The more intensive treatment schedules also come with more nausea and vomiting, making adequate anti-emetic treatment even more necessary. Thus, optimal supportive care is necessary to be able to prescribe the heavy treatment protocols from these days. The improvement that has come with modern treatment protocols consisting of surgery, radiotherapy and chemotherapy could not have happened without adequate supportive care [7]. In this chapter, aspects of supportive care in children with cancer will be highlighted concentrating on: 1 . Infection prevention and management 2. The role of central venous catheters in children with cancer 3. Vaccinations during and after treatment 4. Emergency situations in paediatric oncology [tumour lysis syndrome (TLS)] 5. Pain management 6. Anti-emetic management

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_6, © Multinational Association for Supportive Care in Cancer Society 2011

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M.D. van de Wetering and W.J.E. Tissing

Fig. 6.1  Childhood malignancies (Dutch cancer registry)

Fig. 6.2  5-year survival rates in childhood malignancies in developed countries (Dutch cancer registry)

Unfortunately, improved prognosis of the children with ­cancer has also led to increased long-term adverse effects. The severity of these late effects is dependent on the type of cancer treated, the age of the child at time of treatment, type of treatment and agents used. These effects include second neoplasms, organ dysfunction, endocrine and metabolic problems, orthopaedic problems and psychosocial and cognitive problems [8]. Due to the importance of being aware of long-term adverse effects and the absolute need for a longterm follow-up clinic, the chapter ends with an overview of the most important long-term adverse effects that can be expected after treatment for childhood cancer.

Infection Prevention and Management Prevention of Infection The use of chemotherapy in childhood cancer can have a devastating effect on the immune system, reducing defences against infections, especially bacterial infections. Patients and parents need to be instructed on how to avoid these infections. Of absolute importance is good hand hygiene and careful management of what the child eats and drinks, and advice needs to be given on how to manage the

6  Supportive Care in Paediatric Oncology

environment of the child. Most important is creating a balance between avoiding infection and allowing the child to lead a normal social life, including attending school. Concerning the environment of the child during neutropenia (ANC <500 cells/mm3), one tries to encourage a normal lifestyle where children continue their school life and hobbies. Teachers should be informed about the situation and asked to inform the parents when contact with viral infections such as varicella or measles has taken place. Concerning nutrition/diet, there is no proof of the usefulness of special measures concerning food products during neutropenia (ANC <500 cells/mm3), but it is recommended to avoid raw food, soft cheeses and “snack foods”. A comparison of cooked and non-cooked diets in patients undergoing remission induction therapy for acute myeloid leukaemia was done, and no difference in the two groups was found in severity of infection, time to major infection or mortality due to infection [9]. Currently, a Cochrane review is being performed to summarise the evidence concerning this topic. The parents should be aware that in case of any signs of infection during neutropenia, their physician should be notified, and this type of care should be available 24 h per day [10]. Other ways to possibly prevent infection include the use of (selective) gut decontamination: Oral non-absorbable and absorbable antibiotics are used to preserve beneficial anaerobic organisms while preventing colonisation of the gut by pathogenic aerobic organisms. Antibiotics are given orally before and during neutropenia. Systematic reviews have been published confirming that antibiotic prophylaxis significantly decreased the risk for death from infection when compared with placebo or no intervention (RR, 0.66 [95% CI 0.54–0.81]) [11–13]. The most significant reduction in mortality was observed in trials assessing prophylaxis with quinolones. The benefit demonstrated in these reviews outweighs harm, such as adverse effects, and development of resistance, since all-cause mortality is reduced. In patients with an estimated risk of infection exceeding 10%, such as patients with haematologic cancer, bone marrow transplant patients and relapse patients, prophylaxis, preferably with a quinolone, should be considered. Because very few paediatric trials have been performed, it is not possible in these reviews to separately analyse the paediatric oncology population. In young children <6 years of age, usually the combination of trimethoprim–sulfamethoxazole (TMP–SMZ) with colistin is used, due to possible side effects of quinolones, and >6 years quinolones are used. Newer studies combining quinolones or TMP/SMX with erythromycin or roxithromycin to decrease gram-positive bacteraemias have not been shown to give a significant reduction. Based on this systematic review and two other published systematic reviews, it is recommended that selective gut decontamination should be started 5 days before the expected neutropenia and continued until the neutrophil count is >500/mm3.

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The need for fungal prophylaxis is not as clearly stated as for bacterial prophylaxis, but with the increasing intensity of chemotherapy, anti-fungal prophylaxis is recommended as standard of care in high-risk patients (that is, bone marrow transplant patients, haematological patients and relapse patients). This recommendation is stated by the IDSA guidelines (Infectious Diseases Society of America), the CDC (Center for Disease Control) and the ASBMT (American Society Bone Marrow Transplantation). Early diagnosis is expected to improve results of treatment, but prevention of invasive fungal infection remains the ultimate goal [14]. A meta-analysis performed by Bow et al and Glasmacher et al [15, 16] concluded that itraconazol prophylaxis is effective in reducing invasive aspergillosis mortality (OR 0.58). However, if subgroup analyses were performed for paediatric studies, this advantage could not be verified. This might be caused by not giving adequate dosages of itraconazol [17]. Newer studies in adults with posaconazol seem promising [18], and paediatric trials are awaiting. Although good RCT’s are lacking, the current recommendation for prophylaxis in high-risk patients is Itraconazol oral solution (5 mg/kg/day 1–2× daily max 400  mg). Itraconazole capsules are not advised due to large inter- and intra-individual differences in bio-availability. One must be cautious in children receiving vincristine as inhibition of cytochrome 450 and blocking of the p glycoprotein pump interfere with vincristine metabolism, causing severe toxicity in these children [19, 20]. In those children, one can either choose to monitor carefully for invasive aspergillosis signs and not give prophylaxis, or only give fluconazole prophylaxis (6 mg/kg/day) to prevent Candida invasive infections. Another very important infection to prevent in immunocompromised patients is PCP (Pneumocystis carinii pneumonia) or Pneumocystis jirovecii infection, as it is now called. Over two-thirds of children have antibodies by the age of 4, but this infection can have serious implications for the immunocompromised paediatric oncology population. Due to the widespread use of TMP-SMZ prophylaxis, morbidity and mortality have decreased [21]. TMP inhibits dihydrofolate reductase and SMZ inhibits dihydropteroate synthetase, and by inhibiting both steps in the folic acid synthesis pathway, the combination stops thymidine synthesis and ultimately DNA replication [22]. All patients with leukaemia, lymphoma, BMT (allogeneic or autologous) receive prophylaxis. Children with solid tumours who are expected to have prolonged episodes of neutropenia are also advised to use TMP/SMZ as prophylaxis. The CDC advice is 150  mg/m2/day TMP dose on three consecutive days, or 3 mg/kg TMP, 15 mg/kg SMZ 2× daily all days of the week. An alternative to this prophylaxis is aerosolised pentamidine (300 mg/m2 every 4 weeks). A disadvantage of this approach is the need for specialised equipment and personnel [23]. Another alternative is intravenous pentamidine 4 mg/kg diluted with dextrose 5% and given over 2 h

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[23]. In smaller studies, the breakthrough rate was 1.3%, so iv pentamidine is considered a good alternative. Other possible ways to decrease duration and severity of infections is with the use of granulocyte colony stimulating factors (GCSF). Guidelines of the American Society of Clinical Oncology suggest that CSFs be used as primary prophylaxis (before the onset of neutropenia) when the expected incidence of febrile neutropenia is 40% or more [24]. Since these guidelines are not that clear in children, a meta-analysis was performed by Sung et  al. [25] in which 16 studies were included. They concluded that prophylactic CSFs (5 mg/kg/day sc) reduced the rate of febrile neutropenia by 20% and decreased duration of hospitalisation by 2 days. It also reduced the documented infection rate by 22% and amphotericin B use by 50%. But GCSFs did not reduce the infection-related mortality rate. Sub-analysis in children with haematologic malignancies showed the same results. GCSF should be administered to children as standard treatment only if the tumour treatment protocol requires it. Otherwise, the use of GCSF should be advocated only if it improves the quality of life of the child. Therefore, future studies on the use of prophylactic GCSF and QOL measurements should be performed.

Treatment of Infection in Children with Cancer The frequency and severity of infections that occur in the cancer patients depend on a complex interaction of a number of factors, of which granulocytopenia is the most important. Granulocytopenia (or neutropenia) is defined as an absolute neutrophil count of less than 500 cells/mm3. The frequency and severity of infections increase even more as the neutrophil count drops below 100 cells/mm3. The duration of neutropenia influences the outcome of the infectious episode. Patients with neutropenia shorter than 7 days had a 95% response rate to initial antibiotic therapy compared to a 35% response rate in patients with neutropenia duration of more than 15 days [6, 26, 27]. Incidence of infections in neutropenic patients is around 10–15% [9], with children aged 10–19 at higher risk than children 1–9 years old [28]. Poor outcome has been reported in between 7 and 10% of patients [29]. Thus, patients presenting with febrile neutropenia need specific attention. Children more often present with febrile neutropenia without an apparent site of infection than adults, making this an even more important issue in children than in adults [30]. Guidelines for the management of fever in neutropenic adult cancer patients include broad-spectrum antibiotic therapy at the onset of fever as outlined by the Infectious Diseases Society of America [6]. These guidelines describe both the

M.D. van de Wetering and W.J.E. Tissing

evaluation of the patient as well as the empirical treatment. For children, such guidelines by the Infectious Diseases Society of America do not exist, although a lot has been published on this topic [31]. Fever is defined as a single temperature >38.3°C, or a temperature of >38°C for more than 1  h. In the management, the clinician is directed to carefully and repeatedly evaluate for specific signs and symptoms of a focus or type of infection. Lack of neutrophils leads to minimal signs of inflammation at the site of infection. In children on presentation, a thorough physical examination is needed, including emphasis on the mucosal membranes, the lungs, soft tissues (e.g. perianal inspection) and the central venous catheter (CVC). Laboratory evaluation should include a complete blood count, liver enzymes, renal function and blood cultures (if a CVC is present, a culture should be taken from this orifice). Blood cultures from both the ventral venous catheter and the peripheral line (when both are present) should only be advocated if the department of microbiology can perform semi-quantitative cultures. In that case, it can help distinguish between a central venous line infection and a bacteraemia. Urine culture, stool culture and testing for Clostridium toxin should only be done if indicated. Routine culture of the cerebro-spinal fluid is not recommended, unless signs or symptoms of meningitis are present. ChestX-ray should only be done when signs are present suggesting a pulmonary infection [6]. The management of febrile, neutropenic children with cancer differs due to institutional variations in the spectrum of infections, antimicrobial susceptibility patterns of pathogenic micro-organisms, and the underlying aetiology of the neutropenia. The pattern of infective pathogens has changed significantly over time. Whereas in the 1960s and 1970s Gramnegative bacteria such as Klebsielle pneumoniae and Pseudomonas aeruginosa were the most frequent bacteria isolated in patients with febrile neutropenia, more recently gram positive bacteria are the predominant species, accounting for 70% of proven bacteraemias [32]. Of the Grampositive organisms, the Coagulase-negative staphylococci are the most common, but enterococcal and viridans group streptococcal species are becoming increasingly problematic due to increasing antibiotic resistance. Of the Gramnegative organisms, the most frequently observed pathogens are Escherichia coli, Klebsiella species, Serratia species, Proteus species and P. aeruginosa. With more intensive chemotherapeutic protocols and bone marrow transplantation, other serious infections emerge due to the prolonged severe neutropenia. Infections with fungal organisms such as Candida species, Aspergillus species or other opportunistic fungi occur (now 2% of all bloodstream infections, with high mortality).

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Empirical Therapy for Children Presenting with Febrile Neutropenia Initial Antibiotic Therapy Because the progression of infection in neutropenic patients can be rapid, and because such patients with early bacterial infections cannot be reliably distinguished from non-infected patients at presentation, empirical antibiotic therapy should be started promptly. The initial goal is to provide broad-spectrum antimicrobial cover, for both Gram-negative and Gram-positive organisms, including Pseudomonas species (therefore a contraindication for third generation cephalosporins for Gramnegative coverage). This has mostly been achieved by offering a combination of antibiotics, such as a cephalosporin and an aminoglycoside. Monotherapy is a reasonable alternative, in the form of a cephalosporin with anti-pseudomonal coverage, carbapenem® or meropenem®. In case of cephalosporin monotherapy, a glycopeptide should be added in case of high suspicion of staphylococcal infection [e.g. acute myeloid leukaemia (AML) patients treated with high-dose Cytosar].

should be taken, if possible. Awaiting the results of these evaluations anti-fungal drugs should be started [33]. The fifth option of stopping all antibiotics on the grounds that fever may be due to the medication as such is not recommended by the CDC guidelines. In adults, several risk stratifications have been validated, for example to start with oral antibiotics at presentation with febrile neutropenia. In paediatric oncology patients presenting with febrile neutropenia, much research has been done to determine a subgroup patients in whom no antibiotics or antibiotics for a shorter duration of time can be considered. However, up until now no validated risk assessment model has been found [31, 34].

Treatment of Fever without Neutropenia Good evaluation and physical examination is an absolute necessity. Laboratory evaluation will include a blood count, c-reactive protein (CRP) and blood cultures from the CVC. If there is no CVC, one can wait for the blood-culture result before starting antibiotics. If there is a CVC present, antibiotics can be given orally, for instance Amoxicillin, or Augmentin, until the blood-culture result is known.

Modification of Treatment The therapeutic plan should be reassessed after 3–5 days. If the patient becomes afebrile within the 3–5 days and has a positive blood-culture one should provide optimal cover for that specific organism, although broad spectrum antibiotic cover should be maintained to prevent breakthrough bacteraemia. Antibiotic treatment should be continued for a minimum of 7 days or until the organism is eradicated. It is not necessary to continue until the neutrophils recover. If the patient has persistent fever after 3–5 days of treatment, reassess the patient carefully, and add diagnostic tests such as an abdominal ultrasound and chest X-ray looking for a focus. If neutrophils are recovering and the child is not septic the same antibiotics can be continued despite the continuing fever. The second option is adding antibiotics with better gram positive coverage (e.g. coagulase negative streptococci are not covered by ceftazidim) in case monotherapy is started initially. The third option is to change antibiotics to target anaerobes, The fourth option is to add anti-fungal agents especially if one expects neutropenia to be prolonged [patients at higher risk of developing fungal infections; patients with acute lymphoblastic leukaemia (ALL), AML, stage III and IV Non-Hodgkin Lymphoma and aplastic anaemia]. In these patients, galactomannan values should be determined and a high resolution CT scan of the chest should be performed (even in patients with normal chest X rays). In case of abnormal signs on the chest CT scan, a broncho-alveolar lavage should be done, or in cases of high suspicion a biopsy

Anti-viral Drugs Due to the increased use of high-dose chemotherapy, cellular immunity can also be depressed, and therefore, the chance of acquiring viral infections is increased, especially in bone marrow transplant patients. However, the real incidence of viral infections in children with febrile neutropenia remains unknown, especially since viruses are not always studied. A recent paper has showed viral pathogens in 34% of episodes of febrile neutropenia in paediatric cancer patients [35]. Like other children, the viruses found were respiratory tract viruses like respiratory syncytial virus (RSV), parainfluenza virus, influenza and rhinovirus, or viruses in the gastrointestinal tract like adenovirus and rhinovirus. These viruses are usually not related to severe illness in the neutropenic child but in rare cases can cause serious morbidity. Treatment is largely supportive; in case of severe RSV infection, Ribavarin may offer therapeutic benefit. In patients after stem cell transplant, these viruses can cause serious infections. The viruses causing most problems in the immunocompromised children are the herpes viruses including herpes simplex virus (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV). These viruses can cause infections as a primo infection which usually occurs during childhood, or by reactivation of viral replication dur­ing the immunocompromised stage. Herpesviruses can result in  mucosal lesions, skin lesions and neurologic symptoms.

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Systemic treatment with acyclovir is needed at a dose of 750  mg/m2/day, divided in three doses intravenously for at least 5 days. Primary infection with VZV results in chickenpox. In the immunocompromised, severe complications may be seen leading to a fulminate illness with visceral dissemination of the virus. Untreated VZV pneumonitis can be fatal in up to 7% of affected children. Treatment should be systemic with acyclovir or the newer oral drugs such as Famcyclovir® or Valacyclovir®, which show a better oral absorption than acyclovir. CMV can result in fever, rash, hepatosplenomegaly, pneumonia, neurologic symptoms and retinitis. Treatment is with Gancyclovir 10 mg/kg/day in two divided doses intravenously or Foscarnet 90 mg/kg every 12 h. Prolonged courses of therapy are necessary to eradicate the infection.

The Role of Central Venous Catheters in Children with Cancer In high-income countries, most children receiving chemotherapeutic treatment will have a CVC inserted (>80–90%), in contrast to adults. The catheters that are inserted are internal long-term catheters called port-a-caths or external long-term catheters such as the Broviac or Hickmann catheter. These catheters have many advantages for administering chemotherapy, blood products and fluids. Complications related to the long-term use of CVCs are minimised by recommended protocols for catheter-placement, dressing, care, administration of solutions and monitoring [36]. The two most important complications in CVCs are infections and thrombosis. Infections in CVCs in children with cancer occur in about 30% of patients, which is 2 infections per 1,000 catheter days for port-a-caths. In patients at high risk of infection such as bone marrow transplant patients, these numbers will be even higher. Infectious complications are those that result in infection of the bloodstream and/or device, the subcutaneous pocket, the tunnel or exit site. Treatment of the infected catheter can be successful in more than 80% of documented catheter-related infections. Usually these infections are caused by Gram-positive organisms (mainly coagulasenegative staphylococci). However, cover for Gram-negative organisms is necessary until an organism is identified. Treatment failures result from infections with multiple organisms: fungi, P. aeruginosae, resistant Gram-negative organisms and tunnel infections. Thus, in cases of persistent fever despite adequate antibiotics, removal of the catheter should be considered. In case of a Staphylococcus aureus infection, the treatment should be administered for at least 2–3 weeks if the catheter is left in place, as S. aureus is associated with a late complication rate of 6.1%. If the catheter is left in place, the systemic

M.D. van de Wetering and W.J.E. Tissing

antibiotics should be administered through the catheter. Cycling antibiotics through each lumen or placing concentrated antibiotics within the locked catheter hub (antibiotic-lock technique) is not widely validated yet for children so cannot be recommended [36]. Thrombosis is far less well documented, but it is thought that at least 50% of the children experience an episode of occlusion during the duration of the catheter for which intervention is needed. If the catheter is occluded, mechanical obstruction has to be ruled out. If this is not the case, causes could be the precipitation of drugs, the use of parenteral nutrition or the formation of a thrombus. In children, not many studies have been performed to establish the optimal management of thrombosis in CVCs. If the catheter is not needed anymore, then remove; otherwise, treat with lowmolecular-weight heparin for at least 3 months and measure anti-Xa concentration until it is in an adequate range (0.6– 1.0 U/ml) [37] (Fig. 6.3).

Vaccinations Children with cancer who receive high-dose chemotherapy (autologous or allogeneic bone marrow transplant) or patients with haematological malignancies (leukaemia and lymphoma) will not only become granulocytopenic but will also have low lymphocytes and therefore most likely lose their antibody response to their vaccinations that were administered prior to chemotherapy. Thus, these children need attention concerning the vaccinations needed during chemotherapy and reimmunisation schedules need to be given after chemotherapy [38]. Children on standard chemotherapy with an increased chance of lymphocyte dysfunction are reimmunised no sooner than 6 months after stopping chemotherapy. Allogeneic transplant children are revaccinated 12–18 months after BMT (according to the guidelines of the country they live in).

Immunisation During Chemotherapy Even if small children diagnosed with cancer have not completed their immunisation schedule, it should be clear that these children are NOT allowed live vaccines such as measles–mumps–rubella (MMR), oral polio (OPV), oral typhoid and yellow fever vaccine. In countries where tuberculosis is prevalent, the BCG vaccination is not allowed to be administered. Killed or inactivated vaccines do not represent a danger to the immunocompromised host, although it is well known that the immunogenic response to vaccinations is decreased during chemotherapy. However, this immunogenic response is not zero, which makes it possible

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Fig. 6.3  Algorithm for management of a central venous catheter obstruction. DVT deep vein thrombosis, MRI magnetic resonance imaging, MRA magnetic resonance angiography. (Reprinted from Baskin et al. [37], with permission from Elsevier.)

to vaccinate with certain vaccines, especially in areas where herd immunity is low. Certain conditions should be met which include an adequate number of lymphocytes (>1,000 × 109/L), an adequate number of granulocytes (>1,000 × 109/L) and no use of dexamethasone 14 days before the vaccine and 1 week after the vaccine. If herd immunity for measles is low, single-antigen measles vaccine should be given before starting chemotherapy with the understanding that this should be repeated after stopping chemotherapy. If herd immunity for polio is low, eIPV (enhanced inactivated polio vaccine) is recommended in the household contacts and for the immunocompromised patient. It is safe and can confer some degree of protection. DTP (Diphtheria–Tetanus–Pertussis) can be administered to the immunocompromised patient, including the use of acellular pertussis containing vaccines (DtaP). Haemophilus influenzae b conjugate Vaccine (Hib) should be administered in those situations where the risk of Haemophilus influenzae type b is high, in persons with anatomical or functional asplenia or additional sickle cell anaemia.

Hepatitis B vaccination should ideally be given after stopping chemotherapy, but in high-risk groups or areas it can be given to the immunocompromised with a lesser immunogenic response. The vaccine advised then is Recombivax HB 40 mg/ml. Periodic booster doses are usually necessary following successful immunisation, with the timing determined by serologic testing at 12 month intervals.

Special Vaccinations During Chemotherapy Influenza Vaccination A Cochrane systematic review [39] was published emphasising the paucity of data on this vaccine. Serological responses are generally lower than expected in healthy controls, and antibody levels considered protective in healthy individuals may not prevent clinical infection in those with malignant disease. There are no data on whether vaccination of peadiatric

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cancer patients protects for clinical infection. The vaccine is well tolerated; therefore, it is not contraindicated. Most countries recommend yearly vaccination and to vaccinate household contacts, but to date there is no evidence that this will decrease complications due to influenza.

need to be revaccinated a year to 18 months after transplant, and the immunogenic response should be measured.

Varicella Zoster Vaccination

TLS is a set of complications that can arise from treatment of rapidly proliferating and drug-sensitive neoplasms. In children, it mostly occurs in Burkitt’s lymphoma, lymphoblastic lymphoma, acute lymphocytic leukaemia with hyperleukocytosis and T-cell ALL. The chance of developing a TLS in above-mentioned cancers in childhood is around 2–4%. In acute myeloid leukaemia, the chance of TLS is much less. In very rare cases, TLS has been reported in solid tumours such as neuroblastoma, medulloblastoma and germ cell tumours [41]. The metabolic disturbances include hyperuricaemia, hyperphosphatemia, hypocalcemia and hyperkalemia. Low-risk patients should be treated with allopurinol (100–200 mg/m2 2× dd) combined with hyperhydration (2–3 l/m2 per 24 h), No consensus has been reached as yet if one needs to alkalanize these patients (urinary pH 6.5–7.5). Urine output is extremely important and should be measured at 3 ml/kg/h. If not adequate, loop diuretics are administered, furosemide at 1 mg/kg/iv. High-risk patients (such as Burkitt’s lymphoma and ALL with hyperleucocytosis) should receive urate-oxidase Uricozyme® or the recombinant form rasburicase (Europe Fasturtec® and in the United States Elitek® ) at the dose of 0.20 mg/kg/day, infused over 30 min, administering the first dose at least 4 h before the start of tumour-specific therapy and continuing for at least 3–5 days. In these patients, concomitant use of allopurinol is not allowed, and alkalinisation of urine is not recommended [41]. In a randomised prospective multicentre trial, it was shown that the risk of developing renal complications requiring dialysis in patients treated on Rasburicase was 0.4%. Therefore, in the high-risk groups, this is the drug of choice [42]. Note that if Rasburicase is used, blood samples for uric acid measurement should be taken on ice, to prevent false low values. Depending on the risk of severe tumour lysis syndrome, once or twice daily blood should be drawn for levels of Potassium, Phosphate, Calcium, Uric Acid and Creatinine.

Although this is a live vaccine, it has been proven to be possible to administer safely during chemotherapy and raise an adequate immune response. As more complications of varicella zoster infection are seen in immunocompromised patients, it would be of great benefit if oncological patients with no detectable antibodies to VZV could receive the vaccine and seroconvert. It is, however, not yet routinely recommended. If considered appropriate to give the VZV vaccine, then chemotherapy should be suspended for 1 week before and 1 week after vaccination, and the patient should not be receiving steroids. Two doses are required [40]. Cases of vaccine-associated varicella have been reported and oral or intravenous acyclovir, as appropriate, should be used if the child develops a skin rash consistent with varicella. Seroconversion to VZV occurred in 82% of vaccinees after one dose and in 95% after two doses. In addition, the incidence of clinical reactivation in vaccinated children is lower than in unvaccinated leukaemic children. Therefore, varicella vaccine administered under these conditions might be beneficial to the leukaemic patient. Pneumococcal Vaccine This is recommended for use in persons >2 years of age with increased risk of pneumococcal disease, such as patients with splenic dysfunction or anatomical asplenia, Hodgkin disease with involvement of the spleen or after radiotherapy, to the spleen.

Immunisation Post-Chemotherapy Patients with haematological malignancies (leukaemia, lymphoma) after standard chemotherapy are recommended in most countries to be revaccinated 6 months post-chemotherapy. Most programmes recommend a booster dose for the routine childhood vaccines (Hib-conjugate, diphtheria/tetanus/acellular pertussis (DtaP), MMR, inactivated poliovirus (IPV) and meningococcal C conjugate), and in some countries the pneumococcus conjugate vaccine (PCV7) is included, although no studies have been done on the response to PCV7 after chemotherapy [38]. Those patients who have undergone an allogeneic bone marrow transplant or autologous BMT

Tumour Lysis Syndrome

Pain-Management Pain in children with cancer is mainly therapy- or procedurerelated. This is contrary to that in adult patients where pain is mainly tumour-related. Fortunately, children have a much better survival rate than the adult patients, and only 15% of patients have pain related to the tumour, either in the initial stage or in their palliative phase [43]. The first step in managing pain is to accurately assess the presence of pain. In children less than

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4 years old, the assessment relies on behavioural pain scales, where crying, posture and facial expression are tools used to assess pain. Over 4 years of age, different validated scales are used, for instance the FACES pain rating scale (see Fig. 6.4) [44] or the word graphic rating scale. It is extremely important that the pain is assessed at regular intervals over the day by parents or nursing staff, and the score found is acted on. Therapy-Related Pain or Tumor-Related Pain As in adults, the step ladder of the World Health Organisation is used as a guideline for the adequate treatment of pain. This recommends: Step 1: acetominophen (paracetamol). Step 2: mild opioid acetominophen (paracetamol) combined with step 1. Step 3: opioids (morphine 10  mg/kg/h continuous iv or sc) combined with step 1. The dose of morphine must be increased until adequate pain control is achieved.

If the patient does not achieve adequate pain control on the above step-wise approach, adjuvant therapy should be considered (See Table 6.1). Children need pain control most often less than 1 week, much shorter than the adult patient. This concerns mainly the therapy-related pain, which is given in an in-patient setting. Children should not suffer, so rather start too high on the WHO step ladder, than allowing these children to struggle up the ladder. In adults, step 1 also includes NSAID’s such as Ibuprofen and Naproxen. In children, thrombocytopenia is a frequent adverse effect of treatment. Since NSAIDs have the theoretical potential to increase the bleeding risk due to NSAID-induced thrombocytopathy, their usage is avoided. If a child needs step 3, morphine, most often this is administered intravenously when the pain is therapy-related because the duration will be short; mostly shorter than 1 week. If the child is in the palliative phase and should better be at home with adequate pain medication, Fentanyl patches are preferred together with rescue medication via the oral or rectal route.

Fig. 6.4  FACES Pain Rating Scale. (From Hockenberry MJ, Wilson D, Winkelstein ML: Wong’s Essentials of Pediatric Nursing, ed. 7, St. Louis, 2005, p. 1259. Used with permission. Copyright, Mosby.)

Table 6.1  Pain management Medication

Doses

Remarks Max. 4,000 mg/day

Naproxen (NSAID) Diclofenac

Oral 15 mg/kg/dose 4–6 per day Supp. 20–30 mg/kg/dose 2–4 per day Oral 5 mg/kg/dose 2–3× per day Oral 1–2 mg/kg/dose 3× per day

Step 2 Continue Medication step 1 Tramadol

>1 year 1–2 mg/kg/dose 3–4 per day orally or iv

Max. 400 mg/day Weak opioid

Oral 0.3–0.6 mg/kg/dose 2–3× per day 0.1–0.3 mg/kg/dose 4–6× per day 0.2–0.4 mg/kg/dose 4–6× per day i.v. start dose 0.01–0.03 mg/kg/h or 0.25 mg/kg/24 h Bolus 0.02 mg/kg/10 min. Infusion: 0.005 or 0.01 mg/kg/h iv Transdermal, change every 72 h Dose: 60–90 mg morphine oral per day ~ fentanyl 25 mg/h.

Antagonist: naloxone 0.1 mg/kg i.v. or i.m.

Step 1 Acetaminophen

Step 3 Continue Medication step 1 Morphine (MS Contin) Morphine solution Morphine supp Morphine i.v.   Morphine i.v. patient-controlled analgesia (PCA) Fentanyl patch: 25, 50, 75 en 100 mg/h

Adapted from van de Wetering [46], with permission of Oxford University Press

Cave thrombocytopathy

Need rescue medication; patient should have oral or suppository (rectal application of medication) morphine as rescue medication to administer if pain is present with the patch

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Table 6.2  Adjuvant pharmacological therapy Group of drugs Example Dose

Indication

Anxiolytics

Muscle relaxant

Diazepam Oxazepam

0.1–0.2 mg/kg/dose 3–4× per day oral <6 years 2.5–10 mg/dose 3–4 per day oral >6 years 2.5–15 mg/dose 3–4 per day oral Sedatives Nitrazepam 1–6 years 2.5–5 mg/dose 1× daily oral >6 years 5 mg/dose 1× daily oral Temazepam 10–20 mg 1 per day oral Anti-depressants Amitriptyline Start dose 0.2–0.5 mg/kg in 2 dd oral. Dose can be increased to 3 mg/kg/day Anti-epileptics Carbamazepine 1.5–3 mg/kg/dose increase to 2.5–5 mg/kg/dose 2–4× daily oral Gabapentin 5 mg/kg 1 dd, max 8–30 mg/kg in 3 dd oral Rivotril 0.05–0.1 mg/kg/dose apply mucosal Steroids Prednisone 1 mg/kg/day oral Dexamethasone 10 mg/m2/day oral Reprinted from van de Wetering [46], with permission of Oxford University Press

Special Pain Syndromes Vincristine-induced neuropathy is a special pain syndrome. Symptoms vary from a feeling of paresthesia underneath the feet to severe pain in the extremities. Regular opiates usually do not relieve optimally. Anti-epileptic drugs like gabapentin can be used, and sometimes a combination with other drugs is necessary. Mucositis: methotrexate and other chemotherapeutic drugs can induce oral mucositis. When the patient needs pain medication, the pain is usually of such a magnitude that morphine is needed; when possible, use PCA (patient-controlled analgesia). Beyond the use of pharmacologic and medical care, one needs to consider non-pharmacologic adjunctive therapy. Although much less evidence is available, it is well known that hypnosis, fantasy, art therapy, etc can help relieve anxiety and stress, and therefore, the experience of pain will hopefully be less severe [45] (Table 6.2).

Treatment of Pain Associated with Diagnostic Procedures The main goal during paediatric procedures is to make the child comfortable so that the child and parents will not dread the subsequent procedures. Since paediatric oncology patients frequently need invasive, painful procedures, it is of utmost importance that the child gets optimal pain management during the first of a series of procedures. Both pain and anxiety have to be managed to achieve adequate control. In general, one must achieve a situation in the treatment room where adequate staff will create a calm environment where the procedure can be performed rapidly and efficiently. Sedation is performed in many different ways. The American Academy of Pediatrics [47] and The American Society of Anesthesiology [48] have set up guidelines, but

Neuropathic pain Neuropathic pain and phantom pain

Intracranial raised pressure brain tumours And severe end stage tumours

these have to be individualised to the particular situation for that specific child. 1. For minor procedures such as venipunctures or access to subcutaneous reservoirs, topical anaesthetic cream can be used 1  h before the procedure (EMLA® or Rapydan®). 2. For procedures such as bone-marrow puncture, conscious sedation can be given. Usually, this consists of midazolam (Versed®) 0.15–0.03  mg/kg rectally 15  min before the procedure or 0.05 mg/kg/iv slowly, but if the iv route is followed, trained anaesthetic personnel should be available, as midazolam can give respiratory depression. In countries where anaesthetics can be given, it is preferred to do bone-marrow aspirations and lumbar punctures under general anaesthetic (Propofol). 3. Procedures such as bone-marrow trephine are always performed under general anaesthetic where airway patency, breathing and circulation can be assured. In all above steps, it is also important to help the child with non-pharmacologic methods in reducing stress and anxiety. Although the evidence available is poor, it is important to find a way to minimise stress and anxiety [45].

Anti-Emetics Nausea and vomiting (N + V) remain an important concern in cancer treatment. The American Society of Clinical Oncology has updated the guidelines in 2006 [49], and MASCC performed the latest update in 2008 [50] Both are for adult cancer patients. With the treatment given nowadays, adequate control is usually achieved, but these guidelines used in adult oncology cannot automatically be adjusted for children, as no adequate pharmacokinetic trials have been performed in children. First, it is important to assess with a validated nausea and

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6  Supportive Care in Paediatric Oncology

vomiting tool how severe the score is for nausea and vomiting. This scale was developed and is called the PENAT score [51], and is comparable with the FACES pain rating scale for assessment of pain. It is extremely important that the N + V is assessed at regular intervals over the day by parents or nursing staff and that the score found is acted on, only then will it be possible to optimally manage N + V in the child with cancer. Chemotherapeutic agents are grouped in four classes: minimal emetogenic (<10% of patients experience nausea and vomiting), low risk (10–30%), moderately emetogenic (30–90%) and highly emetogenic (90% and greater). Medication is adjusted to the degree of emetogenicity. In low emetogenic chemotherapy, no anti-emetic therapy is needed. Occasionally, agents such as metoclopromide, domperidone or promethazine can be used. In moderately emetogenic chemotherapy, a  serotonin receptor antagonist should be used, usually Table 6.3  Anti-emetic agents Emetogenic potential Drug Low emetogenic

Ondansetron®. If this is not effective alone, corticosteroids should be added. Both drugs will work synergistically. In  highly emetogenic chemotherapy, the combination of a serotonin receptor antagonist plus steroids should be used. In this group, it is recommended to continue one of the antiemetics till 72 h after stopping the chemotherapy (to prevent delayed emesis). In adults, NK1 antagonists are added in the high emetogenic chemotherapy, as they have been proven to be very effective when administered with serotonin antagonists and steroids. However, for the NK1 antagonists no trials in children have been performed so far; therefore, they are not given routinely as yet, although older children on high emetogenic chemotherapy do better with the NK1 antagonists. It is very important to attempt an aggressive plan at the start of therapy to avoid or minimise the initial experience of nausea, since there is a greater chance of preventing the

Anti-emetic therapy

Delayed emesis

Bleomycin None or Domperidone dose 0.3 mg/kg oral 4× daily or None Promethazine 0.5 mg/kg oral in 4× daily Busulfan oral Steroids Fludarabine Hydroxyurea Interferon Melphalan oral Mercaptopurine Methotrexate <50 mg/m2 Thioguanine Vinblastine Vincristine Moderate Aspariginase None Ondansetron children <12 years 15 mg/m2 in 3× daily iv or oral and in children >12 years 15 mg/m2 Cytarabine <1 g/m2 in 2× daily or dexamethasone and dexa loading dose Doxorubicin 5 mg/m2 iv or oral max 8 mg per dose followed by Etoposide 5 mg/m2 in 3× daily iv or oral. Fluouracil <1,000 mg/m2 Gemcitabine Methotrexate –1 g/m2 Thiotepan Topotecan Cyclophosphamide <750 mg/m2 Actinomycin Epirubicin Idarubicin Mitoxantrone <15 mg/m2 Continue Ondansetron High Carboplatin Ondansetron + Dexamethasone and dexa loading dose × 72 h after stop 10 mg/m2 iv or oral max 20 mg per dose followed by Carmustine chemotherapy 5 mg/m2 in 3× daily iv or oral. Cisplatin If NK1 antagonist is given 125 mg oral before start CT Cyclophosfamide >750 mg/m followed by 80 mg daily x 3 days. NB; 80 mg daily x 3 Cytarabine >1 g/m2 days. following the moderate emetogenic group but Actinomycin beware no dosages known in paediatrics Doxorubicin >60 mg/m2 Irinotecan Melfalan (iv) Methotrexate >1 g/m2 Mitoxantrone >15 mg/m2 Procarbazine Data from Holdsworth [52]. Reprinted from van de Wetering [46], with permission of Oxford University Press

60

development of anticipatory nausea and vomiting. If anticipatory vomiting does occur, benzodiazepines are usually effective (Summary see Table 6.3). Radiotherapy can also lead to nausea and vomiting. Therefore, it is recommended that a serotonin-receptor antagonist is given about 30 min before the start of radiotherapy. Obviously, the above-mentioned guidelines are recommended based on the best available evidence. However, discomfort associated with nausea and vomiting is a very subjective experience; therefore, treatment should be individualised, allowing the patient’s and parent’s opinions to influence antiemetic regimens with subsequent courses [49].

Late Adverse Effects The prognosis of childhood cancer has improved dramatically; unfortunately, this has come with a rising incidence of

M.D. van de Wetering and W.J.E. Tissing

treatment-related (long term) complications. Adverse effects that occur one or more years later are called long-term adverse effects and are caused by all the treatments given: surgery, chemotherapy and radiotherapy. Because of the potential long-term effects, follow-up care is extremely important. In many countries, this has been realised already, which gives a much better insight into all the late effects that occur. At 5 year follow-up, nearly 75% of childhood cancer survivors had at least one adverse event, and 40% had at least one severe or life-threatening disabling adverse event. Radiotherapy is the most important cause for adverse events in follow-up, leading to cardiovascular, endocrine, neurological, second malignancies and psychosocial and cognitive adverse events. Some chemotherapeutic agents can have severe long-term sequelae. Risk of cardiovascular adverse events is increased following anthracycline containing chemotherapy. Alkylating agents can give an increased risk of renal adverse events and infertility. This is also the case after platinum-­containing chemotherapy. One of the adverse

Table 6.4  Risk of second malignancies in long-term survivors of childhood cancer Observed casesa Second malignancy

Expected cases

SIRb

95% CIc

Absolute excess riskd

All second malignancies (incl. benign meningiomas)e 60 5.37 11.2 8.53–14.4 3.20 All second malignancies (excl. benign meningiomas) 48 5.08 9.45 6.97–12.5 2.51 Solid tumoursf 51 4.20 12.1 9.05–16.0 2.74 Solid tumours including third primary tumoursg 56 4.20 13.3 10.1–17.3 3.03   Bone 5 0.18 28.1 9.14–65.7 0.28   Connective tissue 10 0.21 48.6 23.3–89.4 0.57   Breast 3 0.50 5.98 1.23–17.5 0.15   Ovary 2 0.12 16.1 1.95–58.2 0.11   Brain 4 0.37 10.8 2.93–27.6 0.21   CNSh 13 0.32 40.1 21.4–68.6 0.74    Meningioma 12 0.29 41.2 21.3–71.9 0.69   Thyroidi 6 0.16 38.7 14.2–84.2 0.34 Basal cell carcinomaj 18 2.01 8.95 5.30–14.1 0.94 Leukaemia & lymphomak 9 1.16 7.76 3.55–14.7 0.46   Leukaemia 4 0.36 11.1 3.02–28.3 0.21   Leukaemia & MDSl 7 0.36 19.4 7.79–39.9 0.39   Non-Hodgkin lymphoma 4 0.32 12.7 3.45–32.4 0.22 Lymphomam 9 1.15 7.82 3.58–14.9 2.40 Reprinted from Cardous-Ubbink [53], Copyright Elsevier 2007 a At least two observed cases per category are represented in table b Standardised incidence ratio c Confidence interval d Per 1,000 person-years e 12 Benign meningioma cases are included in the analysis; expected rate is based on the incidence of benign CNS tumours. 3 MDS cases and 16 basal cell carcinoma cases are excluded, since incidence rates in population are not available f Includes, other than the specific sites denoted below, 12 benign meningiomas, and 2 malignant orbita tumors, 2 melanomas, 1 abdominal adenosarcoma, 1 cervical carcinoma, 1 carcinoma sinus maxillaris, 1 carcinoma colon and 1 carcinoma of tongue g Includes also 5 third primary cancers (2 lung carcinomas, 1 meningioma, 1 thyroid carcinoma and 1 rectal carcinoma) h Includes 12 second benign meningiomas i Including 1 third malignant thyroid carcinoma j Expected rate of basal cell carcinoma was calculated using the incidence rates of the Eindhoven Cancer Registries; observed number includes 2 third primary basal cell carcinomas k 2 ALL, 1 AML, 1 CML, 4 Non-Hodgkin lymphomas, 1 Hodgkin lymphoma l Includes 3 second myelodysplastic syndromes; MDS only included in this subgroup m Includes 1 benign meningioma

6  Supportive Care in Paediatric Oncology

effects with major impact on the quality of life is the development of a second malignancy. This chance is increased if compared with the general population but will depend on the chemotherapy or radiotherapy given (Table 6.4). Radiotherapy was the strongest risk factor for new primary malignancies, and this excess risk remains even after 25 years of follow-up. All these long-term effects stress the need for long-term follow-up, to monitor these children into adulthood and evaluate possible subclinical events, and possibly treat these adverse events in an early stage (for instance, hypertension or cardiac failure), and try to improve the quality of life after childhood cancer [8, 53, 54].

References 1. Kellie SJ, Howard SC. Global child health priorities: what role for paediatric oncologists? Eur J Cancer 2008;44(16):2388–96. 2. Ribeiro RC, Steliarova-Foucher E, Magrath I, Lemerle J, Eden T, Forget C, et al. Baseline status of paediatric oncology care in ten low-income or mid-income countries receiving My Child Matters support: a descriptive study. Lancet Oncol 2008;9(8): 721–9. 3. Wyke JA. Science, the UICC and global cancer control. Int J Cancer 2004;110(4):471–4. 4. Bleyer WA, Tejeda H, Murphy SB, Robison LL, Ross JA, Pollock BH, et al. National cancer clinical trials: children have equal access; adolescents do not. J Adolesc Health 1997;21(6):366–73. 5. Castagnola E, Fontana V, Caviglia I, Caruso S, Faraci M, Fioredda F, et al. A prospective study on the epidemiology of febrile episodes during chemotherapy-induced neutropenia in children with cancer or after hemopoietic stem cell transplantation. Clin Infect Dis 2007;45(10):1296–304. 6. Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002;34(6):730–51. 7. Ritchey A. The pediatric oncology group, supportive care manual. 1-9-1996. Smthkline Beecham. 8. Cardous-Ubbink MC, Heinen RC, Langeveld NE, Bakker PJ, Voute PA, Caron HN, et  al. Long-term cause-specific mortality among five-year survivors of childhood cancer. Pediatr Blood Cancer 2004;42(7):563–73. 9. Gardner A, Mattiuzzi G, Faderl S, Borthakur G, Garcia-Manero G, Pierce S, et al. Randomized comparison of cooked and noncooked diets in patients undergoing remission induction therapy for acute myeloid leukemia. J Clin Oncol 2008;26(35):5684–8. 10. Hawkins J. Supportive care: managing febrile neutropenia. Paediatr Nurs 2009;21(4):33–7. 11. Gafter-Gvili A, Fraser A, Paul M, van de WM, Kremer L, Leibovici L. Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy. Cochrane Database Syst Rev 2005;(4):CD004386. 12. Gafter-Gvili A, Fraser A, Paul M, Leibovici L. Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients. Ann Intern Med 2005;142(12 Pt 1):979–95. 13. van de Wetering MD, de Witte MA, Kremer LC, Offringa M, Scholten RJ, Caron HN. Efficacy of oral prophylactic antibiotics in neutropenic afebrile oncology patients: a systematic review of randomised controlled trials. Eur J Cancer 2005;41(10):1372–82. 14. Hovi L, Saxen H, Saarinen-Pihkala UM, Vettenranta K, Meri T, Richardson M. Prevention and monitoring of invasive fungal infec-

61 tions in pediatric patients with cancer and hematologic disorders. Pediatr Blood Cancer 2007;48(1):28–34. 15. Bow EJ, Laverdiere M, Lussier N, Rotstein C, Cheang MS, Ioannou S. Antifungal prophylaxis for severely neutropenic chemotherapy recipients: a meta analysis of randomized-controlled clinical trials. Cancer 2002;94(12):3230–46. 16. Prentice AG, Glasmacher A, Djulbegovic B. In meta-analysis itraconazole is superior to fluconazole for prophylaxis of systemic fungal infection in the treatment of haematological malignancy. Br J Haematol 2006;132(5):656–8. 17. Simon A, Besuden M, Vezmar S, Hasan C, Lampe D, Kreutzberg S, et al. Itraconazole prophylaxis in pediatric cancer patients receiving conventional chemotherapy or autologous stem cell transplants. Support Care Cancer 2007;15(2):213–20. 18. Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356(4):348–59. 19. Sathiapalan RK, El Solh H. Enhanced vincristine neurotoxicity from drug interactions: case report and review of literature. Pediatr Hematol Oncol 2001;18(8):543–6. 20. Sathiapalan RK, Al Nasser A, El Solh H, Al Mohsen I, Al Jumaah S. Vincristine-itraconazole interaction: cause for increasing concern. J Pediatr Hematol Oncol 2002;24(7):591. 21. Thomas CF, Jr., Limper AH. Pneumocystis pneumonia. N Engl J Med 2004;350(24):2487–98. 22. Shankar SM, Nania JJ. Management of Pneumocystis jiroveci pneumonia in children receiving chemotherapy. Paediatr Drugs 2007;9(5):301–9. 23. Kim SY, Dabb AA, Glenn DJ, Snyder KM, Chuk MK, Loeb DM. Intravenous pentamidine is effective as second line Pneumocystis pneumonia prophylaxis in pediatric oncology patients. Pediatr Blood Cancer 2008;50(4):779–83. 24. Update of recommendations for the use of hematopoietic colonystimulating factors: evidence-based clinical practice guidelines. American Society of Clinical Oncology. J Clin Oncol 1996;14(6): 1957–60. 25. Sung L, Nathan PC, Lange B, Beyene J, Buchanan GR. Prophylactic granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor decrease febrile neutropenia after chemotherapy in children with cancer: a meta-analysis of randomized controlled trials. J Clin Oncol 2004;22(16):3350–6. 26. Pizzo PA. Fever in immunocompromised patients [see comments]. N Engl J Med 1999;341(12):893–900. 27. Roguin A, Kasis I, Ben Arush MW, Sharon R, Berant M. Fever and neutropenia in children with malignant disease. Pediatr Hematol Oncol 1996;13(6):503–10. 28. Mendes AV, Sapolnik R, Mendonca N. New guidelines for the clinical management of febrile neutropenia and sepsis in pediatric oncology patients. J Pediatr (Rio J) 2007;83(2 Suppl): S54–S63. 29. NCCN practice guidelines for fever and neutropenia. National Comprehensive Cancer Network. Oncology (Huntingt) 1999; 13(5A):197–257. 30. Hann I, Viscoli C, Paesmans M, Gaya H, Glauser M. A comparison of outcome from febrile neutropenic episodes in children ­compared with adults: results from four EORTC studies. International Antimicrobial Therapy Cooperative Group (IATCG) of the European Organization for Research and Treatment of Cancer (EORTC). Br J Haematol 1997;99(3):580–8. 31. Sung L, Johnston DL. Approach to febrile neutropenia in the general paediatric setting. Paediatr Child Health 2007;12(1):19–21. 32. Paulus S, Dobson S. Febrile neutropenia in children with cancer. Adv Exp Med Biol 2009;634:185–204. 33. Arendrup MC, Fisher BT, Zaoutis TE. Invasive fungal infections in the paediatric and neonatal population: diagnostics and management issues. Clin Microbiol Infect 2009;15(7):613–24.

62 34. te Poele EM, Tissing WJ, Kamps WA, de Bont ES. Risk assessment in fever and neutropenia in children with cancer: what did we learn? Crit Rev Oncol Hematol 2009;72(1):45–55. 35. Hakim H, Flynn PM, Knapp KM, Srivastava DK, Gaur AH. Etiology and clinical course of febrile neutropenia in children with cancer. J Pediatr Hematol Oncol 2009;31(9):623–9. 36. Mermel LA, Farr BM, Sherertz RJ, Raad II, O’Grady N, Harris JS, et  al. Guidelines for the management of intravascular catheterrelated infections. Clin Infect Dis 2001;32(9):1249–72. 37. Baskin JL, Pui CH, Reiss U, Wilimas JA, Metzger ML, Ribeiro RC, et  al. Management of occlusion and thrombosis associated with long-term indwelling central venous catheters. Lancet 2009; 374(9684):159–69. 38. Patel SR, Chisholm JC, Heath PT. Vaccinations in children treated with standard-dose cancer therapy or hematopoietic stem cell transplantation. Pediatr Clin North Am 2008;55(1):169–86, xi. 39. Goossen GM, Kremer LC, van de Wetering MD. Influenza vaccination in children being treated with chemotherapy for cancer. Cochrane Database Syst Rev 2009;(2):CD006484. 40. American Academy of Pediatrics Committee on Infectious Diseases. Prevention of varicella: recommendations for use of varicella vaccines in children, including a recommendation for a routine 2-dose varicella immunization schedule. Pediatrics 2007;120(1):221–31. 41. Tosi P, Barosi G, Lazzaro C, Liso V, Marchetti M, Morra E, et al. Consensus conference on the management of tumor lysis syndrome. Haematologica 2008;93(12):1877–85. 42. Navolanic PM, Pui CH, Larson RA, Bishop MR, Pearce TE, Cairo MS, et al. Elitek-rasburicase: an effective means to prevent and treat hyperuricemia associated with tumor lysis syndrome, a Meeting Report, Dallas, Texas, January 2002. Leukemia 2003;17(3): 499–514. 43. Zernikow B, Schiessl C, Wamsler C, Janssen G, Griessinger N, Fengler R, et  al. [Practical pain control in pediatric oncology. Recommendations of the German Society of Pediatric Oncology and Hematology, the German Association for the Study of Pain, the German Society of Palliative Care, and the Vodafone Institute of Children’s Pain Therapy and Palliative Care]. Schmerz 2006;20(1): 24–39.

M.D. van de Wetering and W.J.E. Tissing 44. Wong DL, Baker CM. Pain in children: comparison of assessment scales. Pediatr Nurs 1988;14(1):9–17. 45. Rheingans JI. A systematic review of nonpharmacologic adjunctive therapies for symptom management in children with cancer. J Pediatr Oncol Nurs 2007;24(2):81–94. 46. van de Wetering M. Supportive care during treatment. P.A. Voute, A. Barrett, M. Stevens, H. Caron, editors. Cancer in Children; Clinical Management. 5th, 86–93. 1-10-2005. Oxford, Oxford University Press. 47. American Academy of Pediatrics Committee on Drugs: Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics 1992;89(6 Pt 1):1110–5. 48. Practice guidelines for sedation and analgesia by non-anesthesiologists. A report by the American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Anesthesiology 1996;84(2):459–71. 49. Kris MG, Hesketh PJ, Somerfield MR, Feyer P, Clark-Snow R, Koeller JM, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006;24(18): 2932–47. 50. Herrstedt J. Antiemetics: an update and the MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol 2008;5(1):32–43. 51. Dupuis LL, Taddio A, Kerr EN, Kelly A, MacKeigan L. Development and validation of the pediatric nausea assessment tool for use in children receiving antineoplastic agents. Pharmacotherapy 2006; 26(9):1221–31. 52. Holdsworth MT, Raisch DW, Frost J. Acute and delayed nausea and emesis control in pediatric oncology patients. Cancer 2006;106(4): 931–40. 53. Cardous-Ubbink MC, Heinen RC, Bakker PJ, van Den BH, Oldenburger F, Caron HN, et  al. Risk of second malignancies in long-term survivors of childhood cancer. Eur J Cancer 2007;43(2): 351–62. 54. Geenen MM, Cardous-Ubbink MC, Kremer LC, van Den BC, van der Pal HJ, Heinen RC, et al. Medical assessment of adverse health outcomes in long-term survivors of childhood cancer. JAMA 2007;297(24):2705–15.

Chapter 7

Quality-of-Life Assessment: The Challenge of Incorporating Quality-of-Life and Patient-Reported Outcomes into Investigative Trials and Clinical Practice Richard J. Gralla and Patricia J. Hollen

Evaluating quality of life as part of cancer treatment and in the analysis of clinical investigations has been a key goal for many years. There are now compendia describing healthrelated quality of life (HRQL) measures, in hard copy and on the Internet. Navigating through this wealth of information can be daunting; however, these collections provide new opportunities for all willing to devote some time to understanding the value and limitations of these measures. HRQL measures can aid in understanding the patient’s experience with cancer treatment or with dealing with the many issues involved with cancer. Many treatments are associated with only modest benefit. The balance between the benefits and the difficulties associated with cancer and its treatment remain key issues for many patients and for those caring for them.

The Evolution of the Concept of Hrql as an Endpoint in Oncology An overview of historical markers related to the HRQL concept demonstrates that progress has been made in refining this concept as a useful endpoint for clinical trials. These include the early development of the first performance status measure of the Karnofsky Scale in 1949 to the 1985 Food and Drug Administration ruling on new drugs that recognized quality of life as an endpoint in addition to survival [1, 2]. Moreover, the 1996 American Society of Clinical Oncology treatment guidelines reinforced that quality of life was one of three key endpoints for cancer clinical trials in addition to response and survival [3]. Yet, a dilemma in HRQL measurement was voiced in 1989 by Donovan and colleagues when reviewing 17 HRQL instruments for cancer patients [4]. Only three of the meaR.J. Gralla (*) Division of Medical Oncology and Hematology, Hofstra North Shore-LIJ School of Medicine, Lake Success, NY 11042, USA e-mail: [email protected]

sures for specific use with cancer patients were judged to have adequate psychometric properties. These properties referred to the evaluation of individual instruments to assure that they were feasible for use in the setting (acceptable to patients and staff), reliable (consistent and reproducible), and valid (measure what they are supposed to measure). Other problems among HRQL instruments included a lack of focus on clinically important areas and long questionnaires that risked collecting unnecessary or confounding information. Overly long instruments can be difficult for patients or staff to complete and often result in missing data. Such problems can lead to increased patient burden, which is a particularly crucial consideration when measurement over time is expected. To overcome these problems, more recently HRQL measures have been developed with greater focus. This has been accompanied in many cases by more thorough testing to ensure that the instruments have acceptable psychometric properties for the population of interest. Developers concentrated assessment on dimensions or domains (often called “life areas”) of quality of life that were considered “healthrelated.” This resulted in a trend from developing general HRQL measures to ones specific for a disease (such as cancer); and in many cases site-specific instruments have been developed (defined as organ-specific in relation to oncology, such as measures for breast cancer). In some instances, treatment-specific measures have been developed (such as those for bone marrow transplant, or for clinical trials). In 2006, guidelines for industry use of health and qualityof-life outcomes were drafted by several federal departments, including the U.S. Department of Health and Human Services FDA Center for Drug Evaluation and Research [5]; a 2009 revision is now available [6]. These guidelines reviewed the need for strong psychometric properties and also discussed how the FDA evaluates patient-reported outcome (PRO) instruments used as effectiveness endpoints in clinical trials. Reviewers have expressed varying views on this guidance document; however, all can agree that well-validated instruments following established psychometric principles are central to proper HRQL evaluation.

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_7, © Multinational Association for Supportive Care in Cancer Society 2011

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HRQL is mainly used as a secondary endpoint in clinical trials and is not often used formally in daily practice. Paradoxically, while there are now over 650 HRQL measures on one Web site alone [7], no measures are commonly used in oncologic practice for help with clinical decision making. There are several requirements needed to have HRQL accepted as a key endpoint in research or applied in daily practice. These include (a) a greater and broader understanding by oncology health care professionals of the process of HRQL evaluation and the instruments available, (b) the use of more practical and “user-friendly” instruments that have little impact on time in busy clinical settings, and (c) the development of the incorporation of the data derived from HRQL evaluation as a formal part of clinical decision making.

The Need for Evaluating Hrql in Patients with Cancer Is there a need to measure quality of life in studies of anticancer treatments and in the management of individual patients? Survival improvements with newer therapies are often modest at best in many malignancies. With all cancers and treatments, there is variation in side effects and risk profiles. Only through acquiring patient input can one understand the balance between patient perceived benefits and the toxicities or burdens of treatment. HRQL assessment helps to assess and communicate this balance especially since health-care professionals are less accurate than patients when assessing a patient’s HRQL and patient-reported outcomes (PROs). Often in advanced malignancies, there is a clear decline in quality of life which can be seen at the time of diagnosis. Additionally, most stage III and IV cancers are highly symptomatic. Examples of this are seen in lung cancer where over 80% of patients reported that they had three or more major symptoms at their initial presentation in a trial of 673 stage III and IV patients [8], and in mesothelioma in which more than 90% of patients reported three or more symptoms prior to beginning chemotherapy [9].

HRQL and Pros: Can they be Measured and how do they Differ? The concept of quality of life has been prominent in oncology for several decades. The term quality of life was recently modified to include “health-related” to be more specific and to exclude a primary emphasis on such factors as economic considerations. While defining quality of life can be controversial, most can agree on its components or dimensions. Often five dimensions or domains (“life areas”) are identified

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as composing HRQL: physical, functional, psychological, social, and spiritual. While all are important considerations, some of these dimensions are likely to be more affected than others in patients with advanced cancer. Unlike those who are healthy, the physical and functional dimensions tend to influence the overall HRQL the most in patients with stage III and IV malignancy. Additionally, cancer treatment will typically have a greater impact on these dimensions. While all dimensions of HRQL are important, concentrating on those aspects most likely to be influenced by the intervention being used will address most clearly the purpose of the evaluation. Clinical benefit has come to refer to control of common cancer-related problems. While this term has no accepted definition, it appears to include mainly three areas of concern (pain control, weight loss, and performance status [10]). These issues are factors in almost all malignancies and have a common sense basis if not a scientific one. As discussed in the section above, quality of life is composed of several dimensions. This clinical benefit definition includes items from two important dimensions, the physical and the functional. While this bi-dimensional measure has appeal, it will clearly miss areas of great concern to many patients as reported by more than 3,500 patients with cancer [11]. While HRQL assessment encompasses clinical benefit issues, it differs in two fundamental ways: it is multidimensional, and it has carefully researched theoretical and scientific backgrounds. The acronym of “PROs” for patient-reported outcomes is relatively new and defined as subjective measures completed by self-report. PROs often emphasize evaluation of symptoms; however, other aspects can be included in PROs. Global and summative items dealing with patient perceptions of their independence, quality of life, or their activity level all can be self-reported by patients and included as part of PRO assessment.

Selecting an Appropriate Hrql Measure There are a few suggestions that can aid in choosing an appropriate quality-of-life measure among the many available. Below are six steps that are recommended to help in comparing key features and psychometric properties of HRQL measures when choosing an instrument for research or practice (Table 7.1). Psychometric properties refer to the evaluation of the instrument. With many well-tested measures available, it is usually not necessary to develop a new instrument. If one does originate an instrument, rigorous psychometric testing is mandatory. Testing ensures three properties: (1) that it is feasible (e.g., easy to use by patients and staff in terms of administration time and reading level), (2) that it is reliable (the questions are clear over time, produce similar results in similar

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Table 7.1  Steps for choosing an instrument for research or practice 1. Compare the key features of the measures of interest: • Focus • Number of items • Type of response format • Time frame for assessment • Dimensions assessed • Inclusion of therapy-related side effects • Other unique features • Available languages 2. Compare the feasibility of the instruments of interest, with good feasibility including: • Self-reporting style • Short administration time • Low reading level • Patient/staff acceptance • Multisite utility 3. Evaluate the reliability of each measure:  • Internal consistency – most used is Cronbach’s alpha, which is an indicator of undimensionality or the extent to which a set of questions reflect a single construct or answers the question of how the items relate to each other. • Stability – use of test-retest method with a short timeframe to assess the reproducibility of the measure over time, such as clarity of questions; reproducibility using test-retest method with a short timeframe to assess the clarity of items over time. • Equivalence – generally find three types: a) interrater reliability estimates agreement between or among two or more raters across sites and within sites when their judgment is used; b) intrarater reliability compares rater to self at one or more times and is needed for longitudinal studies; and c) parallel forms determines whether two forms are measuring the same attribute when one randomly selects two sets of items for the full set. 4. Examine support for validity of the measures of interest: • Content validity – validates content using logic rather than empirical testing and is usually supported by a panel of experts in the particular construct of interest who judge a) adherence to theory, b) domain representation, c) item proportionality, and d) other important aspects of the instrument. • Construct validity – addresses how well the measure captures the construct or theoretical conceptualization. Four common methods are used to obtain support for construct validity: a)  Contrasted group approach – uses high/low groups on some characteristic to determine if the measure is sensitive to the groups. b)  Relationship testing – testing of important clinical relationships drawn from the theory c)  Factor analysis – a method of reducing large set of variables (representing the construct) to a smaller set of underlying dimensions (factors) with common characteristics. d)  Multitrait-multimethod approach – in which one has two similar constructs (traits) that one wants to distinguish as well as two methods to measure each construct (e.g., patient VAS scale, observer Likert scale), resulting in a matrix depicting convergent validity (high correlation) and discriminant validity (low correlation).  • Criterion-related validity – one compares the new instrument to some other criterion that one is confident measures the construct of interest. The criterion must be the same construct but a “superior” well-known measure with strong psychometric properties (“gold-standard”); thus, the new measure must be justifiably better in some way (e.g., more specific, shorter, etc.). There are two types: a) concurrent, with measurement now; and b) predictive, with measurement in the future.   5. Determine whether a minimal important difference (MID) has been established (interpretation scores, cut-off scores). 6. Refer to the normative data for the measure, published in a manual or journal article (norms refer to collected statistical information describing scores from defined populations which can act as reference groups and aid in result interpretation).

populations, and all items relate well to one another), and (3) that it is valid (it measures what it purports to measure). Without an understanding of how to judge these properties a priori, some researchers and clinicians have used two HRQL measures, thus increasing patient and staff burden unnecessarily. Moreover, some just use the term validated to encompass all of the three properties. The first step in choosing a HRQL measure is to compare the key features of the measures of interest and to select a measure that is appropriate for the intended evaluation. These features generally include: (1) focus, (2) number of items, (3) type of response format, (4) time frame for assessment, (5) HRQL dimensions/domains assessed, (6) inclusion of

therapy-related side effects, (7) other unique features, and (8) available languages. Using HRQL measures most familiar to the author, three HRQL measures will be presented as examples: the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire, the general measure combined with the lung cancer module; the Functional Assessment of Cancer Therapy – Lung Cancer Quality-of-Life Instrument; and the Lung Cancer Symptom Scale [12–14]. These measures have good psychometric properties and are used frequently in clinical trials [15]. Focusing on the reason for evaluating quality of life in a trial or practice can help in the selection of the instrument used. It is reasonable for instruments to vary depending on the

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concepts or experiences they intend to capture. As an example, assessing quality of life a year after surgery in patients free of cancer will most likely be somewhat different than measuring quality of life in patients with advanced stages of cancer under treatment with either of two chemotherapy regimens in a randomized trial. Both assessments can be useful, and many of the same considerations are shared. However, the differences between the two situations illustrates that one evaluation solution is unlikely to address all important issues. The second step in choosing a HRQL measure is to compare the feasibility of the instruments of interest. The characteristics for good feasibility include: (1) self-reporting style, (2) short administration time, (3) low reading level, (4) patient and staff acceptance, and (5) multisite utility. It is desirable to minimize both patient and staff burden. This is especially crucial if serial measurement over time is the plan. When a measure is selected that is appropriate for the population of interest and the clinical aims of interest, it should be determined if it is important to capture each dimension in detail, or if concentrating on the dimensions likely to be affected by an intervention more globally is a better approach. Keeping patient and staff burden as low as possible will improve patient acceptance and lessen data loss. It has been proposed that the minimally acceptable percentage of evaluable cases for a clinical trial is 85% (a guideline proposed by Simon and Wittes from the National Cancer Institute, Cancer Therapy Evaluation Program [16]). Additionally, an inevaluability rate of ³15% implies inappropriate subject selection and if the disqualification rate is similar to the size of the difference being tested, the findings are not reliable [17]. An error in HRQL evaluation is for investigators or clinicians to drop or add items from a scale. This attractive but methodologically mistaken approach invalidates the published psychometric properties for an instrument and may violate an instrument’s copyright. The third step in delineating a suitable HRQL measure is to evaluate the reliability of each measure. There are three common forms of reliability: (1) internal consistency (most used is Cronbach’s alpha, which is an indicator of unidimensionality or the extent to which a set of questions reflect a single construct or answers the question of how the items relate to each other), (2) stability (use of test–retest method with a short time frame to assess the reproducibility of the measure over time, such as clarity of questions), and (3) equivalence (interrater reliability estimates agreement between or among two or more raters across sites and within sites when their judgment is used; intrarater reliability compares rater to self at one or more times and is needed for longitudinal studies; and parallel forms determines whether two forms are measuring the same attribute when one randomly selects two sets of items for the full set). Most use Nunnally’s,

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a possessive guideline of a coefficient of 0.70 or greater as an acceptable reliability coefficient for new instruments and 0.80 for established measures [18]. In 2007, the Mayo/FDA Patient-Reported Outcomes Consensus Meeting Group reiterated a minimum reliability threshold of 0.70 for group comparisons [19]. This has particular credibility in that it is the same value as recommended previously by Nunnally and the one that has been used extensively in many behavioral fields [18, 19]. The Consensus Group recommended that sample sizes for testing should include at least 200 cases initially and at least one replication; additionally a rationale is given for this recommendation [19]. The group acknowledged; however, that sample size is dependent on potential patient accrual and chosen analysis methods [19]. The fourth step in choosing an appropriate measure for HRQL assessment is to examine support for validity of the measures of interest. There are three basic types of validity: (1) content validity, (2) construct validity, and (3) criterionrelated validity. Content validity is validation of content using logic rather than empirical testing and is usually supported by a panel of experts in the particular construct of interest who judge (a) adherence to theory, (b) domain representation, (c) item proportionality, and (d) other important aspects of the instrument. Support for content validity through input of a large number of patients with the condition is highly desirable. Regulatory agencies such as the FDA have criticized some instruments for lacking this patient contribution. Construct validity addresses how well the measure captures the construct or theoretical conceptualization. Four common methods are used to obtain support for construct validity: (a) contrasted group approach, which uses high/low groups on some characteristic to determine if the measure is sensitive to the groups, (b) relationship testing of important clinical relationships drawn from the theory, (c) factor analysis, which is a method of reducing a large set of variables (representing the construct) to a smaller set of underlying dimensions (factors) with common characteristics, and (d) multitrait-multimethod approach in which one has two similar constructs (traits) that one wants to distinguish as well as two methods to measure each construct (e.g., patient VAS scale, observer Likert scale), resulting in a matrix depicting convergent validity (high correlation) and discriminant validity (low correlation). Criterion-related validity is when one compares the new instrument to some other criterion that one is confident measures the construct of interest. The criterion must be the same construct but a “superior” well-known measure with strong psychometric properties (“gold-standard”); thus, the new measure must be justifiably better in some way (e.g., more specific, shorter, etc.). There are two types: (a) concurrent, with measurement now, and (b) predictive, with measurement in the future. According to Anastasi who cites multiple sources, three criteria can be used to judge validity testing: (1) use of multiple procedures,

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(2) sequential use of these procedures, and (3) assessment of validity at various stages of instrument development [20]. Initial support for construct validity must be established after the property of reliability. As reported by the Mayo/FDA Patient-Reported Outcomes Consensus Meeting Group, construct validity provides empirical support that the measure “behaves” as predicted [19], for example, reported scores match level of illness severity. The fifth step involved in the selection of an instrument, is to determine whether a minimal important difference (MID) has been established. The MID refers to a cut-off score or score range of what is meaningful in terms of symptom change. This is now presented with each measure in addition to the psychometric properties. The MID helps lead to more consistent interpretation and statistical analysis [21]. It is important to consider the interplay of statistical and clinical significance in quality of life assessment. If a measured difference in a clinical comparison does not reach statistical significance, one cannot be certain that the finding is real. Conversely, a finding may be statistically significant, but if it is very small, it may not be clinically meaningful for patients. Statistical significance is dependent on the number of patients and the magnitude of the difference, not on whether the difference is meaningful for patients. Clinical significance is dependent on the magnitude of the difference, not the number of patients. How meaningful is the change on this scale for the patient? This is information needed for power analysis for a study as well as the clinician in practice to interpret outcomes. Developers of the three most used HRQL measures for lung cancer (EORTC-QLQ-LC13, FACT-L, and LCSS) determined minimal clinically significant differences for different quality of life scales independently [22–24]. Interestingly, the differences are all similar. The minimal clinically meaningful change on these HRQL measures seems to be about a 10% difference. The dilemma of determining MID as well as statistically significant results exists in all oncologic research. Finally, a sixth step that adds to assessing HRQL instruments is to determine if there are published normative data in a manual or journal article for the measures. Norms refer to collected statistical information describing scores from defined populations, which can act as reference groups and aid in result interpretation [18]. Table 7.2  Strategies for overcoming dilemmas in HRQL measurement 1. Select an HRQL measure with features appropriate for the population of interest and purpose of the assessment 2. Ascertain that the measure has well-established psychometric properties of feasibility, reliability, and validity 3. Measure HRQL at appropriate intervals 4. Choose an HRQL measure with a defined minimally important difference to help with consistent interpretation of scores 5. Select an HRQL measure with published norms when possible to provide descriptive statistics for reference group

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Table 7.3  Examples of HRQL Web sites • The Mapi Research Institute/Trust at http://proqolid.org/proqolid/ layout/set/print • Patient Reported Outcomes Measurement Group for University of Oxford at http://phi.uhce.ox.ac.uk/ • European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group at http://groups.eortc.be/qol/ • Functional Assessment of Chronic Illness Therapy (FACIT) at http://www.facit.org/ • Lung Cancer Symptom Scale (LCSS) at http://www.lcss-ql.com

These strategies to consider when planning HRQL measurement have been summarized for reference (Table  7.2). They include selecting an HRQL measure with features appropriate for the population of interest and purpose of the assessment, ascertaining that the measure has wellestablished psychometric properties of feasibility, reliability, and validity, measuring HRQL at appropriate intervals (see the section below), choosing an HRQL measure with a defined MID, and selecting an HRQL measure with published norms when possible.

Finding Tested HRQL and PRO Instruments There are now large compendia describing HRQL instruments in book format as well as databases on the Internet. Several examples of online web sites are listed in Table 7.3. One online compendium of quality-of-life measures, PROQOLID by the Mapi Research Institute, has over 650 instruments listed. These measures are for all diseases, including cancer [7]. The U.S. National Institutes of Health has established a cooperative agreement mechanism for individual research teams to provide access to a common repository of HRQL items, called the Patient-Reported Outcomes Measurement Infor­mation System (PROMIS) initiative [25, 26]. In addition, many of the instruments have dedicated web sites. Each of these sources can be easily found by using common computer search engines.

Appropriate Interval for Assessing HRQL and PROs The appropriate frequency for repeating assessments remains an unanswered question in many aspects of cancer clinical trials. How often should tumor measurements be repeated in a chemotherapy trial in advanced pancreatic cancer, or in stage III breast cancer? Similarly, the frequency of HRQL and PRO assessment has not been established for most settings in many malignancies. Two exceptions are found in lung cancer and mesothelioma [27, 28]. In both cases, various intervals of assessment (from twice weekly to every

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6 weeks) were analyzed. The results indicated that an every 3-week evaluation in these diseases is an appropriate HRQL interval for use in clinical trials of these malignancies. As discussed above, this frequency retained nearly 95% of the information that would be found with weekly or twice weekly assessment and helps to minimize the burden on patients and staff. Diseases and stages with a less rapid trajectory may not require assessment as frequently; however, trials directed at determining the proper frequency need to be conducted.

Steps to Improve Adherence and to Address Missing Data Quality-of-life assessments and studies are often troubled by missing data [29]. These occur for two major reasons. The first is that HRQL data may not be collected. The second is that as a patient’s disease progresses, HRQL assessments are often omitted. For clinical trials, statisticians have labored over models, which remain controversial, to correct for such missing data. All can agree that in a clinical strategy, the best approach is to collect the data. Most instruments are not difficult to administer, and good instruments are highly accepted by patients. Rather than search for statistical strategies (this is not done for missing imaging or laboratory studies), better planning includes using an appropriate assessment interval as a part of the study design and emphasizing to investigators that the HRQL data must be collected with the same rigor as any other part of the trial. Another key source of missing information occurs when a patient goes off treatment. Just as we do not stop measuring survival when a patient completes a treatment course, HRQL needs to be followed thereafter as well. Treatment side effects or benefits may occur well after completion of the therapy. It has been shown that those patients with lower HRQL at the outset of a trial have a markedly poorer prognosis. Dropouts from studies are not random; those with poor baseline HRQL drop out at a faster rate [30]. It may be useful to envision the entire “amount” of quality of life of each patient in a trial, rather than examine HRQL at an arbitrary time.

Barriers to HRQL Assessment and Strategies to Improve Acceptance One representative survey sampled 260 oncologists, with 59% responding. Morris and colleagues [31] found that 80% believed that HRQL information should be collected before treatment, yet only 50% assessed any such information. Not surprisingly, fewer than half evaluate such information to monitor patients’ response to treatment. These oncologists

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reported their perceived barriers as including: (1) insufficient time and resources, and (2) a lack of knowledge of appropriate HRQL instruments. Recently, many developers of HRQL instruments have turned to technology to deal with this problem. Several different approaches to computerization of validated instruments have been tested with different types of computeradministered versions (e.g., EORTC item bank, FACIT multimedia touch screen program, and eLCSS-QL and ePCSS-QL using handheld computers). By doing this, HRQL instruments in many languages are easily available and data are automatically stored in the computer without need for transcription. With some programs, results of the patient’s responses are immediately available and can show results over time without effort. A recent example using the eLCSS-QL (the computerized version of the LCSS using a hand held pocket PC or “PDA”) was tested in a trial in patients with lung cancer [32]. Nearly all of the 148 patients found that this format was easy to learn and easy to use; 98% found that it was acceptable to complete the evaluation at every 3-week visit to the clinic. Most found that this enhanced their awareness of PRO issues and fostered discussion with their treatment team. Additionally, nurses and physicians found the instrument highly successful and that it enhanced their satisfaction with the patient’s visit. Physicians found that this assessment added no time to the visit and felt that they could assess a patient’s progress more readily with the availability of the HRQL results. Further trials will test these findings in a larger group of patients, and health-care professionals will see if fewer imaging tests are needed.

Conclusions HRQL and PRO assessments have become more frequently used, and useful instruments have become more available, straight-forward, and easier to analyze. Consensus on methods of analyzing and presenting these endpoints is progressing with several groups now meeting to provide more guidance and developers presenting to groups on an ongoing basis. There is strong support for assessing HRQL in clinical trials. Important lessons learned from multisite clinical trials such as the pemetrexed mesothelioma trial demonstrate that HRQL can successfully complement classical endpoints in oncology trials and can illustrate that small survival benefits are particularly valued if they are also associated with quality of life and PRO benefits [9]. In Table  7.4, lessons learned that enhance successful HRQL assessment are listed. A broader question deals with whether HRQL assessment should be incorporated into daily practice. A recent Phase III trial illustrated both the usefulness of HRQL evaluation in

7  Quality-of-Life Assessment: The Challenge of Incorporating Quality-of-Life and Patient-Reported Outcomes Table 7.4  Lessons learned from conducting large HRQL multicenter/ multinational trials 1. Emphasis on HRQL/PRO Importance: a) Outline and emphasize HRQL methodology and its importance at study initiation b)  Incorporate HRQL data in randomization criteria c)  Continue emphasis throughout the trial d) Recognize and ascertain that investigators understand that patients value HRQL and PRO assessment; failure to obtain these data is an investigator problem and not a patient acceptance issue e)  RESULT ⇒ 90% compliance in large multinational trials 2. Methodology and Analysis Considerations: a)  Use of reliable and valid instrument ⇒ LCSS-Meso b) Define time-frame of interest, collect data throughout this period c)  Detail prospectively planned analysis d) Include the entire period of interest, not just the time of treatment period and not just “snap shot” during the trial e) Consider and plan for statistical issues involved with multiple assessments and comparisons

trials and its potential impact in patient management. In this example, 488 patients with advanced lung cancer were randomly assigned to receive either pemetrexed or docetaxel. de Marinis and colleagues concluded that HRQL data (using the validated LCSS instrument) “…provides complementary efficacy information that can guide routine clinical practice” [33, p. 30]. Thus, HRQL evaluation was necessary for the clinical trial, but at the same time it provided additional information that was vital for clinical decision making, that would not have been available from scans and examinations. Only through HRQL assessment can the full impact of the treatment on the patient be evaluated sufficiently. Physicians and nurses do this informally; however, formal evaluation with validated instruments provides a more reliable assessment and includes the patient in a more rigorous manner. The challenge is to continue to make the HRQL/PRO instruments easier to administer and to use in daily practice. Additionally, even with user-friendly instruments, incorporating such measures into daily practice represents a major change in how health-care professionals evaluate patients. Questions remain as to whether there is economic benefit in using HRQL/PRO measures in this manner and whether they can aid in earlier assessment of treatment efficacy. Welldesigned trials can help address these issues and lead to more shared decision making with the use of HRQL and PRO information.

References 1. Karnofsky DA, Burchenal JH: (1949) The clinical evaluation of chemotherapeutic agents in cancer, in MacLeod CM (ed): Evaluation of Chemotherapeutic Agents. Symposium, Microbiology Sections,

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New York Academy of Medicine, New York, NY, Columbia University Press, pp 191–205 2. Johnson JR, Temple R: (1985) Food and Drug Administration requirements for approval of new anticancer drugs. Cancer Treat Rep 69:1155–1157. 3. Outcomes Working Group, Health Services Research Committee, American Society of Clinical Oncology. (1996) Outcomes of cancer treatment for technology assessment and cancer treatment guidelines. Journal of Clinical Oncology, 14:671–9. 4. Donovan K, Sanson-Fisher RW, Redman S: (1989) Measuring quality of life in cancer patients. Journal of Clinical Oncology, 7:959–968. 5. U.S. Department of Health and Human Services FDA Center for Drug Evaluation and Research Guidance for industry: (2006) Patient-reported outcome measures: use in medical product development to support labeling claims: draft guidance. Health and Quality of Life Outcomes, 4: 79. 6. U.S. Department of Health and Human Services (2009) FDA Center for Drug Evaluation and Research; U.S. Department of Health and Human Services FDA Center for Biologics Evaluation and Research; U.S. Department of Health and Human Services FDA Center for Devices and Radiological Health. Guidance for industry, (2006) Patient-reported outcome measures: use in medical product development to support labeling claims. draft guidance. Health and Quality of Life Outcomes, 11;4–79. 7. Emery M, Perrier L, & Acquadro C, Patient-Reported Outcome and Quality of Life Instruments Database (PROQOLID): (2005) Frequently asked questions. Health and quality of life outcomes, 3,12. Retrieved from http://www.hqlo.com/content/3/1/12. 8. Gralla RJ, Hollen PJ, Eberly S, & Cox C. (1995). Quality of life score predicts both response and survival in patients receiving chemotherapy for non-small cell lung cancer. 7th MASCC International Symposium, Luxembourg, September 20–23, 1995. Supportive Care in Cancer, 3 (5), 378. 9. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham J, Kaukel E, Ruffie P, et al. (2003). Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clinical Oncology, 21: 2636–2644. 10. HA Burris, MJ Moore, J Andersen, MR Green, ML Rothenberg, MR Modiano, MC Cripps, RK Portenoy, AM Storniolo, P Tarassoff, R Nelson, FA Dorr CD Stephens and DD Von Hoff. (1997). Improvements in survival and clinical benefit with gemcitabine as first- line therapy for patients with advanced pancreas cancer: a randomized trial. Journal of Clinical Oncology, 15: 2403–2413. 11. Raftopoulos H, Gralla RJ, Hollen PJ, Davis BJ, Petersen JA, & Horigan JL (2010) What do patients rank as more important in quality of life (QL) and patient reported outcome (PRO) evaluation: symptoms or summative assessments? Results of a 3860 patient survey in lung, breast and prostate cancers with implications for drug development. Journal of Clinical Oncology, (abstract) In press. 12. Bergman B, Aaronson NK, Ahmedzai S, et al: The EORTC QLQ-LC13: (1994) A modular supplement to the EORTC core Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials. Eur J Cancer 30A: 635–642. 13. Cella DF, Bonomi AE, Lloyd SR, Tulsky DS, Kaplan E, Bonomi P: (1995) Reliability and validity of the Functional Assessment of Cancer Therapy – Lung (FACT-L) quality of life instrument. Lung Cancer 12:199–220. 14. Hollen PJ, Gralla RJ, Kris MG, Potanovich, L et al.: (1993) Quality of life assessment in individuals with lung cancer: Testing the Lung Cancer Symptom Scale (LCSS). Eur J Cancer 29A:S51-S58. 15. Earle CC, & Weeks JC, (2005). The science of quality-of-life measurement in lung cancer. In outcomes assesments in cancer(1st ed.) In J. Lipscomp, C.C. Gotay & C. Snyder (Eds.), Outcomes assessments in cancer: Measures, methods and applications (pp. 160–177). Cambridge: Cambridge University Press.

70 16. Simon R, & Wittes RE: (1985) Methodological guidelines for reports of clinical trials, Cancer Treat Rep 69:1–3. 17. Simon R, Friedman MA (1992) The design and interpretation of clinical trials. In: Perry MC (ed) The chemotherapy source book. Baltimore: Williams & Wilkins, 130–143. 18. Nunnally JC, Bernstein PH: Psychometric theory (eds). (1994) New York, NY, McGraw-Hill. 19. Landis JR, Koch GG:. (1997) The measurement of obserrer agreement for categorical data. Biometrics 33:159–174. 20. Anastasi A. (1988). Psychological testing (6th ed). New York, NY, Macmillan. 21. Revicki DA, Cella D, Hays RD, Sloan JA, Lenderking WR, & Aaronson NK. (2006). Responsiveness and minimal important differences for patient reported outcomes. Health and Quality of Life Outcomes 2006, 4:70 doi:10.1186/1477–7525–4-70; Retrieved from http://www.hqlo.com/content/4/1/70 22. Bottomley A, Gaafa R, Manegold C, Burgers S, Coens C, Legrand C, et al. (2006). Short-term treatment-related symptoms and quality of life: Results from an international randomized Phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: An EORTC Lung-Cancer Group and National Cancer Institute, Canada, Intergroup Study. Journal of Clinical Oncology, 24, 1435–1442. 23. Cella D, Eton TD, Fairclough DL, Bonomi P, Heyes AE, Silberman C, et al. (2009). What is a clinically meaningful change on the Functional Assessment of Cancer Therapy–Lung (FACT-L) Questionnaire? Results from Eastern Cooperative Oncology Group (ECOG) Study 5592. Journal of Clinical Epidemiology, 55 (3), 285–295. 24. Hollen PJ, & Gralla RJ. (2000) Clinical vs statistical significance: Using the LCSS quality of life instrument and Karnofsky performance status (KPS) to approach the problem in patients with non-small cell lung cancer. Journal of Clinical Oncology, 19, Abstract 636. 25. Cella D, Gershon R, Lai J, & Choi S, (2007a). The future of outcomes measurement: Item banking, tailored short-forms, and computerized adaptive assessment. Quality of Life Research, 16 (Supp1), 133–41.

R.J. Gralla and P.J. Hollen 26. Garcia SF, Cella D, Clauser SB, Flynn KE, Lai J, Reeve BB, Smith A, et al. (2007). Standardizing patient-reported outcomes assessment in cancer clinical trials: A patient-reported ­outcomes measurement information system initiative. Journal of Clinical Oncology, 25, 5106–12. 27. Hollen PJ, Gralla RJ, & Rittenberg CN. (2004). Quality of life as a clinical trial endpoint: Determining the appropriate interval for repeated assessments in patients with advanced lung cancer. Supportive Care in Cancer, 12, 767–773. 28. Liepa AM, Hollen PJ, Gralla RJ, & Rusthoven JJ. (2002) Does Timing of QOL Evaluation Make a Difference? Using the Lung Cancer Symptom Scale (LCSS) Modified for Mesothelioma as an Example. 9th Annual Meeting of the International Society for Quality of Life Research, Orlando, FL, October 30-November 2, 2002. 29. Fairclough DL, Peterson FH, Chang V. (1998) Why are missing quality of life data a problem in clinical trials of cancer therapy? Stat Med 17: 667–677 30. Hollen PJ, Gralla RJ, Cox C, Eberly SW, & Kris MG. (1997). A dilemma in analysis: Issues in the serial measurement of quality of life in patients with advanced lung cancer. Lung Cancer, 18, 119–136. 31. Morris J, Perez D, McNoe B: The use of quality of life data in clinical practice. (1998) Quality of Life Research 7, 85–91. 32. Gralla RJ, Hollen PJ, Leighl NB, Meharchand JM, Krieger H, & Solow, H. (2006) A prospective evaluation of the attitudes of patients, physicians and nurses after using a computer-assisted quality of life instrument (LCSS-QL) as part of a multicenter clinical trial in Non-Small Cell Lung Cancer (NSCLC). Journal of Clinical Oncology, 24, 18S, Abstract 6123. 33. de Marinis F, Rodrigues J, Pereira JR, Fossella F, Perry MC, Reck M, Salzberg M, Jassem J, Peterson P, Liepa AM, Moore P, & Gralla RJ (2008). Lung Cancer Symptom Scale outcomes in relation to standard efficacy measures: An analysis of the phase III study of pemetrexed versus docetaxel in advanced non-small cell lung cancer. Journal of Thoracic Oncology; 3:30–36.

Part III

Cardiovascular

Chapter 8

Cardiac Toxicities of Cancer Therapies: Challenges for Patients and Survivors of Cancer Winson Y. Cheung

Introduction Modern developments in diagnostic and treatment strategies within all aspects of cancer management – medical, surgical, and radiation oncology – mean that an increasing number of patients who are diagnosed with cancer today will live to become long-term cancer survivors. The majority of these individuals would have received some form of anticancer treatment during the course of their illness as a means to ­control their cancer or manage their symptoms. Because many systemic therapeutic agents, including chemotherapy and molecularly targeted therapy, as well as radiation techniques can be associated with acute, early, or late cardiac toxicities, a significant number of patients with a prior history of cancer are at risk of developing cardiovascular ­complications. Manifestations are diverse and can span the full spectrum of cardiac arrhythmias, cardiomyopathies, and ischemic heart diseases. In addition to worsening overall quality of life, these conditions are frequently irreversible or fatal; therefore, they highlight the importance for members of the cancer care team to share a basic awareness of the potential risk factors, causes and management of these ­various cardiac toxicities. Chemotherapy-related cachexia, emesis, and myelosuppression are dose-limiting toxicities which in the past have prevented the administration of chemotherapy doses that are sufficiently high enough to cause cardiac toxicities. Over the last decade, however, advances in symptom control and supportive care measures, including the frequent use of 5-HT3 antagonists (e.g., ondansetron, granisetron) and granulocyte colony-stimulating factors, have not only improved patient tolerability towards chemotherapy, but they have also allowed

W.Y. Cheung (*) British Columbia Cancer Agency, Division of Medical Oncology, 600 W. 10th Avenue, 4th Floor, Vancouver, BC, Canada V5Z 4E6 e-mail: [email protected]

clinicians to deliver more intensive and prolonged courses of treatment in an effort to maximize cancer control. With the uptake of more aggressive systemic treatment regimens, cardiac complications are increasingly recognized in a growing population of cancer patients and survivors. The more widespread availability of imaging facilities coupled with recent improvements in radiographic modalities have further resulted in the detection of more subclinical cardiac abnormalities. Conversely, newer radiation techniques are designed to limit unnecessary exposure to vital organs, such as the heart. Such efforts have decreased the incidence of radiation-related cardiac dysfunction, but some degree of risk remains. Cardiac toxicities can be classified as “acute” (e.g., those that occur during or immediately after chemotherapy administration), “early” (e.g., several hours, days, or months after chemotherapy delivery), or “late” (e.g., years to decades after chemotherapy or radiation exposure). As clinicians develop a higher vigilance for the risk of treatment-related cardiac toxicities, a variety of strategies have been employed to minimize this serious risk without unnecessarily compromising treatment efficacy. These various strategies include modifying the schedule of drug administration or radiation exposure, altering the actual drug molecule or the vehicle for drug delivery, or using adjunctive “cardioprotective” agents during active treatment. Unfortunately, none of these approaches has proven to be completely successful, thereby underscoring the ongoing need to closely monitor patients who are either currently receiving or have previously received potentially cardiotoxic agents. In this chapter, the cardiotoxicity profiles of several pertinent, commonly used classes of anticancer agents, including anthracyclines (e.g., doxorubicin, epirubicin), molecularly targeted drugs (e.g., trastuzumab), nonanthracyclines (e.g., 5-fluorouracil, taxanes), and radiotherapy will be introduced and discussed. There will be an emphasis on anthracyclines since they are the most frequently implicated agents for cancer treatment-related cardiac dysfunction. Potential cardiovascular side effects of hormonal anticancer treatments are beyond the scope of this review.

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_8, © Multinational Association for Supportive Care in Cancer Society 2011

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Anthracyclines Background As a chemotherapy drug class, anthracyclines act by inserting into the DNA of replicating cells. This process causes fragmentation of the DNA, which in turn leads to inhibition of polymerases, a subsequent decrease in protein synthesis, and ultimately cell death. Because cancer cells are rapidly proliferating, these various inhibitory actions of anthracyclines can confer effective antitumor activity. Interestingly, the mechanisms by which anthracyclines contribute to cardiac dysfunction and myocardial damage probably differ from its anticancer effects, particularly since myocytes of the heart are not actively replicating. One possible mechanism for their cardiotoxicity is that anthracyclines cause a significant decrease in endogenous levels of antioxidant enzymes that are normally responsible for scavenging oxygen free radicals throughout the body. Upon exposure to anthracyclines, elevated levels of these toxic free radicals are likely produced. This can lead to an increase in oxidative stress, which may then cause an accumulation of fibrous tissue around myocytes and result in irreversible myocardial damage [1].

Risk Factors Specific clinical factors have been identified that predispose individuals to an elevated risk of developing anthracyclineinduced cardiac toxicities. One of the strongest and most reliable predictors is the cumulative dose of anthracycline drug delivered. In the case of doxorubicin, for example, adults who have received a cumulative dose of 400, 550, and 700 mg/m2 have been shown to experience a 3, 7, and 18% risk, respectively, of experiencing cardiac dysfunction [2]. Based largely on this observation, patients receiving doxorubicin are recommended not to exceed a cumulative dose of 550 mg/m2. For epirubicin, there is a similar recommendation, but the maximal cumulative dose is set at 900 mg/m2. While these cumulative dose thresholds serve as a general guideline for clinicians and patients, treatments should ­ideally be individualized. With the availability of noninvasive surveillance techniques, such as echocardiograms and MUGA scans, that can assess cardiac function, therapy should be stopped at much lower cumulative doses if there is early evidence of cardiac dysfunction. Conversely, treatment to higher cumulative doses may also be considered if there are no signs of cardiac toxicities or if anthracyclines are clinically indicated for maintaining tumor control. Extreme age is another well established risk factor. Children have been consistently shown to develop cardiac

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toxicities at much lower cumulative doses than in adults. A similar relationship is observed in older patients, many of whom have preexisting hypertension or heart conditions. The precise reasons for this age-related association are unclear, but it is possible that the very young and very old age groups have less functional cardiac reserve to accommodate the strain that anthracyclines place on myocytes [3]. In a similar manner, a prior history of radiotherapy also increases susceptibility to cardiotoxic effects, possibly because of diminished cardiac reserve caused by previous radiation exposure. This is particularly evident for those who have received mediastinal or chest wall irradiation. Such exposures probably introduce moderate degrees of damage to the cardiac endothelium and coronary blood vessels, and subsequent treatment with anthracyclines results in further insults to the heart [4]. Likewise, the use of cardiotoxic nonanthracycline agents in combination with anthracyclines often poses a synergistic toxic effect. One common example would be the concurrent or sequential administration of taxanes and trastuzumab, both of which are cardiotoxic, along with anthracyclines for the management of both early and advanced stage breast cancers [5, 6].

Clinical Manifestations Cardiac toxicities can manifest in many different ways and the severity of dysfunction is also highly variable. Toxicities may present as rhythm disturbances (such as atrial fibrillation), constitutional symptoms from pericarditis or myocarditis, chest discomfort due to cardiac ischemia, or dyspnea as a result of heart failure. The latter is associated with the most morbidity burden. Fortunately, acute and serious forms of these cardiac events are rare, and many are actually subclinical in nature with minimal sequelae. Therefore, formal cardiac monitoring is usually not warranted during the initial administration of anthracyclines, unless there are pertinent findings on patient history, physical examination, or recent cardiac tests that suggest a heightened risk for complications. While acute cardiac dysfunction may occur, the peak time for the appearance of cardiac toxicities is typically about 3–6 months after the last anthracycline dose, at which point serial monitoring of cardiac function should be considered. If early symptoms and signs of possible cardiomyopathy are left undetected or untreated, mortality can exceed 50% [7]. Fortunately, the advent and widespread use of primary and secondary cardiopreventive drugs, such as angiotensin converting enzyme (ACE) inhibitors and b-blockers, in recent years has permitted more aggressive management of such toxicities. According to some preliminary reports, the use of these agents in the setting of chemotherapy-related cardiac dysfunction has resulted in improved quality of life and overall survival [7].

8  Cardiac Toxicities of Cancer Therapies: Challenges for Patients and Survivors of Cancer

Although less common, the onset of cardiac dysfunction can occur more than 10 years after the last dose of anthracycline administered, as evident by cases of serious heart failure found among long-term childhood cancer survivors, who were previously treated with high doses of anthracyclines as part of their chemotherapy regimens. In most of these situations, the cardiac abnormality presents as nonischemic dilated cardiomyopathy. Interestingly, the risk of such late cardiac problems appears to be lower among young women with early stage breast cancers who have received only a short, adjuvant course of anthracycline-based chemotherapy, with the proviso that the cumulative dose did not exceed 300  mg/m2 [4]. This finding further emphasizes the strong dose–response pattern that exists between the cumulative dose administered and risk of cardiac toxicities. One important caveat remains: when compared to those receiving chemotherapy without anthracyclines or those not given any chemotherapy at all, the overall cardiac risk remains higher in patients who have previously been treated with any anthracyclines, irrespective of dose.

Minimizing the Risk Several approaches have been introduced to potentially lower  the risk of anthracycline-induced cardiac toxicities, including: (1) altering the schedule of drug administration, (2) encapsulating the anthracycline drug molecule within liposomes, and (3) using adjunctive “cardioprotective” agents during treatment. Along with these strategies, intensive and serial monitoring with noninvasive cardiac imaging techniques has also been advocated to detect the earliest possible evidence of cardiotoxicity, at which point prompt and necessary measures can be taken to prevent the development of more severe forms of cardiac dysfunction. A continuous infusion of anthracycline over the course of 48–96 hours may lower the incidence of cardiotoxicity. This potential benefit has been suggested based on small observational studies, which showed that patients treated with prolonged infusions of anthracyclines were less likely to develop heart problems, defined as >10% reduction in left ventricular ejection fraction, when compared to those who received the conventional bolus treatment [8]. Interestingly, there was also a trend towards an increased rate of metastasis in the subset of individuals receiving infusion therapy. For this reason, in spite of possible cardioprotective effects from infusional delivery, anthracyclines are still typically administered by the bolus route. There are also ongoing efforts aimed at modifying the anthracycline molecule to minimize cardiotoxic effects, while maintaining its antitumor efficacy. A prime example of this strategy is the incorporation of anthracyclines into liposomes,

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which has been shown in studies to have a similar efficacy as free, unbound anthracyclines. In addition, this formulation is appealing because it lowers the incidence of cardiac ­dysfunction and also permits substantially higher cumulative doses to be delivered [9]. Finally, the use of adjunctive cardioprotective agents, such as dexrazoxane, in conjunction with anthracyclines may reduce cardiotoxicity. Dexrazoxane is an EDTA-like chelator [10]. It can be used at the onset of anthracycline treatment or started only after a cumulative dose of 300 mg/m2 has been reached. In either scenario, it has been shown in randomized controlled trials to reduce the incidence of anthracyclineassociated heart failure [11]. Dexrazoxane is believed to prevent cardiac damage by binding to iron stores that are released from intracellular storage during oxidative stress. While this cardioprotective agent can be helpful, it is imperfect amidst concerns of its potential to interfere with cancer therapy, its apparent association with lower treatment response rates, and its possible exacerbation of anthracycline-induced myelosuppression [12]. Unfortunately, data in these areas have been inconsistent; thus, it is currently unclear whether the benefits of dexrazoxane truly outweigh its risks. At the present time, the American Society of Clinical Oncology endorses the use of dexrazoxane only for patients who have received a cumulative dose of doxorubicin ³300 mg/m2 or an equivalent dose of epirubicin for the treatment of metastatic disease. Given its potential detrimental impact on antitumor efficacy as well as on myelosuppression, dexrazoxane is not recommended for use in the adjuvant setting when the goal of therapy is cure. Of clinical relevance, the use of dexrazoxane never completely eliminates the risk of cardiotoxicity. As such, its use does not preclude the need for regular ­cardiac monitoring. Preliminary research points towards a possible benefit of administering b-blockers and ACE inhibitors with anthracyclines as a primary preventive measure against cardioto­xicity. In some of these prior studies, the prophylactic use of b-blockers, ACE inhibitors or both was associated with ­better preservation of left ventricular ejection fraction [13]. Definitive conclusions, however, are difficult to draw as data in this regard have been based on small retrospective studies and will require further prospective validation. Whether ­benefit from these agents is statistically and clinically ­significant remains to be seen.

Cardiac Monitoring Since methods to eliminate anthracycline-related cardiac ­dysfunction are not absolute, serial cardiac monitoring continues to be an important component in the ongoing management of anthracycline-treated patients so that the earliest possible

76 Table 8.1  Recommendations for cardiac monitoring in patients receiving anthracyclines A baseline assessment of left ventricular ejection fraction is recommended before starting treatment with an anthracycline Anthracyclines should not be administered if left ventricular ejection fraction is less than 30% If ejection fraction is between 30 and 50%, ejection fraction should be reevaluated prior to each dose of anthracycline Anthracyclines should be discontinued if there is cardiotoxicity, defined as an absolute decrease in ejection fraction by greater than 10% or a final ejection fraction of less than 30% Serial reassessments of ejection fraction should be performed once the cumulative dose threshold has been reached, and even sooner in patients with known heart disease, radiation exposure, or abnormal electrocardiographic results

evidence of cardiotoxicity can be detected. A variety of monitoring techniques have been employed; one set of proposed guidelines is shown in Table 8.1. Echocardiography is perhaps the most frequently used, noninvasive strategy for evaluating left ventricular ejection fraction. This modality is currently endorsed by the American College of Cardiology for monitoring anthracycline-induced cardiotoxicity. Owing to its widespread availability and its lack of radiation exposure, echocardiograms remain a popular standard. Disadvantages, however, include its poor reproducibility and variability in interpretation among clinicians. In addition, it can be occasionally difficult to accurately quantify the global ventricular function. A related approach is the use of multigated blood pool imaging, also known as the MUGA scan, which has become a well-regarded technique for monitoring cardiac dysfunction. This modality is sometimes preferred given its ability to detect cardiotoxicity at very early stages of dysfunction, even before the development of clinical symptoms of heart failure. Specifically, the MUGA scan can identify increased interstitial fibrosis of the heart by measuring subtle changes in systolic and diastolic function. As a result of such early detection, some cardiac abnormalities may be potentially reversible. A case in point: In a small study, patients who experienced an asymptomatic absolute decline in ejection fraction of 15% based on MUGA were discontinued on doxorubicin. Upon treatment cessation, none of the patients progressed to symptomatic heart failure when followed. In fact, repeat measurement of ejection fraction several months after stopping doxorubicin showed a modest improvement in ejection fraction in all patients [14]. There is also emerging interest in exploring newer approaches to cardiac monitoring. Cardiac magnetic resonance imaging, for instance, may be particularly useful for patients where there is significant concern about changes in cardiac structure (rather than function) induced by cancer drug exposure. Alternately, there is ongoing research to clarify the role of cardiac biomarkers, such as troponin and natriuretic

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peptide. The hypothesis is that these biomarkers may provide earlier signs of cardiac damage than any other ­standard imaging techniques. In preliminary studies, elevations in troponin and natriuretic peptide were associated with the severity of myocardial damage secondary to anthracyclines, correlated with the degree of decrease in left ventricular ejection fraction, and were predictive of subsequent cardiac-related morbidity and mortality [15]. A related question that remains unanswered is whether elevations in these biomarkers predict response to conventional therapeutic agents for heart failure, such as b-blockers and ACE inhibitors. Overall, these early data are promising for identifying early anthracycline-related cardiotoxicity, but there is insufficient evidence to support their use at the present time. Finally, it is important to recognize that the “gold ­standard” of assessing anthracycline cardiotoxicity is the endomyocardial biopsy since this method allows for direct evaluation of both the presence and the degree of cardiac damage [16]. Characteristic features of chemotherapy-related injury include depletion of myofibrillary bundles, evidence of myofibrillar lysis, mitochondrial disruption, and intramyocyte vacuolization. Understandably, this procedure is invasive and itself carries the risk of complications, such as arrhythmias and bleeding. Furthermore, the interpretation of the biopsy specimens requires special expertise in histology and pathology. For these reasons, endomyocardial biopsy has typically been reserved for patients in whom a definitive diagnosis is required or for those whom noninvasive imaging modalities fail to ­provide adequate information regarding the cardiac functional status.

Prognosis and Management The short- and long-term prognosis of individuals affected by anthracycline-induced cardiac toxicities appears to depend heavily on the severity and stage of cardiac symptoms at the time when dysfunction is initially diagnosed. This observation further underscores the importance of prompt and early detection. Patients who manifest with clinical symptoms at diagnosis have a worse outcome when compared with those who present with an asymptomatic decrease in left ventricular ejection fraction. Currently, it is unclear whether patients with chemotherapy-associated cardiac dysfunction respond to similar medical therapy, such as b-blockers and ACE inhibitors, as those with heart failure from other causes, although preliminary data suggest that there is some benefit with this approach [13]. Likewise, it is uncertain if prophylactic use of such drugs will prevent the risk of developing treatment-related cardiac dysfunction. At least one study suggests that ACE

8  Cardiac Toxicities of Cancer Therapies: Challenges for Patients and Survivors of Cancer

inhibitors should be considered as first-line treatment for both asymptomatic left ventricular dysfunction and symptomatic heart failure. In this small series of women with metastatic breast cancer who received epirubicin, 7 of 8 women treated with ACE inhibitors had an increase in ejection fraction ³15% whereas only 1 of 33 women without ACE inhibitor therapy demonstrated a similar response [13]. Until more evidence becomes available, medical management of chemotherapy-related heart failure should incorporate the use of these medications. To this end, most experts also concur that for patients in whom anthracycline-induced cardiotoxicity is refractory to standard medical therapy, interventions such as cardiac resynchronization therapy should at the very least be considered.

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e­ mbryonic cardiac development. It also participates in ­protecting the heart from potential cardiotoxins where studies show that HER-2 gene knockout mice are more likely to develop dilated cardiomyopathy and their myocytes demonstrate increased susceptibility to anthracycline-induced cell death [18]. In further support, serum HER-2 levels appear to be increased in patients with chronic heart failure with levels correlating inversely with left ventricular function [19]. The following section briefly reviews the clinical manifestations of trastuzumab cardiotoxicity, the guidelines for monitoring cardiac function during treatment, and the management of patients who experience cardiotoxicity as a result of trastuzumab exposure.

Risk Factors Trastuzumab Background Trastuzumab is a humanized monoclonal antibody that binds to HER-2 on the surface of breast cancer cells, and inhibits downstream signal transduction, thereby resulting in cellular growth inhibition. For the approximately 20–25% of the breast cancer patient population whose tumors overexpress HER-2, this molecularly targeted agent has quickly become an important component in the management of both locally advanced and metastatic disease. More recently, trastuzumab has also been integrated into many adjuvant chemotherapy regimens for the treatment of early stage, HER-2 overexpressing breast cancers due to the statistically significant survival benefit that has been demonstrated in several large randomized controlled trials. Importantly, these benefits must be carefully weighed against the added risk of cardiac toxicities from trastuzumab treatment. The precise mechanisms underlying trastuzumab-associated cardiac dysfunction are as yet unclear. Of note, considering that many patients who receive trastuzumab have also been previously treated with anthracyclines, it was once postulated that potentiation of prior anthracycline-induced cardiac damage was the most responsible factor. However, histopathological studies from endomyocardial biopsy specimens from individuals with trastuzumab-related cardiac dysfunction have refuted this hypothesis, since anthracycline-based structural changes were not always observed. Moreover, trastuzumab dysfunction can develop even in the setting of anthracycline-naïve patients. Preliminary studies indicate that trastuzumab cardiotoxicity may be directly related to HER-2 blockade [17]. Early animal models, for instance, suggest that HER-2 signaling is an important step in

The overall incidence of cardiac dysfunction from trastuzumab alone ranges between 3 and 8%, but the rate becomes significantly higher among individuals who receive trastuzumab concurrently with other potentially cardiotoxic agents, especially anthracyclines and taxanes [20]. In the pivotal phase III trial that evaluated the benefit of adding trastuzumab to conventional cytotoxic chemotherapy for metastatic breast cancer, the incidence of any cardiac dysfunction was 27% for trastuzumab plus adriamycin and cyclophosphamide (AC) vs. 8% for AC alone, and 13% for trastuzumab plus paclitaxel vs. 1% for paclitaxel alone [6]. As expected, the incidence of severe heart failure, consisting of either class III or IV symptoms, was substantially lower: 16% with trastuzumab plus AC vs. 4% for AC alone and 2% with trastuzumab plus paclitaxel vs. 1% for paclitaxel alone [6]. These findings resulted in the recommendation that concurrent delivery of anthracyclines and trastuzumab be generally avoided or used with great caution in favor of sequential therapy because of the increased risk of cardiotoxicity associated with concurrent administration. The precise mechanisms underlying the additive cardiotoxicity of anthracyclines and trastuzumab are unclear, but upregulation of HER-2 blockade by anthracyclines is thought to be at least partially responsible for this synergistic effect. Aside from concurrent anthracycline and taxane use, additional risk factors have been identified that may predispose individuals to a higher likelihood of developing trastuzumabrelated cardiotoxicity. In one series, prior chest irradiation, diabetes mellitus, valvular heart disease, and coronary artery disease were noted to increase the toxicity risk [21]. In the phase III trial by Slamon et al., advanced age was identified as the most significant risk factor [6]. Unfortunately, both of these analyses were based on a limited number of patients; as a result, their conclusions should be interpreted with caution.

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Clinical Manifestations Unlike the adverse events observed with anthracyclines, ­trastuzumab-related cardiac toxicities tend to manifest as asymptomatic reductions in ejection fraction as opposed to overt heart failure. In further contrast, trastuzumab-­associated cardiac disease is not dependent on the cumulative dose of drug administered. It is commonly reversible with treatment cessation and frequently amenable to treatment rechallenge if cardiac function recovers after a planned treatment break. Because of these differences, chemotherapy-related ­cardiac abnormalities are categorized by some experts into Type I and Type II dysfunction [22]. The former “Type I” refers to anthracycline-associated injury, which results in permanent myocyte destruction and clinical heart failure. Conversely, the latter “Type II” refers to trastuzumab-associated damage, which is more often associated with transient loss of cardiac contractility and less likely to involve myocyte death or clinical heart failure. Owing to its somewhat transient nature, this form of dysfunction may be reversible.

Minimizing the Risk At least in the adjuvant setting, two approaches have been proposed as potential ways to lower the risk of trastuzumabrelated cardiotoxicity. First, most adjuvant breast cancer trials involving trastuzumab have administered the agent over the course of 12 months. In the important FinHer trial, however, an anthracycline and taxane-containing regimen was compared to the same chemotherapy regimen plus a 9-week course of trastuzumab [23]. There was a survival benefit, but no cardiac dysfunction was observed in the trastuzumab study arm, suggesting that a decrease in the duration of exposure to trastuzumab may confer substantially less cardiac risk. Certainly, these results are only hypothesis-generating, since longer follow-up and a larger number of patients are required to validate whether this approach leads to a better cardiac risk profile without unduly compromising the survival benefits seen with longer courses of trastuzumab. There is also increasing interest in integrating trastuzumab into noncardiotoxic, nonanthracycline containing adjuvant regimens. One example consists of docetaxel and carboplatin, plus trastuzumab. Indeed, early results from the BCIRG 006 trial, in which one of the three arms utilized a nonanthracycline containing adjuvant chemotherapy regimen, are promising with respect to lowering cardiac risk [24]. However, pressing questions remain in regards to the efficacy of nonanthracycline containing adjuvant regimens, and

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these will need to be addressed in additional, longer follow-up of these study participants.

Cardiac Monitoring Heart function should always be evaluated prior to the instigation of trastuzumab therapy as well as regularly during treatment. Only patients with a normal baseline ejection fraction based on imaging, and neither symptoms nor signs of heart failure on history and physical examination, respectively, should be considered eligible for trastuzumab therapy. While the following are not absolute contraindications to therapy, special caution should be taken when patients with a prior history of hypertension, coronary artery disease, and valvular heart disease are receiving trastuzumab. Currently, there are no universal recommendations on the optimal methods or schedules for monitoring patients for trastuzumab cardiotoxicity. However, some early clinical guidelines have been proposed by several tertiary centers and major organizations. A set of proposed guidelines is outlined in Table 2. Briefly, the British Society of Echocardiography presently recommends that left ventricular ejection function be assessed before commencing trastuzumab therapy and then regularly at 3-month intervals during therapy. Likewise, guidelines from the Memorial Sloan Kettering Cancer Center suggest that heart rate and body weight be monitored weekly once treatment has started. As Table 8.2 illustrates, there are additional indications that should trigger a formal reassessment of left ventricular ejection fraction during trastuzumab therapy. Table 8.2  Recommendations for cardiac monitoring in patients receiving trastuzumab Asymptomatic patients If ejection fraction remains normal or decreases by less than 10%, continue with trastuzumab and repeat ejection fraction assessment in 3–4 weeks If ejection fraction decreases by 10–20% and overall ejection fraction is more than 40%, continue with trastuzumab and repeat ejection fraction assessment in 2 weeks If ejection fraction decreases by 20–30% or overall ejection fraction is less than 40%, hold trastuzumab and repeat ejection fraction assessment in 2 weeks Once held, trastuzumab can be resumed if overall ejection returns to more than 40%; otherwise, trastuzumab should be stopped Symptomatic patients If ejection fraction decreases by less than 10%, continue with trastuzumab, search for other causes of symptoms, and repeat ejection fraction assessment in 3–4 weeks If ejection fraction decreases by more than 10–20% and overall ejection is more than 50%, continue with trastuzumab and repeat ejection fraction assessment in 2 weeks If ejection fraction decreases by more than 20%, stop trastuzumab

8  Cardiac Toxicities of Cancer Therapies: Challenges for Patients and Survivors of Cancer

Prognosis and Management In contrast to anthracyclines, data indicate that trastuzumabrelated cardiac toxicities are frequently reversible in the majority of cases. Moreover, early evidence suggests that reintroduction of trastuzumab appears to be safe as long as cardiac abnormalities that develop while receiving the drug have resolved. In the phase III trial by Slamon et  al., for instance, 33 patients continued trastuzumab for a median of 26 weeks despite developing an asymptomatic decline in ejection fraction. The cardiac status of 85% improved or remained the same, while symptoms were reversible for 75% of those who received standard medical therapy for heart failure [6]. Similarly, in a retrospective review from MD Anderson Cancer Center, the majority of those who stopped trastuzumab after developing symptomatic heart failure recovered with appropriate medical therapy, which consisted of b-blockers and ACE inhibitors [21]. While recovery was not universal, treatment was reinitiated in more than half of patients who interrupted trastuzumab for either an asymptomatic or symptomatic cardiac event, of whom most remained free of subsequent cardiac problems.

Radiation Therapy Background Radiation therapy, which can be applied either by itself or in combination with systemic treatment agents, has contributed to significant improvements in the survival of patients with specific cancers, including the breast, Hodgkin disease, as well as malignancies involving the thorax (e.g., lung, esophagus). Such advances have resulted in a higher prevalence of cancer survivors, who are now at increased risk for late complications of radiation treatment, which can frequently involve the heart. Most of the data pertaining to the cardiovascular toxicities of radiation therapy are derived primarily from survivors of breast cancer and Hodgkin lymphoma, since these are diseases in which radiation is a frequent component of initial management and for which survival is often prolonged to a significant degree. Radiation, if administered in sufficiently high doses or large volumes, can potentially damage any and all aspects of the heart, including the pericardium, myocardium, heart valves, coronary blood vessels, and conduction system. Pericarditis is a common manifestation of acute radiation injury, while chronic pericardial disease, coronary artery ­disease, restrictive cardiomyopathy, valvular disease, and conduction abnormalities can present years or decades after

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the original treatment. All of these conditions can potentially result in significant morbidity and mortality. The increasing recognition of radiation-induced cardiac toxicities has led to the development of improved radiotherapy techniques that aim to minimize the dose and volume of exposure to the heart. These contemporary measures appear to have drastically reduced the incidence of radiation-related cardiac complications, although there is still some residual risk.

Risk Factors Several factors increase the risk for developing radiationinduced cardiac toxicities. These include the total radiation dose administered, the dose per fraction, the volume of heart irradiated, and the concurrent delivery of cardiotoxic systemic therapeutic agents, such as anthracyclines and trastuzumab [25]. In breast cancer, for example, the older generation of radiation techniques used in the management of this disease has almost always involved irradiation to the chest wall and surrounding lymph nodes. This classically resulted in a relatively high dose of radiation being delivered to a substantial volume of the heart. There is abundant evidence that this form of radiation delivery was associated with excess cardiovascular morbidity and mortality. Modern techniques currently deliver much less radiation to the heart and appear to have reduced the number of cases and degree of associated cardiotoxicity. In many of these cases, however, longer follow-up is required to confirm these safety findings. Patient dependent factors, such as younger age at the time of initial radiation exposure and the presence of other personal risk factors for coronary heart disease, including hypertension, high serum cholesterol, and smoking history, may also increase the risk of radiation-associated cardiac dysfunction [25].

Clinical Manifestations The main mechanism for radiation-related cardiac toxicities involves radiation damage to coronary blood vessels. This injury is believed to subsequently lead to the production of reactive oxygen species that disrupts DNA strands, which then results in secondary inflammatory changes and ultimately fibrosis. The classic hallmarks of radiation-induced cardiotoxicity consist of diffuse fibrosis of the myocardium coupled with narrowing of arterial and capillary lumens [26]. The ratio of capillaries to cardiac myocytes decreases by 50%, which contributes to cell death, cardiac ischemia, and further fibrosis. Collagen replaces the normal adipose tissue

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that usually forms around the outer layer of the heart, leading to pericardial fibrosis, effusion, and possibly tamponade. All of these changes can culminate in various forms of coronary artery diseases, valvular heart diseases, pericardial diseases, diastolic dysfunction, and dysrhythmias. There are subtle differences between chemotherapyrelated cardiac dysfunction and radiation-induced cardiac toxicities. First, irradiation causes fibrosis of the myocardium, which can lead to a restrictive cardiomyopathy. This appears to have a greater impact on diastolic rather than systolic cardiac function. This contrasts the general effects of anthracyclines, which predominantly causes systolic dysfunction. Second, radiotherapy (specifically mediastinal irradiation) has been associated with an increased risk of clinically significant valvular abnormalities. Of potential clinical importance, many of the common abnormalities found in mediastinal irradiated patients are slowly progressive and may necessitate lifelong follow-up, some of which may also require antibiotic prophylaxis for endocarditis. Third, radiation can cause fibrosis of the conduction pathways in the heart, potentially leading to life-threatening arrhythmias and conduction defects that develop years after initial radiation therapy. Examples of such dysfunction include bradycardia and sick sinus syndrome, as well as complete and lesser degrees of heart block.

Additional Aspects Unlike chemotherapy-induced cardiotoxicity, cardiac ­dysfunction related to radiation may be more challenging to  manage in part because of its diverse manifestations. Improvements in radiotherapeutic techniques have been the primary means of decreasing the cardiac risk by minimizing the amount of radiation received by the heart. It is noteworthy that cardiovascular complications still appear more ­frequently in patients with left-sided than right-sided tumors, providing some evidence that the risk associated with radiation has not been completely eliminated with the newer ­generation of methods for radiotherapy. Awareness of key factors that modify the risk of cardiovascular toxicity is another channel in which complications can be reduced. The size of the radiation field and the dose of exposure, for instance, determine the amount of incidental irradiation to the heart. Studies that compared breast cancer patients who received internal mammary lymph node irradiation were noted to have an increased risk of cardiovascular complications than those in whom the internal mammary lymph nodes were not included in the field [27]. Thus, radiation field and radiation dose are parameters that should be minimized, whenever possible. Care must also be taken to modify other risk factors for cardiovascular

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disease, such as hypertension, hyperlipidemia, and ­smoking, as well as to adequately manage preexisting coronary artery disease, since all of these variables may increase and potentiate radiation-related cardiotoxicity. Special attention is further warranted when radiation is used in patients who have or will receive known cardiotoxic agents, such as anthracyclines and trastuzumab.

Nonanthracycline Agents 5-Fluorouracil 5-Fluorouracil is widely used in various chemotherapy ­regimens to fight a diverse array of cancers. Because of its frequent use, it is the second most common cause of chemotherapy-related cardiotoxicity after anthracyclines. The most frequent cardiac side effect from 5-fluorouracil is anginal chest pain. Myocardial infarction, acute pulmonary edema, and pericarditis can also occur, but these events are much rarer. The underlying mechanism for 5-flourouracil cardiotoxicity is thought to be due to coronary artery vasospasm. Its incidence is estimated to be around 8% [28]. The risk may be related to the mode of 5-flourouracil administration where infusional therapy is associated with a higher risk than bolus treatment. A prior history of coronary artery disease and concurrent use of cardiotoxic agents, including chemotherapy and radiation, also increase the risk. Fortunately, cardiac symptoms typically resolve with either the cessation of 5-flourouracil treatment or the instigation of standard antianginal medical therapy. Rechallenging patients who have previously experienced 5-fluoruracil related cardiac toxicities is somewhat controversial and generally not recommended. Alternately, if rechallenge is being considered, it should be done under cardiac monitoring and close observation by specialized medical personnel. Furthermore, symptomatic patients should ideally undergo stress testing or coronary angiography to rule out occult coronary ischemia.

Capecitabine Capecitabine is a flouropyrimidine that is metabolized by the enzyme thymidine phosphorylase to 5-flourouracil, which is the active anticancer form of the drug. Thus, the cardiac toxi­ city profile of capecitabine is very similar to that observed for 5-flourouracil [29]. Furthermore, patients who have a history of 5-flourouracil cardiotoxicity may also have a predisposition to capecitabine toxicity. The most frequent clinical

8  Cardiac Toxicities of Cancer Therapies: Challenges for Patients and Survivors of Cancer

manifestations include angina, arrhythmias, and myocardial infarction. It is presumed that the mechanism for cardiotoxicity is akin to that reported for 5-flourouracil, with coronary artery vasospasm being most responsible.

Taxanes For taxanes such as paclitaxel, mild bradycardia and heart blocks can occur, although these are usually relatively asymptomatic. Overall, the incidence of these events is very low, and thus routine cardiac monitoring is not required for typical patients without risk factors. It is important to note that the nanoparticle albumin-bound paclitaxel (e.g., nab-paclitaxel) bodes the same cardiac toxicity profile as the regular, nonalbumin-bound formulation. Similarly, conduction abnormalities and angina have been reported in users of docetaxel. Both paclitaxel and docetaxel also appear to potentiate the cardiotoxic effects of anthracyclines, as described previously [30].

Summary In summary, advances in early detection and treatment strategies have prolonged the natural history of many cancers and contributed to an increasing prevalence of cancer survivors. Some of these patients are now faced with the sequelae of early and late treatment-related toxicities, many of which involve the heart. Anthracyclines, trastuzumab, and radiation are increasingly incorporated into current treatment paradigms, but each agent is associated with a spectrum of ­cardiac side effects. As members of the cancer team, a basic awareness of the mechanisms, risk factors, management and prognosis of these various treatment-associated cardiac ­toxicities is important for addressing the specific needs and optimizing care for present and future cancer survivors.

References 1. Elliot P. Pathogenesis of cardiotoxicity induced by anthracyclines. Semin Oncol 2006; 33: 2–7. 2. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 2003; 97: 2869–79. 3. Hershman DL, McBride RB, Eisenberger A, Tsai WY, Grann VR, Jacobson JS. Doxorubicin, cardiac risk factors, and cardiac toxicity in elderly patients with diffuse B-cell non-Hodgkin’s lymphoma. J Clin Oncol 2008; 26: 3159–65. 4. Shapiro CL, Hardenbergh PH, Gelman R, Blanks D, Hauptman P, Recht A, et al. Cardiac effects of adjuvant doxorubicin and ­radiation

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therapy in breast cancer patients. J Clin Oncol 1998; 16: 3493–501. 5. Bria E, Giannarelli D, Felici A, Peters WP, Nistico C, Vanni B, et al. Taxanes with anthracyclines as first-line chemotherapy for metastatic breast carcinoma. Cancer 2005; 103: 672–9. 6. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783–92. 7. Nakamae H, Tsumura K, Terada Y, Nakane T, Nakamae M, Ohta K, et al. Notable effects of angiotensin II receptor blocker, valsartan, on acute cardiotoxic changes after standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone. Cancer 2005; 104; 2492–8. 8. van Dalen EC, van der Pal HJ, Caron HN, Kremer LC. Different dosage schedules for reducing cardiotoxicity in cancer patients receiving anthracycline chemotherapy. Cochrane Database Syst Rev 2006; 4: CD005008. 9. Gabizon AA, Lyass O, Berry GJ, Wildgust M. Cardiac safety of pegylated liposomal doxorubicin (Doxil/Caelyx) demonstrated by endomyocardial biopsy in patients with advanced malignancies. Cancer Invest 2004; 22: 663–9. 10. Seifert CF, Nesser ME, Thompson DF. Dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity. Ann Pharmacother 1994; 28: 1063–72. 11. Dalen E, Caron H, Dickinson H, Kremer L. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev 2005; 1: CD003917. 12. Swain SM, Whaley FS, Gerber MC, Weisberg S, York M, Spicer D, et al. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 1997; 15: 1318–32. 13. Kalay N, Basar E, Ozdogru I, Er O, Cetinkaya Y, Dogan A, et al. Protective effects of carvedilol against anthracycline-induced ­cardiomyopathy. J Am Coll Cardiol 2006; 48: 2258–62. 14. Nousiainen T, Jantunen E, Vanninen E, Hartikainen J. Early decline in left ventricular ejection fraction predicts doxorubicin cardiotoxicity in lymphoma patients. Br J Cancer 2002; 86: 1697–700. 15. Kuittinen T, Husso-Saastamoinen M, Sipola P, Vuolteenaho O, ­Ala-Kopsala M, Nousiainen T, et  al. Very acute cardiac toxicity ­during BEAC chemotherapy in non-Hodgkin’s lymphoma patients undergoing autologous stem cell transplantation. Bone Marrow Transplant 2005; 36: 1077–82. 16. Cooper LT, Baughman KL, Feldman AM. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Circulation 2007; 116: 2216. 17. Ewer MS, Vooletich MT, Durand JB, Woods ML, Davis JR, Valero V, et al. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol 2005; 23: 7820–6. 18. Crone SA, Zhao YY, Fan L, Gu Y, Minamisawa S, Liu Y, et  al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 2002; 8: 459–65. 19. Perik PJ, de Vries EG, Gietema JA, van der Graaf WT, Smilde TD, Sleijfer DT, et al. Serum HER2 levels are increased in patients with chronic heart failure. Eur J Heart Fail 2007; 9: 173–7. 20. Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002; 20: 1215–21. 21. Guarneri V, Lenihan DJ, Valero V, Durand JB, Broglio K, Hess KR, et  al. Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the MD Anderson Cancer Center experience. J Clin Oncol 2006; 24: 4107–15. 22. Ewer M, Lippman S. Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J Clin Oncol 2005; 23: 2900.

82 23. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006; 354: 809–20. 24. Robert NJ, Eiermann W, Pienkowski T. BCIRG 006: docetaxel and trastuzumab-based regimens improve DFS and OS over AC-T in node-positive and high risk node-negative HER2 positive early breast cancer patients: quality of life at 36 months follow-up. J Clin Oncol 2007; 25: 719. 25. Aleman BM, van den Belt-Dusebout AW, De Bruin ML, van’t Veer MB, Baaijens MH, de Boer JP, et al. Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood 2007; 109: 1878–86. 26. Hardenberg PH, Munley MT, Hu C. Doxorubicin-based chemotherapy and radiation increase cardiac perfusion changes in patients treated for left-sided breast cancer. Int J Radiat Oncol Biol Phys 2001; 51: 158.

W.Y. Cheung 27. Hooning MJ, Botma A, Aleman BM, Baaijens MH, Bartelink H, Klijn JG, et  al. Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst 2007; 99: 365–75. 28. Akhtar SS, Salim KP, Bano ZA. Symptomatic cardiotoxicity with high-dose 5¢fluorouracil infusion: a prospective study. Oncology 1993; 50: 441–4. 29. Ng M, Cunningham D, Norman AR. The frequency and pattern of cardiotoxicity observed with capecitabine used in conjunction with oxaliplatin in patients treated for advanced colorectal cancer. Eur J Cancer 2005; 41: 1542–6. 30. Malhotra V, Dorr VJ, Lyss AP, Anderson CM, Westgate S, Reynolds M, et al. Neoadjuvant and adjuvant chemotherapy with doxorubicin and docetaxel in locally advanced breast cancer. Clin Breast cancer 2004; 5: 377–84.

Chapter 9

Malignant Pericardial Effusion and Cardiac Tamponade (Cardiac and Pericardial Symptoms) Marek Svoboda

Introduction The malignant pericardial effusion (PCE) and cardiac tamponade are known life-threatening complications in cancer patients. Early recognition and prompt treatment may dramatically relieve patients of symptoms and decrease a shortterm risk of death from the effusion. Although pericardial involvement by malignancy is the leading cause, other etiological factors need exclusion and the underlying medical status of a patient has to be considered before the final treatment strategy determination. An optimal management of the PCE improves the quality of life and increases the overall survival of cancer patients, especially those with diseases that are potentially responsive to current therapies [1–3].

Etiology and Pathogenesis of Pericardial Effusion Malignancy Pericardial involvement by malignancy is the leading cause of PCE and a cardiac tamponade in cancer patients. The prevalence of pericardial involvement varies from 2 to 65% in cancer patients’ autopsies. The tumors most frequently associated are lung cancer, breast cancer, melanoma, lymphomas, and leukemias, followed by unknown primary tumors, sarcomas, esophageal cancer, and ovarian cancer. Adenocarcinomas represent up to 70% of documented malignant effusions. A primary mesothelioma of the pericardium, an exceedingly rare tumor, comprises less than 1% of all mesothelioma cases [2, 4]. The pathologic cause of the effusive process often involves hematogeneous or lymphatic metastasis to the parietal pericardium, although direct invasion of the epicardial surface or M. Svoboda (*) Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Center, Zluty kopec 7, Brno 65653, Czech Republic e-mail: [email protected]

myocardium can also be present. Alternatively, the presence of mediastinal lymph node metastases may lead to disruption of homeostatic mechanisms of lymphatic drainage, resulting in the PCE [1].

Other Causes Although other causes of pericarditis and/or accumulation of an effusion were identified in less than 5% of PCE cases in cancer patients, they should be considered before the final treatment strategy is determined. A radiation induced pericarditis or a disruption of the lymphatic drainage is relatively the most common of these. Less frequent causes are drugs, bacterial and viral infections (especially HIV associated), thoracic surgery, percutaneous and endoscopic procedures, chronic renal failure (uremia), GVHD (graft-versus-host disease), and connective tissue diseases. An extrapericardial tamponade has rarely been reported and may be caused by pleural effusions or a dilated retrosternal gastric roll, when elevated pressures are transmitted to the pericardial space, resulting in an impaired cardiac filling and a tamponade-like physiology [3].

Radiation Therapy The PCE due to radiation was identified in only 3% of general clinical series, whereas it may be observed in as many as 30% of patients receiving mantle therapy for lymphomas or Hodgkin disease. An acute radiation pericarditis may occur weeks to months after radiotherapy and is usually self-limiting and often asymptomatic. However, a chronic effusive or a constrictive process may occur as many as 20 years after radiotherapy and can be insidious at the onset of tamponade, leading to death [2]. Presently, there is a concern about the occurrence of such complications after chemoradiotherapy, which is a widely used therapeutic strategy in many different types of solid tumors (esophageal and gastric cancer, lung cancer), although

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such treated patients may survive longer. For example, the risk of PCE is 5 times greater after induction with chemoradiotherapy than after a surgery alone in patients with a locally advanced esophageal cancer [5, 6]. In patients with an inoperable esophageal cancer treated with a definitive concurrent chemotherapy and radiation therapy, the crude rate of PCE was 27.7% and a median time of an onset of PCE was 5.3 months after radiotherapy. In multivariate analysis, a volume of pericardium receiving a dose greater than 30  Gy (V30) was selected as the only parameter significantly associated with risk of PCE [6].

Drugs There are many drugs capable of causing pericarditis, especially in the presence of pericardial abnormalities and prior or concurrent mediastinal radiation [7]. Doxorubicin, cyclophosphamide, BCNU, and gemcitabine are mentioned as the most important, but any cardiotoxic drugs may induce PCE, despite their cancer cell selectivity [3, 5, 8, 9]. Tyrosine kinase inhibitors can serve as an example. Despite the apparent selectivity of these agents, significant side effects can occur, including a serosal inflammation manifested by a pleural and/or PCE. The serosal inflammation is frequently associated with dasatinib therapy but is occurring less frequently during imatinib and nilotinib therapies. The pathogenesis is uncertain but may involve an inhibition of platelet-derived growth factor or an expansion of cytotoxic T and natural killer cells. The development of the serosal inflammation with dasatinib poses a significant challenge to physicians. It cannot be predicted, the time of onset is variable, and its management frequently requires repeat invasive procedures [10].

GVHD The PCE and the cardiac tamponade have been described in patients with a “GVHD” reaction in the posttransplant period. Rarely, the PCE may occur as an isolated GVHD manifestation [11].

Diagnosis The malignant PCE can be difficult to diagnose because its onset is often insidious, and its clinical manifestations may be attributed to a gradual deterioration in cardiopulmonary function in patients with an advanced state of the disease [1, 2]. The consequences of the PCE depend mainly on the rate of exudation, the compliance of the pericardium, and the

M. Svoboda

underlying medical status of a patient [12]. In one of the early clinicopathologic series, on one hand, 64% of patients with autopsy-proven pericardial metastases were asymptomatic and had a normal cardiac exam [2]. On the other hand, the cardiac tamponade was the immediate cause of death in about 85% of previously asymptomatic cancer patients [13].

Signs and Symptoms The majority of patients with PCEs are asymptomatic or demonstrating a gradual onset of symptoms rather than an acute tamponade. The most common presenting symptom is dyspnea followed by thoracic pain, orthopnea, dizziness, cough, and fatigue [1, 2]. Physical signs include tachycardia (a heart rate >90  beats/min), absolute or relative hypotension, tachypnea, pulsus paradoxus (inspiratory fall in systolic blood pressure >10 mmHg), jugular venous distension, and distant heart sounds. If the tamponade develops subacutely, peripheral edema, hepatomegaly, and ascites are frequently present [14].

Chest Imaging On a chest radiograph, any type of a large cardiac silhouette in a patient with clear lung fields should suggest the presence of a PCE [14]. On the one hand, a normal chest radiograph may be observed with rapidly accumulating or small (<250 ml) effusions. On the other hand, mediastinal masses and pleural effusions can make determination of the cardiac size difficult. An enlarged cardiac silhouette is noted in 50–76% (Fig.  9.1), whereas a concurrent pleural effusion is observed in less than a half of all cases of the PCE [2]. A computed tomographic imaging or a magnetic resonance provide another noninvasive means of evaluating the pericardium and may be the best alternative in patients in whom echocardiogram is technically not feasible due to a pulmonary disease, obesity, or thoracic musculoskeletal deformities [2].

Echocardiography Echocardiography is the simplest, safest, and most commonly used diagnostic modality that should be performed whenever a PCE is suspected since it can detect as little as 15  ml of

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Fig. 9.1  Chest X-ray film (a) of a 51-year-old man with lung cancer shows enlarged cardiac silhouette. Pericardial effusion (PCE) was confirmed by echocardiography (b)

pericardial fluid with as much as 100% diagnostic accuracy (Fig.  9.1). Echocardiographic signs of a right ventricular and a right atrial diastolic collapse are the most consistent findings in hemodynamically significant PCEs. Although an echocardiogram is extremely sensitive and specific, attempts to accurately correlate the size of a PCE by the echocardiogram and the amount of fluid obtained surgically have been unsuccessful [2].

diastolic compression, or a swinging heart (Fig.  9.1)) [1]. Cardiac tamponade does not require a large-sized PCE to cause hemodynamic compromise (at least 250  ml might be sufficient). The effect is mainly due to the nature of the effusion (blood clots), the poor right ventricular reserve, and the rapidity of developing an effusion [3]. The frequency of tamponade as the initial manifestation of a malignant effusion is highly variable (20–72%) [15].

ECG

Cytology/Histology

ECG findings may show signs of pericarditis, but the only quasispecific sign of tamponade are electrical alternans, which may affect any of all ECG waves or only the QRS complex. Combined P and QRS alternation is virtually specific for tamponade. Other ECG findings include sinus tachycardia, atrial fibrillation, nonspecific ST segment, and T-wave changes. A normal electrocardiogram is documented in 5–10% of cases [1, 2].

Effusions are diagnosed as malignant based on the histologic findings of the excised pericardium and/or the cytologic evaluation of the aspirated fluid [1]. The cytological analysis is positive in 44–87% of malignant PCEs [15], more frequently in solid tumors than hematologic malignancies (65– 87% vs. 35–47%) [1, 2, 15, 16]. In contrast to the high sensitivity of cytologic analysis, the yield from a pericardial biopsy is only 27–55% in patients with known or suspected malignancy. This could be explained by the observation that tumors generally spread from the mediastinal and subepicardial lymphatics to the visceral pericardium, pericardial fluid and, lastly, to the parietal pericardium. Others suggest the scattered pattern of pericardial involvement as an explanation for the relatively low diagnostic yield of biopsy. The cytology and the pericardial biopsy have sensitivities of 90 and 56%, respectively. Of note, an addition of the pericardial biopsy to the routine cytologic analysis increased the sensitivity only by 4%, from 90 to 94% [2].

Cardiac Tamponade Cardiac tamponade is defined either clinically (by the presence of pulsus paradoxus, jugular vein distension, tachycardia, and hypotension) or with echocardiographic findings of tamponade (including right atrial compression, right ventricular diastolic collapse, left atrial compression, left ventricular

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M. Svoboda

Management of Pericardial Effusion As described above, an early recognition of the PCE and a prompt treatment may dramatically relieve patients of symptoms and decrease the short-term risk of death from the effusion [1]. However, in case of patients with the asymptomatic PCEs, cardiac tamponade, which is the immediate cause of death in about 85% of these patients, is difficult to predict [12, 13]. It is therefore recommended that the PCE be evacuated in symptomatic patients and/or in all patients with moderate to large PCEs (more than 2 cm at echocardiography or CT scan) [4]. The treatment of malignant PCEs must be individualized with consideration given to the patient’s condition and tumor type, the success rates and risks of the various modalities, and local availability and expertise. The initial relief of

symptoms is achieved in most cases with percutaneous pericardiocentesis. A subsequent drainage of the PCE with an indwelling catheter and a local sclerotherapy and/or chemotherapy alleviates the effusion without recurrence in most of the patients. These procedures are associated with low morbidity and mortality and are preferred in the initial management of symptomatic malignant PCEs (Fig. 9.2). Recommended therapy for a recurrent malignant PCE includes repeating pericardiocentesis with intrapericardial instillation of an agent with both sclerosing and cytostatic activity, creation of a pericardial window by surgery, or a percutaneous balloon pericardiotomy [17]. Of the several surgical options, a subxiphoid pericardiotomy has the advantage of low morbidity and mortality, can often be performed under local anesthesia, and is highly effective in preventing a recurrence of the PCE. A percutaneous balloon pericardiotomy has

Symptomatic pericardial effusion or Any pericardial effusion > 2 cm

Ultrasound-guided pericardiocentesis and placement of indwelling pericardial catheter

Intrapericardial instillation of agent with sclerosing and/or antineoplastic activity

Effective therapy

Pericardial fluid cytology

Yes Systemic anticancer therapy

No Rapid reaccumulation

No

Systemic anticancer therapy or mediastinal irradiation *

Yes Life expectancy > 6 months

Yes

No

Fig. 9.2  Algorithm for management of PCE in cancer patient

Repeating of pericardiocentesis and local therapy or percutaneous approaches of creating a pericardial window (Annotation: * see indication under Noninvasive Modalities )

Pericardial window

9  Malignant Pericardial Effusion and Cardiac Tamponade (Cardiac and Pericardial Symptoms)

recently been described as an alternative technique to create a pericardial window [17]. More aggressive surgical approaches involve anterolateral thoracotomy, thoracoscopy or videoassisted thoracoscopy (VATS) with removal of a portion of the parietal pericardium to form a pleuropericardial window and to allow drainage into the pleural space. These procedures are advocated by some who feel that there is a high incidence of recurrence after the subxiphoid pericardiotomy [2]. These techniques afford an excellent diagnostic yield due to improved visualization of intrathoracic disease, better exposure of the pericardium, and a potential to obtain more tissue for study. Disadvantages include the need for a general anesthesia and the occasional need for prolonged postoperative ventilatory support.

Initial Management of Pericardial Effusion – Percutaneous Approaches Percutaneous treatment of a PCE has undergone an evolution in recent years with the use of less invasive drainage techniques. Percutaneous needle puncture routes, ultrasound (echocardiography)-guided drainage, and percutaneous management of the pericardial fluid effusion (pericardial sclerosis and balloon pericardiotomy) can be performed under local anesthesia [3]. Limits of percutaneous paraxiphoid ultrasound-guided procedures include obese patients, patients with Morgagni hernias, narrow costal margins, or those who have had prior thoracic surgery, or patients presenting with bowel obstruction or severe ascites. A presence of hematoma within the pericardium, a minimal (diaphragmatic thickening less than 10 mm) or loculated posterior PCE represent contraindications to a percutaneous approach [3].

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Indwelling Pericardial Catheter To drain a large PCE and/or for instillation of the sclerosing and/or cytostatic agents into the pericardial sac, the indwelling pericardial catheter (e.g., pigtail drain) is usually used. The catheter is inserted into the pericardial space by the Seldinger technique under local anesthesia and ultrasound control. Catheter specific complications are rare and include catheter occlusions and infections [3].

Balloon Pericardiotomy A subxiphoid approach is used to insert a pigtail pericardial drain. After drainage of the fluid, the pericardial space is delineated with contrast, and a 12 × 20  mm balloon angioplasty catheter is introduced into the pericardial space to form a pericardial stoma or window. Several inflations (usually 12–14 atmospheres for 60–80 s) are performed until waisting of the balloon by the pericardium disappears [18]. The exact mechanism by which the fluid is drained is unclear. The window appears to facilitate drainage into the peritoneal or pleural space, where the resorptive surface and function are greater than in the pericardium [18]. Intravenous antibiotics (e.g., flucloxacillin) are given as prophylaxis. This procedure is performed using local anesthesia, but opiate analgesia (i.v. morphine) before and during the procedure, often together with benzodiazepine sedation is given routinely for pain relief, as stretching of the pericardium is often painful. Subsequent studies have shown the efficacy of this therapy in larger series, in children and in nonmalignant conditions. Relative contraindications to the procedure include an INR >2 or platelet count <50 × 109/l. In these (rare) situations, a balloon pericardiotomy could be deferred until the coagulation status had normalized or fresh frozen plasma given [18].

Local Sclerotherapy and/or Chemotherapy Pericardiocentesis A simple blind needle pericardiocentesis, using the paraxiphoid approach, is acceptable only in case of sudden circulatory collapse, when ultrasound guidance is not available. Complications of such blind procedures include ventricular puncture (10%), laceration of the heart or coronary vessels, arrhythmia, pneumothorax, trauma to the abdominal organs, infection, cardiac arrest, and death. In most series, complication rates of 7–25% and mortality rates of 6% are reported. At least 8% of the procedures were shown to be nonproductive [2, 3]. Compared to blind needle pericardiocentesis, percutaneous ultrasound-guided pericardiocentesis is a well-tolerated treatment procedure without significant mortality and morbidity, even if done in critically ill patients.

Recurrence rates after simple pericardiocentesis and catheter drainage range from 13 to 50%. Therefore, prevention of reaccumulation of the effusion is an important goal [15]. Intrapericardial therapy seems to be the best compromise in terms of the quality of life, prevention of recurrences, and a survival improvement [4]. Intrapericardial therapy with sclerosing and/or antineoplastic agents may be considered the specific etiological therapy, aimed not simply at mere palliation but, if possible, real treatment of malignant PCEs [4]. Different agents have been used, but most data relate to the use of tetracycline hydrochloride and, bleomycin, cisplatin, and thiotepa, as they are capable of controlling about 80% of PCEs in a short-term follow-up [13].

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It should be noted, however, that the effusion control of tetracyclines is due only to sclerosing activity and not to a specific antineoplastic action. Bleomycin and thiotepa are both anticancer and sclerosing agents, and have been used for many years in the treatment of solid tumors and malignant effusions. Despite similar or even better results in recurrence prevention, in comparison to that of tetracyclines, thiotepa, bleomycin, and cisplatin instillation is not associated with significant local or systemic side effects. Cisplatin, however, does not induce sclerosis [13].

Bleomycin Currently, intrapericardial therapy with bleomycin is the most frequently used approach for the initial treatment of malignant PCEs. Bleomycin has both sclerosing and cytostatic activities; it is well tolerated, and its effectiveness was confirmed by a randomized, controlled, prospective clinical trial. After the pericardiocetesis and insertion of a catheter, the pericardial fluid is completely drained and bleomycin is instilled directly into the pericardial space. Two different therapeutic protocols are proposed: (1) 15 mg of bleomycin in 20  ml of normal saline solution is administrated over 5  min, followed by an additional 10  mg bleomycin i.p.c. every 48 h to a cumulative dose of 60 mg. The drainage tube is removed when daily drainage is 20 ml or less; (2) 30 mg/m2 of bleomycin in 50 ml of normal saline solution is injected into the pericardial cavity, the residual fluid is drained and the catheter is removed 4 h later [18]. The first approach was also adopted by JCOG 9811, a prospective randomized trial, which was aimed to evaluate the safety and efficacy of intrapericardial bleomycin instillation (Arm B) as compared to a pericardial drainage alone (Arm A) in lung cancer patients with malignant PCEs. The effusion failure-free survival (EFFS) at 2 months was 29% in arm A and 46% in arm B (one-sided P = 0.086). Arm B tended to favor the EFFS, with a hazard ratio of 0.64 (95% confidence interval: 0.40–1.03, one-sided P = 0.030 by log-rank test). No significant differences in the acute toxicities or complications were observed. The median survival was 79 and 119 days in arm A and B, respectively. Although the trial failed to show a statistical significance in the primary end point, the intrapericardial BLM appears to be safe and effective in the management of the PCE [19]. Retrospective studies comparing i.p.c. use of doxycycline or bleomycin did not show marked differences between the two drugs in terms of overall survival and effusion control at 30 days, however, doxycycline can produce intense pain after its instillation, necessitating the intravenous administration of narcotics in most patients. Fevers in excess of 38.5°C may develop in 50% of patients treated by a higher dose of bleomycin [17].

M. Svoboda

Tetracyclines A number of substances have been utilized for intrapericardial sclerotherapy but a much larger experience and evidence exists about tetracyclines-derivatives (tetracycline, doxycycline). Tetracycline and doxycycline are used at dosages varying from 500 to 1,000 mg, injected with 20 ml of normal saline solution. The most frequent protocol requires drug instillation followed by 1–2 h with a clamped catheter, then reopening for 24 h. The procedure should be repeated until the net drainage is less than 20  ml/day. Recurrences are observed in about 20–29% of patients [4]. In spite of these results, tetracycline-derivatives instillation is often associated with significant side effects. Complications that may be observed include fever and atrial arrhythmias in less than 10% of cases and pain in up to 20% of patients. Retrosternal chest pain following the drug instillation is often very severe and requires opioids for effective treatment [4].

Platinum Agents Cisplatin (cDDP) and carboplatin (CBDCA) administration were evaluated mostly in lung cancer patients. Usually, after pericardiocentesis and insertion of a catheter, the pericardial fluid is completely drained and a platinum derivative is instilled directly into the pericardial space. Two different therapeutic protocols are proposed: (1) 10 mg of cisplatin in 20 ml of normal saline solution is administrated over 5 min during 1–5 consecutive days. Further drainage of newly formed fluid is always performed before the drug administration; (2) 50 mg of cisplatin or 300 mg of CBDCA in 50 ml of normal saline is injected into the pericardial cavity, the residual fluid is drained and catheter is removed 24 (cDDP) or 4 (CBDCA) hours later [20, 21]. A transient atrial fibrillation and a mild nausea were detected in less than 18% of patients treated with cDPP, and no major or minor adverse effects were observed in the case of CBDCA [20, 21].

Thiotepa Thiotepa (triethylenephosphoramide) is an alkylating agent used for many years in the treatment of solid tumors and pleural effusions, due to both sclerosing and cytostatic activities. Usually, 15 mg of thiotepa (and 30 mg of hydrocortisone) diluted in 50 ml of normal saline solution is administered on days 1, 3, and 5 after pericardiocentesis, opening the catheter only immediately before treatment and keeping it closed immediately after the instillation. Twenty-four hours after administering the last dose, the catheter is removed [4, 13].

9  Malignant Pericardial Effusion and Cardiac Tamponade (Cardiac and Pericardial Symptoms)

Compared to other drugs, thiotepa does not produce pain, rarely generates a pronounced febrile response, and it is also more cost-effective.

Subsequent Management of Pericardial Effusion A recommended therapy for the recurrent PCE includes: a repeat of pericardiocentesis and intrapericardial instillation of agents with both sclerosing and cytostatic activities, the percutaneous balloon pericardiotomy (see above), or a surgical treatment. These treatment options can be combined with noninvasive modalities to intensify the overall efficiency. Advantages of percutaneous procedures over surgery include minimal discomfort, a low morbidity rate and efficiency similar to a surgical pericardiotomy without sedation [3].

Surgical Treatment – Pericardial Window A pericardial window is a feasible and effective (<5% failure rate) approach to a recurrent and/or long-term pericardial drainage and provides an opportunity for continued therapy with a potential for improvement in the quality of life and survival in selected patients [1]. In addition, the fluid obtained, the pericardial biopsy, and the direct examination of the pericardial space improve the diagnostic accuracy [2]. A pericardial window can be created using various techniques: (1) by open surgery (subxiphoid pericardiotomy /pericardial or pericardioperitoneal window/ or anterolateral thoracotomy /pleuropericardial window/); (2) by thoracoscopy (thoracoscopy or video-assisted thoracoscopy /pleuropericardial window/); (3) by percutaneous balloon pericardiotomy (pleuropericardial or pericardioperitoneal window). The balloon pericardiotomy (see above) and the subxiphoid pericardiotomy are favored due to their high success, lower recurrence rates, and lower morbidity, compared with the creation of a pericardial window by anterior thoracotomy or thoracoscopy [22]. Both of these procedures can be also performed using local anesthesia.

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This procedure can be performed in 30–45 min using local anesthesia in most patients, even in the critically ill, but light general anesthesia is recommended [1, 2]. The technique provides accurate diagnosis and effective, durable treatment with an operation-related mortality ranging between 0 and 5%, operative morbidity 1–10% and a recurrence rate 0–11% [2, 7]. A recurrent PCE requiring a further surgical intervention occurred in about 2% of patients. Complications include arrhythmias, myocardial laceration, pneumothorax, and wound infection. Isolated cases of constrictive pericarditis after the subxiphoid pericardiotomy have been reported [14]. The subxiphoid pericardiotomy proved to be a safe and effective intervention that successfully relieved PCEs in 99% of cases with recurrence and reoperation rates of 9 and 7%, respectively [2]. In many cases, the treatment is performed in the context of an acutely sick patient, and therefore, exclusion criteria are relative rather than absolute. Relative contraindications to the procedure include extreme obesity, a narrow costal angle, or previous midline abdominal surgery. Variants of subxiphoid pericardiostomy include the creation of a pericardioperitoneal window and balloon pericardiotomy [2].

Thoracoscopy and Anterolateral Thoracotomy More aggressive surgical approaches involve anterolateral thoracotomy, thoracoscopy, or video-assisted thoracoscopy (VATS) with removal of a portion of the parietal pericardium to form a pleuropericardial window (pleuropericardiotomy) and to allow drainage into the pleural space. These procedures are advocated by some who feel there is a high incidence of recurrence after the subxiphoid pericardiotomy [2, 22]. These techniques afford an excellent diagnostic yield due to improved visualization of intrathoracic disease, a better exposure of the pericardium, and the potential to obtain more tissue for study. Disadvantages include the need for general anesthesia and the occasional need for prolonged postoperative ventilatory support [1, 2].

Thoracoscopy Subxiphoid Pericardiotomy The subxiphoid pericardiotomy is performed by making a small vertical incision extending 4–6 cm inferiorly from the xiphoid process. The incision is deepened through the midline fascia between the rectus abdominis muscles, but not through peritoneum. The anterior pericardium is identified, and a piece of pericardium 2–4 cm in diameter is removed and the pericardial sac is drained with a silicone tube [12].

The patient is placed in a lateral decubitus position and, after institution of a single-lung ventilation, thoracoscopy is performed, preferably on the left side, through a 2-cm anterior axillary line incision in the seventh intercostal space. The pericardium can be punctured percutaneously under direct vision and fluid is aspirated through the plastic outer cannula after the removal of the sharp inner needle (16 gauge), or the effusion is evacuated through the thoracoscope. When the parietal pericardium becomes flaccid, it is picked up

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with the endoscopic curved forceps introduced through a second intercostal incision. The phrenic nerve is identified before one or more round incisions approximately 3–4 cm in diameter are created using an endoscopic scissor and electrocautery. Larger windows might allow cardiac herniation. A 32F chest tube is left in place for a day or two after surgery [1, 2, 22].

Anterolateral Thoracotomy Although the thoracoscopic procedure is preferred, in some cases, a 6–8-cm anterior thoracotomy approach is necessary because of hemodynamic instability, inability to safely use single-lung ventilation, or when extensive pleural adhesions are found at thoracoscopy. In cachectic patients, or in patients with a prior ipsilateral mastectomy, a pericardial window could sometimes be created through a single anterior intercostal incision approximately 2  cm in length without the need for thoracoscopic techniques [1, 22].

Noninvasive Modalities Noninvasive modalities including mediastinal irradiation and systemic chemotherapy may be considered in the patient population that presents with mild or slowly progressing symptoms. There are few case reports demonstrating the effectiveness of the intravenous administration of cisplatin, paclitaxel, and ifosfamide for the treatment of small and asymptomatic PCEs [23, 24]. Mediastinal irradiation for malignant effusions caused by a variety of malignancies has an overall 50–60% response rate, with the best success seen in radiosensitive tumors such as lymphoma or leukemia. The dose required is often close to that which may cause myocarditis, and its use is generally restricted to those patients who have not had a previous mediastinal radiation [25].

Prognosis Although malignancy-related PCEs may represent a terminal event in patients with therapeutically unresponsive disease, select patients with malignancies sensitive to available therapies have achieved significant improvement in palliation and a long-term survival with prompt recognition and appropriate intervention [2]. In most studies, patients with hematologic malignancies achieve significantly longer survival (mean OS 20 months) compared with all other patients with malignant diseases and PCEs (mean OS 4.9 months) [16]. Among solid tumors, a diagnosis of lung cancer (median OS 2.8–3.4 months) carries

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a worse prognosis than a breast cancer (median OS 5.2–13.3 months) or other solid-tumor malignancies (median OS 3.2– 3.8 months) [2, 13, 17, 18]. Based on the results of retrospective studies, the multivariate analyses yielded the following significant prognostic factors: the absence of symptoms of cardiac tamponade, the type and the control of the underlying neoplasm (progressive or responding disease), and the occurrence of malignant PCE during chemotherapy. Other factors, such as cytological confirmation of a malignant PCE, age (>60 years), and the volume of PCE (<550 cm3), are usually correlated with a poor survival only in univariate analyses [16]. Nevertheless, all these factors could be helpful in making a decision as to the optimal treatment that should balance treatment efficacy with life expectancy [15, 26].

References 1. Cullinane CA, Paz IB, Smith D, et al; Prognostic factors in the surgical management of pericardial effusion in the patient with concurrent malignancy. Chest. 2004;125(4):1328–34. 2. Wilkes JD, Fidias P, Vaickus L, et al; Malignancy-related pericardial effusion. 127 cases from the Roswell Park Cancer Institute. Cancer. 1995;76(8):1377–87. 3. Marcy PY, Bondiau PY, Brunner P. Percutaneous treatment in patients presenting with malignant cardiac tamponade. Eur Radiol. 2005;15(9):2000–9. 4. Martinoni A, Cipolla CM, Civelli M, et  al; Intrapericardial treatment of neoplastic pericardial effusions. Herz. 2000;25(8):787–93. 5. Murthy SC, Rozas MS, Adelstein DJ, et al; Induction chemoradiotherapy increases pleural and pericardial complications after esophagectomy for cancer. J Thorac Oncol. 2009;4(3):395–403. 6. Wei X, Liu HH, Tucker SL, et al; Risk factors for pericardial effusion in inoperable esophageal cancer patients treated with definitive chemoradiation therapy. Int J Radiat Oncol Biol Phys. 2008;70(3):707–14. 7. Dosios T, Theakos N, Angouras D, et al; Risk factors affecting the survival of patients with pericardial effusion submitted to subxiphoid pericardiostomy. Chest. 2003;124(1):242–6. 8. Krishnan GS, Chaudhary V, Al-Janadi A, et al; BCNU toxicity presenting with a large pericardial and pleural effusion. Ann Transplant. 2008;13(1):44–7. 9. Vogl DT, Glatstein E, Carver JR, et al; Gemcitabine-induced pericardial effusion and tamponade after unblocked cardiac irradiation. Leuk Lymphoma. 2005;46(9):1313–20. 10. Kelly K, Swords R, Mahalingam D, et  al; Serosal inflammation (pleural and pericardial effusions) related to tyrosine kinase inhibitors. Target Oncol. 2009;4(2):99–105. 11. Lev A, Amariglio N, Spirer Z, et  al; Specific self-antigen-driven immune response in pericardial effusion as an isolated GVHD manifestation. Bone Marrow Transplant. 2010;45:1084–1087. (Epub: 2009 Nov 16). 12. Yonemori K, Kunitoh H, Tsuta K, et  al; Prognostic factors for malignant pericardial effusion treated by pericardial drainage in solid-malignancy patients. Med Oncol. 2007;24(4):425–30. 13. Martinoni A, Cipolla CM, Cardinale D, et al; Long-term results of intrapericardial chemotherapeutic treatment of malignant pericardial effusions with thiotepa. Chest. 2004;126:1412–16. 14. Maisch B, Seferovic PM, Ristic AD, et al; Guidelines on the diagnosis and management of pericardial diseases. Executive summary. Eur Heart J. 2004;25:587–610.

9  Malignant Pericardial Effusion and Cardiac Tamponade (Cardiac and Pericardial Symptoms) 15. Vaitkus PT, Herrmann HC, LeWinter MM. Treatment of malignant pericardial effusion. JAMA. 1994;272(1):59–64. 16. Dequanter D, Lothaire P, Berghmans T, et  al; Severe pericardial effusion in patients with concurrent malignancy: a retrospective analysis of prognostic factors influencing survival. Ann Surg Oncol. 2008;15(11):3268–71. 17. Girardi LN, Ginsberg RJ, Burt ME. Pericardiocentesis and intrapericardial sclerosis: effective therapy for malignant pericardial effusions. Ann Thorac Surg. 1997;64:1422–28. 18. Swanson N, Mirza I, Wijesinghe N. Primary percutaneous balloon pericardiotomy for malignant pericardial effusion. Catheter Cardiovasc Interv. 2008;71(4):504–7. 19. Kunitoh H, Tamura T, Shibata T, et al; A randomised trial of intrapericardial bleomycin for malignant pericardial effusion with lung cancer (JCOG9811). Br J Cancer. 2009;100(3):464–9. 20. Tomkowski WZ, Filipecki S. Intrapericardial cisplatin for the management of patients with large malignant pericardial effusion in the course of the lung cancer. Lung Cancer. 1997;16(2–3): 215–22.

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21. Moriya T, Takiguchi Y, Tabeta H, et  al; Controlling malignant pericardial effusion by intrapericardial carboplatin administration in patients with primary non-small-cell lung cancer. Br J Cancer. 2000;83(7):858–62. 22. Gross JL, Younes RN, Deheinzelin D, et al; Surgical management of symptomatic pericardial effusion in patients with solid malignancies. Ann Surg Oncol. 2006;13(12):1732–8. 23. Shimizu S, Yajima M, Yoshii A, et al; Malignant pericardial effusion and cardiac tamponade originating from uterine carcinosarcoma. Arch Gynecol Obstet. 2009;279(3):373–5. 24. Nojiri S, Yumino Y, Sato K, et al; A case of pericardial malignant mesothelioma accompanied by primary lung adenocarcinoma. Nihon Kokyuki Gakkai Zasshi. 2009;47(2):104–9. 25. Petersen EE, Shamshirsaz AA, Brennan TM, et al; Malignant pericardial effusion with cardiac tamponade in ovarian adenocarcinoma. Arch Gynecol Obstet. 2009;280(4):675–8. 26. Laham RJ, Cohen DJ, Kuntz RE, et  al; Pericardial effusion in patients with cancer: outcome with contemporary management strategies. Heart. 1996;75(1):67–71.

Chapter 10

The Vena Cava Syndrome Mario Dicato and Vincent Lens

Introduction Superior vena cava obstruction causes various symptoms such as cough, dyspnea and orthopnea, and headaches, as well as facial and cervical edema and occasionally extensive venous dilatations (easily visible on the upper part of the chest and upper extremities). The symptoms such as facial and upper limb oedema of acute or gradual onset, acute dizziness and headache, and dyspnea and cough are due to impaired venous blood flow. Anatomically, the azygos vein is parallel to the vena cava. If there is obstruction above the azygos vein, collateral veins, like the cervical ones, will dilate. If the obstruction is below the azygos vein, backflow of blood will occur through the azygos vein into the inferior vena cava. If the obstruction is at the level where the azygos vein connects to the superior vena cava, the small superficial thoracic veins will dilate and become quite visible. Drainage will be to the inferior vena cava. Despite the sometimes dramatic and distressing clinical picture, superior vena cava obstruction is usually not an emergency. Most of the time, diagnosis can be secured if obstruction is an initial clinical presentation of malignancy and procedures like biopsies (transthoracic or through mediastinoscopy) can be done safely before treatment. Classically, the superior vena cava syndrome secondary to malignancy is treated with chemotherapy or radiotherapy, and rarely with surgery. Radiotherapy takes some time before having a substantial result, but can certainly be attempted in fast growing tumors that are highly radiosensitive such as lymphomas, small cell lung cancer, and some others. The same can be said for chemotherapy, where also it takes some time to see a substantial improvement of symptoms. The success rate is moderate, depending on the pathology and the clinical setting. In addition, as this syndrome is mostly acute and treatment is to be started as fast as feasible, in both treat-

M. Dicato () Cancer Research Foundation – Luxembourg, Centre Hospitalier de Luxembourg, 1, rue Wieseck, L-8269, Mamer, Luxembourg e-mail: [email protected]

ment modalities, if vena caval syndrime (VCS) is the presenting symptom, procuring a tissue sample for final diagnosis can be problematic. Over the past few years, stenting has become however the first line treatment of choice, particularly in a palliative setting. This type of procedure, done under local anesthesia, is rapid, can be done in a semi-urgent fashion in the radiology department, and failures are rare. Quick relief of symptoms is usual in superior vena cava syndrome, but less rapid in inferior vena cava obstruction. One major advantage of stenting, especially as success rates are high, is securing histology in cases where the vena cava syndrome is the presenting symptom of the malignancy. After relief of symptoms through stenting, tissue samples can be obtained with CT guided percutaneous biopsy, bronchoscopy, mediastinoscopy, and sometimes surgery. The most common cause of superior vena cava obstruction is lung cancer, followed by lymphoma of breast, thyroid, and others. Regarding inferior vena cava syndrome, the incidence is much less frequent and most published studies on vena cava syndromes have, like in our institution, only a small number of cases, and one can generalize by saying that mostly the same attitude is recommended as in the superior vena cava setting, as described below.

Stenting Treatment Indication Virtually any kind of stenosis or occlusion is an indication for stenting. Nevertheless, only a clinically relevant occlusion or stenosis should be treated. For example, treatment of an isolated occlusion of a left innominate trunk does not make sense as long as the blood flow coming from the upper left body still reaches the vena cava system via collateral pathways. The same can be said for the inferior cava system regarding a left or right isolated iliac occlusion. In the specific case of unilateral occlusion, only an acute occlusion can be

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discussed as an indication because of the lack of collateral pathway development [1]. Main stenoses and occlusions of the superior and inferior vena cava are absolute indications if medical therapy cannot rapidly relieve the symptoms.

Contraindication There is no absolute contraindication to treatment and stenting of a superior or inferior vena cava syndrome. Treatment of superior vena cava syndrome due to fibrosis post mediastinitis or catheter-induced tight stenosis however may lead to rupture in attempting to dilate or stent the vessel. These two situations are in fact relative contraindications to be appreciated by the treating clinician [2, 3].

Technique Clinical diagnosis of vena cava syndrome is confirmed by CT scanning. A CT scan should be done by injecting contrast media in both arms simultaneously to explore every single vein or venous trunk of the superior vena cava system that could accept material for an interventional percutaneous procedure. Maximum intensity projections (MIP), CT projection, or virtual reality (VR) views are of great help to plan treatment (Fig. 10.1). This step of mapping is mandatory to plan the treatment procedure, the site of dilatation, the stenting material, and the size of balloon and stent to be used. For the inferior cava system, injection in the legs may help but delayed scanning, as in CT phlebograms, is enough for the purpose described herein. Once the route is chosen with the coupled guide-wire-catheter, the stenosis or occlusion is crossed and a complete phlebogram of the involved cava system is done. This phlebogram has the advantage of being more dynamic than the one performed with the CT scan. The manoeuvres of dilatation and stenting are made under stiff wire control. Over-dilatation should be avoided to reduce the risk of perforation. In our experience, we prefer self-expandable stents to balloon expandable stents for the same purpose. The venous approach is in order of frequency: femoral, brachial, and jugular. A double approach can be used (e.g., femoral and brachial) for specific manoeuvres, such as using the lasso device to capture a guide wire to go through a difficult or very tight stenosis that cannot be passed in the anterograde or retrograde way. Some types of stents are self- or balloon expandable. Also note that self-expandable stents cane be dilated secondarily (Figs. 10.2 and 10.3). Covered and uncovered stents can be used. Special care has to be taken with covered stents in order not to exclude collateral venous pathways. Length and diameter of stents are important:

Fig.  10.1  Superior vena cava. MIP (maximum intensity projection) CT-scanner imaging. Acquisition after I.V. contrast injection simultaneously in both arms. Patient with lung carcinoma. Black star right innominate vein, black arrow azygos vein, white curved arrow superioir vena cava occlusion

Fig. 10.2  Superior vena cava phlebogram (same patient as in Fig. 10.1). Black star catheter introduced in the superioir vena cava system via right femoral approach, black arrow dilated right innominate vein, white arrow azygos vein

10  The Vena Cava Syndrome

Fig. 10.3  Superior vena cava (same patient as in Figs. 10.1 and 10.2). Post stenting cavography with no residual SVC oclusion. Excellent flow through the SVC stent

length to exclude the entire process responsible for the vena cava syndrome and diameter to avoid over-dilatation and perforation or under-sizing that leads to stent migration [4]. In case of involvement of both brachiocephalic venous trunks, treatment may be limited to one brachiocephalic trunk because of the multiple collateral deep and superficial veins running from one to the other side of the cervical region. As previously discussed, this procedure can be performed under local anesthesia and standard monitoring, even on an out-patient basis. Standard heparinization is given: 5,000 UI per procedure. Post procedure anticoagulation therapy with low molecular weight heparin (LMWH) is given ad vitam if there are no contraindications.

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careful covering of the entire site of stenosis and choosing an appropriate size are important to avoid complications. Thirty-one vena cava syndromes were diagnosed: 27 in the superior vena cava system and four in the inferior vena cava. Twenty-four of the 27 superior vena caval syndrome (SVCS) were directly related to lung cancer, while two were related respectively to breast cancer and mediastinal sarcoma, and one was catheter induced SVC stenosis. Mean survival rate after stenting the SVC for the lung cancer group of patients was 2 months. One patient had a late stent occlusion (2 months after stent implantation). For the inferior vena caval (IVC) group, we had one technical failure and three stents were successful. Patients suffered from ovarian carcinoma, cholangiocarcinoma, retroperitoneal sarcoma, and colon adenocarcinoma. At the time of this writing (December 2009), survival rates were inferior to 1 month, and superior to 42 months, 3 months, and 6 months (Figs. 10.4 and 10.5). In SVCS relief of symptoms, successful treatment was almost immediate and practically complete within 72 h. For IVCS, relief was slower with a total relief of pain within a week. Post-stenting heparin therapy is the rule if there are no contraindications. Patients generally received LMWH therapy.

Complications Complications are rare but can be dramatic in these critically ill patients. Indication of treatment based on a non-equivocal

Results Over the past 5 years all our cases were treated within 24 h of clinical diagnosis and radiological assessment. Of 31 cases, all but one succeeded. In the order of frequency, types of stents implanted included Wallstent (Boston Scientific, Natick, MA), Cook Z Stents (Cook Medical, Bloomington, IN), and Omnilink (Abbott Vascular, Santa Clara, CA). Essentially, local policy determines the type of stents used for treatment. There is no published double blind or evidencebased study in favor of any type of stent in terms of covered or bare stents. The same also applies for the use of self expand­ -able or balloon expandable stents. As mentioned before, the Fig. 10.4  Inferior vena cava. Compression of the IVC at the infra-renal choice of stents does not preclude the success rate, but a vein level by retroperitoneal sarcomatous mass (black arrow)

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Conclusion In our experience, as in the recent literature, stenting is the primary treatment to be considered in the event of vena cava syndrome. This difficult clinical situation for the patient can be successfully and rapidly treated alleviating symptoms within 1 day for the superior vena cava syndrome and after several days for the inferior vena cava setting. This procedure allows for post-treatment securing of tissue for diagnosis just as it is possible in patients without this syndrome. Stenting of the vena cava is a purely palliative procedure; it does not interfere with the underlying disease management in terms of treatment with radiation or chemotherapy or retreatment at time of disease recurrence. In case of restenosis or reocclusion, an attempt at ballooning or restenting is possible [5].

References Fig. 10.5  (Same patient as in Fig.  10.4) Post stenting, inferior vena cava phlebogram: no residual stenosis

diagnosis and patients’ informed consent are mandatory. Complications may be present at any step of the procedure. Per procedure complications are vein perforation, stent misplacement and migration, and uncontrollable bleeding at the venous entry site. Main venous trunk perforation due to guide and catheter manoeuvre as well as stent perforation may lead to dramatic hemo-mediastinum and hemopericardium. Stent guides, and catheter induced perforation and their complications can be treated or avoided by systematic use of covered stents. Unfortunately, covered stents are often unavailable and bare stents are used as an alternative in many institutions. A side effect of covered stents is the occlusion of side branches. Vessel rupture can be avoided by carefully adapting, or even slightly undersizing the diameter of the stent’s balloon in relation to the size of the vessel to be treated. Early and late complications are numerous. Recurrence of stenosis or occlusion due to tumor ingrowth or compression is to be considered as a normal event in the palliative setting. The main early and late complications are stent migration, septic episodes, bleeding induced by anticoagulation therapy, massive venous thrombosis, and cardiac arrythmias.

1. Dinkel HP, Mettke B, Schmid F et  al. Endovascular treatment of malignant superior vena cava syndrome: is bilateral wallstent placement superior to unilateral placement? J Endovasc Ther 2003;10: 788–797. 2. De Gregorio Ariza MA, Gamboa P, Gimeno MG et al. Percutaneous treatment of superior vena cava syndrome using metallic stents. Eur Radiol 2003;13:853–862. 3. Rowell NP, Gleeson FV. Steroids, radiotherapy, chemotherapy and stents for superior vena caval obstruction in carcinoma of the bronchus: A systematic review. Clin Oncol 2002;14:338–351. 4. Uberoi R. Quality assurance guidelines for superior vena cava stenting in malignant disease. Cardiovasc Intervent Radiol 2006;29: 319–322. 5. Nagata T, Makutani S, Uchida H et  al. Follow-up results of 71 patients undergoing metallic stent placement for the treatment of malignant obstruction of the superior vena cava. Cardiovasc Intervent Radiol 2007;30:959–967.

Suggested Reading 6. Anaya-Ayala JE, Charlton-Ouw KM, Kaiser CL et  al. Successful emergency endovascular treatment for superior vena cava injury. Ann Vasc Surg 2009;23:139–141. 7. Mansour M, Altenburg A, Haage P. Successsful emergency stent implantation for superior vena cava perforation during malignant stenosis venoplasty. Cardiovasc Interv Radiol 2009;32:1312–1316.

Part IV

Respiratory

Chapter 11

Pulmonary Toxicity of Therapy Andriani G. Charpidou and Kostas K. Syrigos

Pulmonary toxicity can occur as a complication of cancer treatment. The current trend of multimodality therapeutic anticancer approaches makes pulmonary toxicity unavoidable. It is estimated that the frequency of this complication is anywhere between 10 and 30% depending on the type of the regimen used. Unfortunately, the diagnosis of anticancer agent-induced pulmonary toxicity is based on exclusion of other factors that can cause respiratory failure in cancer patients, including pulmonary infections, cardiogenic pulmonary edema, diffuse alveolar hemorrhage, and lym­ phangitic carcinomatosis. Differential diagnosis is difficult because of the lack of specific symptoms and radiological or pathological findings. Regardless of the difficulties, therapyinduced pneumonitis and respiratory failure should be considered in patients receiving chemotherapy or radiation therapy. The prophylactic use of antihistamines and corticosteroids, cessation of the implicated causative agent, and treatment with systemic corticosteroids may result in rapid improvement or prevention of these conditions.

Clinical and Pathological Manifestations The clinical manifestations of therapy-induced toxicity in cancer patients range from cough and low-grade fever to serious severe dyspnea, hypoxemia, and respiratory failure. They can appear early, during the first cycle of treatment, or later following subsequent cycles. Clinically, they can be demonstrated as bronchospasm or generalized hypersensitivity reactions, interstitial lung disease (ILD), noncardiogenic pulmonary edema, and capillary leak syndrome. More ­serious respiratory distress syndromes, such as acute lung injury (ALI) with PO2/FiO2 ratio less than 300 or even ARDS with PO2/FiO2 ratio less than 200, can also be observed [1]. K.K. Syrigos (*) Sotiria General Hospital, Oncology Unit, GPP, Athens School of Medicine, Athens 11527, Greece e-mail: [email protected]

Chest imaging can reveal diffuse or patchy, unilateral or bilateral, ground-glass opacities or consolidations. Lung biopsy specimens appear most commonly as lesions with nonspecific interstitial pneumonitis (NSIP), diffuse alveolar damage (DAD), bronchiolitis obliterans with organizing pneumonia, eosinophilic pneumonia, pulmonary fibrosis, and pulmonary hemorrhage [1]. These pathologic patterns are nonspecific and should be considered diagnostic of druginduced lung toxicity, only if pneumonitis develops shortly after the initiation of treatment, there is lack of an alternative explanation for respiratory failure, and the resolution of lesions occurs shortly after corticosteroid treatment and withdrawal of the presumed agent. Differential diagnosis includes other factors  that can cause respiratory failure in cancer patients such as lung infections, cardiogenic pulmonary edema, diffuse ­alveolar hemorrhage, and lymphangitic carcinomatosis. Appropriate cultures, serology and bronchoscopy with BAL can be helpful to exclude such causes of respiratory failure [1]. Reduced lung volumes and diffusing lung capacity for carbon monoxide (DLCO) are commonly reported but in many cases are clinically silent and reversible without evidence of prediction about which patient will develop lung toxicity [1, 2].

Pathogenesis Anticancer treatment appears to affect both normal and ­neoplastic cells. Drug-associated lung injury results either from cellular dysfunction generating the cell-death mechanism (apoptosis) or by impairing the cell and tissue repair sequence [3]. The normal activation of the apoptosis seems to play an important role in the remodeling of lung tissue after ALI, for the clearance of excess epithelium and mesenchymal cells from resolving lesions. The type II pneumocyte is the stem cell of the alveolar epithelium and is primarily responsible for re-epithelialization and the restoration of integral alveolar architecture. During normal cell turnover or lung damage, these cells divide and differentiate into the predominant

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a­ lveolar type I pneumocytes [3]. Widespread loss of integrity of nonneoplastic pneumocyte types I and II appears to be the primary cause of DAD [1]. Apoptotic dysfunction: Activation of the apoptotic procedure follows two fundamental pathways: the death receptor and the mitochondrial pathway. These two are intimately connected via caspase 8 and BCL-2 interacting domain (BID). Caspases, a family of cysteine proteases, can activate degradation enzymes that destroy the cell. The first pathway is initiated by cell surface receptor-mediated activation of caspase (Fig. 11.1). The death receptors (Fas, tumor necrosis factor receptor-1 and tumor necrosis factor receptor-2) interact with soluble proteins or membrane-bound proteins such as the Fas ligand (FasL). FasL is a cell surface molecule expressed predominantly in activated T-lymphocytes and natural killer cells. It is accumulated in soluble form at sites of tissue inflammation and has the potential to initiate the apoptosis of leukocytes, epithelial cells, and other parenchymal cells. On the other hand, the mitochondrial pathway is composed of members of the B-cell leukemia (Bcl) family of proteins. The Bcl family has both proapoptotic, such as B-cell leukemia 2 (Bcl-2) associated X protein (BAX), Bcl-2 associated K protein (BAK), BID, and antiapoptotic members, such as Bcl-2. When cells are exposed to an apoptotic stimulus, for example anticancer drugs, radiation and reactive oxygen ­radicals, proapoptotic proteins are activated through posttranslational modifications or changes in their conformation.

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These proteins increase the permeability of the outer membrane of the mitochondria resulting in the release of cytochrome C. In the cytosol, cytochrome C activates a caspase cascade that ultimately leads to cell death [4]. Impaired repair: Members of epidermal growth factor (EGF) family (i.e., EGF, transforming growth factor alpha, TGF-a) are likely to be important regulators of epithelial repair by virtue of their ability to stimulate cell migration, proliferation, differentiation, and survival. EGF belongs to a family of growth factors that exert their biological effect by binding to a transmembrane tyrosine kinase receptor EGF receptor (EGFR also known as the c-erB1). In the normal lung, the distribution of EGF and EGFR has been demonstrated by immunohistochemistry, with expression observed in the basal cell layer of the bronchial epithelium and in occasional type II alveolar pneumocytes [4, 5]. Angiogenesis also plays a key role in wound healing. Normal wound repair generates an angiogenic response to deliver nutrients and inflammatory cells to the injured tissue. The mediators of wound angiogenesis include soluble factors, such as vascular endothelial growth factor (VEGF), TNF-a, TGF-b, fibroblastic growth factor (FGF), and platelet-derived growth factor (PDGF), which have been identified in several wound models. As EGF signaling and angiogenesis may represent an important mechanism that helps coordinate the process of recovery from lung injury, it is possible that their inhibition would partly reduce the ability of pneumocytes

Fig. 11.1  Apoptosis pathways: death receptors and mitochondrial pathway

11  Pulmonary Toxicity of Therapy

to respond and repair. The alteration of repair mechanisms or/and abnormal apoptotic function leads to disruption of the alveolar-capillary membrane and clinical, pathological, and radiographic manifestations of ALI [3].

Radiotherapy-Induced Lung Toxicity Radiation can cause acute or chronic injury in nonneoplastic type I and II pneumocytes, endothelial cells, and stromal fibroblasts. At a pathological level, pulmonary damage is presented as ILD and/or fibrosis. The incidence of toxicity can occur early, within weeks after completion of treatment, or later within the first year [6]. The injury of normal lung tissue depends on the total dose, the dose received from the healthy lung and the mean lung dose [6, 7]. Alterations in apoptotic and repair mechanisms can also explain the pathogenesis of radiation pneumonitis, as implied by the role of multiple cytokines (e.g., TGF-b, TNF-a, interleukin-1, IL-1, IL-6, and PDGF) in the pathogenesis and early detection of toxicity. Initial DNA damage instigates the repair mechanisms or the process of inflammation and finally cell death and fibrosis. Pulmonary function tests should be used as markers or predictors of the incidence and severity of pneumonitis. Furthermore, the predictive value of clinical data, such as the site of the radiated lung, the age of the patient, and smoking history, has been investigated in the context of radiation pneumonitis [6].

Systematic Drug-Induced Lung Toxicity Many chemotherapeutic agents have been related to lung toxicity. Some of the older, first and second generation antineoplastic drugs have proven respiratory side effects but the list continues to grow with the extent of use of new third generation drugs and targeted agents in the treatment of solid tumors (Table 11.1). Table 11.1  Anticancer drugs related to pulmonary toxicity Older Novel Targeted chemotherapeutics chemotherapeutics therapies Bleomycin Docetaxel Gefitinib Mitomycin Paclitaxel Erlotinib Busulfan Gemcitabine Imatinib Cyclophosphamide Fludarabine Sunitinib Carmustin Irinotecan Temsirolimus Methotrexate Topotecan Everolimus Etoposide Bevacizumab Oxaliplatin Cetuximab Thalidomide Rituximab Trastuzumab

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Older Chemotherapy Agents Pulmonary injury, from older drugs, can also be triggered either by formation of reactive oxygen metabolites, including superoxide anions, hydrogen peroxide, and hydroxyl radicals, or by upregulation of the death receptors and their ligands resulting in apoptosis dysfunction (i.e., busulfan, cyclophosphamide, bleomycin, miromycin, carmustine) [8, 9]. Imbalance between protease and antiprotease system has also been implicated as a cause of pulmonary disorders related to drug toxicity (i.e., cyclophosphamide) [8]. Bleomycin can be contemplated as a model for the study of chemotherapy-induced lung toxicity. Lack of bleomycin inactivating enzyme and bleomycin hydrolase in lungs partly explains the toxicity in this organ. Pulmonary ­syndromes that have been associated with ­bleomycin administration are bronchiolitis obliterans with organizing pneumonia, eosinophilic pneumonia, and interstitial pneumonitis often resulting in pulmonary fibrosis, which is irreversible. The mortality of bleomycin-induced pneumonitis is 3%. Symptoms usually start gradually during treatment but can appear even up to 6 months after therapy dis­continuation. Age, total doses >400 mg, renal dysfunction, oxygen supplementation therapy, and thoracic irradiation are the most ­identified risk factors. Pulmonary function tests, although they have no clear predictive value, have to be ­performed before, during, and after bleomycinbased ­chemotherapy [9]. Mitomycin’s pathological patterns of lung toxicity are very similar to those of bleomycin. Capillary leak syndrome can occur especially with combined administration of vinca alkaloids. Pulmonary toxicity is not dose related but depends on concurrent oxygen supplementation and administration of other cytotoxic agents and radiotherapy [8]. Busulfan can cause pulmonary toxicity in 4% of patients. The predominant pathological pattern is pneumoncytes dysplasia, which can be revealed with bronchoscopy and lavage examination or open biopsy. Toxicity can occur after 8 months to 10 years after completion of therapy. Radiation and the use of other alkylating agents may enhance the ­pulmonary side effects [8]. Cyclophosphamide has been reported as a cause of doseindependent interstitial pneumonitis, pulmonary edema, or fibrosis in <1% of the cases. As the toxic effect is due to the production of reactive oxygen species, synergistic effects with oxygen supplementation and other agents are possible [8]. Carmustine is a nitrosourea that has been correlated with a high incidence (20–30%) of lung toxicity. Histopathological findings are similar to bleomycin. Toxicity is dose related and can appear even 15 years after treatment completion. Underling lung diseases and tobacco consumption can accelerate the lung toxicity process [8, 9]. Methotrexate is one of the past generation antimetabolites that is related to pulmonary toxicity with an incidence of

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2–8%. A hypersensitivity mechanism of pathogenesis is suggested by the presence of increased T-lymphocytes in lavage fluid and blood eosinophilia [1]. Pulmonary fibrosis is uncommon but interstitial and alveolar infiltrations can be observed [8]. Symptoms usually occur days or weeks after therapy initiation.

Novel Chemotherapy Agents Novel antineoplastic drugs and targeted therapies have been reported as drug-induced lung injury causes. Pathogenesis could be based on direct injury to pneumocytes and alveolarcapillary endothelium, by apoptotic dysfunction or by impaired repair mechanisms [3]. Systemic release of cytokines (i.e., gemcitabine, docetaxel) may also result in capillary leak syndrome and pulmonary edema. Hypersensitivity reactions may also be the cause of respiratory symptoms ­during infusion (i.e., taxanes). Combination chemotherapy or a multimodality approach with chemo- and radiotherapy may have an additive effect with a higher incidence of ­pulmonary toxicity [3, 10]. Docetaxel is a taxane derivative with activity in many solid tumors including breast, gastric, ovarian, and nonsmall-cell lung cancer (NSCLC). Docetaxel disrupts the microtubular network in cells that is essential for mitotic and interphase cellular functions. Binding to free tubulin, docetaxel produces dysfunctional microtubular bundles that inhibit mitosis. The accumulation of such bundles leads to apoptosis. Furthermore, docetaxel is known to inhibit Bcl-2 antiapoptotic protein, which further encourages apoptosis. Hypersensitivity reactions during drug infusion, with clinical manifestation of bronchospasm, pruritus, skin rashes, fever, and hypotension are not rare. Such reactions can be avoided by the prophylactic use of antihistamines and ­corticosteroids as premedication, while in selected patients desensitization could be effective [11]. Hypersensitivity pneumonitis with typical bilateral ground-glass appearance of the lung parenchyma in chest imaging is the most frequent type of the injury [3, 12]. Although in some cases, docetaxel has been connected to edematous states after subsequent cycles, pulmonary edema is rare. It appears to cause a capillary protein leakage, independent of the presence or absence of ILD, and leads to pleural effusion of peripheral edema formation [13]. Serious side effects are diffuse alveolar damage or ARDS which is mostly described when docetaxel is combined with other agents such as thalidomide, ­gemcitabine, and estramustine [3]. The multimodality approach with radiotherapy and docetaxel-based chemotherapy is highly toxic and fatalities have been reported [12, 14].

A.G. Charpidou and K.K. Syrigos

Paclitaxel is another taxane with the action of a microtubule formation inhibitor. It is one of the most active chemotherapeutic agents in the treatment of breast, lung, and ovarian carcinoma and advanced forms of Kaposi’s sarcoma. The most common pulmonary-related toxicity is bronchospasm and chest tightness in the context of type I hypersensitivity reaction due to IgE antibody formation to paclitaxel or to its vehicle or may be mediated by the release of histamine and other vasoactive substances. This side effect was reported in up to 30% of patients in the first trials but can be dramatically reduced to 1%, by proper premedication as with docetaxel [11]. ILD in the pattern of NSIP or hypersensitivity pneumonitis has been described, but it is usually not serious, responds to corticosteroids, and lasts less than those of docetaxel. Fatal cases have been described especially when paclitaxel is combined with other agents [15]. Gemcitabine is a deoxycytidine analog (2',2'-difluorodeoxycytidine), which interferes with DNA synthesis by inhibiting DNA and RNA polymerase. It shows activity against a variety of solid tumors including pancreatic, ovarian, breast, esophageal as well as lung cancer. Although gemcitabine is considered to be a drug with a reasonable safety profile, cases of pulmonary toxicity have been reported. Transient dyspnea has been reported to arise within hours after drug administration in about 8–10% of patients. The symptom is associated with bronchospasm and is usually a self-limiting event [16]. Incidence of gemcitabine-induced pulmonary toxicity is <1%. Pathological patterns can be demonstrated as capillary leak syndrome with pulmonary edema, DAD, and alveolar hemorrhage. Multimodality therapy increases fatal cases [16, 17]. Fludarabine monophosphate is a nucleoside analog that is used successfully in low-grade lymphomas and chronic lymphocytic leukemia. It is characterized by increasing the risk of opportunistic lung infections. Interstitial pneumonitis and fibrosis have also been described, but corticosteroid therapy has been proved sufficient [10]. Irinotecan is a topoisimerase I inhibitor. It is used in colorectal cancer therapy. Pulmonary toxicity, not otherwise specified, has been reported. Severe and fatal side effects after combination with radiotherapy can occur [18]. Topotecan is also a topoisomerase I inhibitor and active in metastatic ovarian carcinoma and lung cancer. Pulmonary toxicity is rare and mild. Dyspnea has been reported in the 3% of patients treated with small-cell lung cancer [19]. Etoposide is a topoisomerase II inhibitor. The most common respiratory adverse event is hypersensitivity reactions with bronchospasm, dyspnea, skin rash, and hypotension. Combination with other agents, especially methotrexate, requires extreme caution because DAD, fibrin formation, and alveolar edema can happen [3, 8].

11  Pulmonary Toxicity of Therapy

Oxaliplatin is a platinum analog that is used in colorectal cancer therapy. Infusion-related hypersensitivity reactions occur in 1.3% of cases. Rare but serious DAD following treatment with oxaliplatin combinations has been reported [11, 20]. Thalidomide is an old drug that was recently approved for the treatment of multiple myeloma. Its antiangiogenic effects that have been already described, forced the investigation for probable activity against solid tumors. The most serious respiratory adverse event related to thalidomide administration is thromboembolic disease. It usually occurs over a 2-months period after initiation of therapy in the 5–43% of patients, depending on the combination chemotherapy. Rarely interstitial pneumonitis and pleural effusions have been reported [10].

Targeted Therapies Several studies of the last decade have indicated the pivotal role of angiogenesis and the EGFR pathway in tumor growth and metastatic dissemination. This has led to an “explosion” of investigating targeted therapies in cancer treatment. Single- and multi-target new agents have been developed and tested as salvage or front-line treatment, alone or combined with chemotherapy in several solid tumors and hematological malignancies. The pathogenesis of the reported pulmonary toxicity is likely to be an effect in the repair process and not a result of biotransformation or chemical injury as with radiotherapy and chemotherapy. Tyrosine kinase inhibitors (TKIs), gefitinib, and erlotinib are oral EGFR inhibitors. They have been tested in several solid tumors but mostly in NSCLC and have been related to interstitial pneumonitis, DAD, alveolar hemorrhage, and pulmonary fibrosis. Pulmonary toxicity occurs in the 0.3% and 0.8–1.0% for gefitinib- and erlotinib-treated patients, respectively. Japanese ethnicity, concurrent chemotherapy, preexisting pulmonary fibrosis, and previous radiotherapy multiply the risk for respiratory adverse events with EGFRTKIs [21–23]. Imatinib mesylate is a protein tyrosine kinase inhibitor against BCL-ABL and its use exceeds chronic myeloid ­leukemia. Pleural effusions due to fluid retention syndrome and ground-glass opacities due to hypersensitivity pneumonitis have been described. These lesions can be reversed after drug discontinuation and proper corticosteroid therapy [24]. Sunitinib is an oral multitargeted TKI with antitumor and antiangiogenic activity. It is approved for the treatment of advanced renal cell carcinoma and imatinib-refractory ­gastrointestinal stromal tumors. The efficacy and safety of

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single-agent sunitinib in previously treated advanced NSCLC were recently evaluated in a multicenter phase II study. Even if patients with baseline hemoptysis were excluded, three hemorrhage-related deaths occurred and two were considered to be related to the study drug and occurred in patients with squamous cell histology [25]. Temsirolimus and everolimus are rapamycin analogs; inhibitors of mTOR. Temsirolimus is an active antitumor agent, while everolimus is still in the investigational phase. Although there is lack of a large pool of data, these agents are involved in lung toxicity. In a series of 22 patients treated with temsirolimus, 36% (eight patients) have developed pulmonary abnormalities with imaging manifesting as groundglass opacities and consolidation. The use of everolimus, in heart transplant patients, was associated with the presence of severe interstitial pneumonitis after 4 weeks after treatment ­initiation [26, 27]. Monoclonal antibodies have recently been added into the quiver of targeted therapies for hematopoietic and solid organ malignancies. Bronchospasm as a clinical manifestation of hypersensitivity reactions during antibody infusions has been reported. Due to the limited time of experience as a standard of care, their toxicities, including pulmonary, remain a challenge for investigation. Bevacizumab is an IgG1 recombinant humanized monoclonal antibody to VEGF with proven antitumor activity in colorectal and NSCLC by the inhibition of angiogenesis. Pulmonary hemorrhage and fatal hemoptysis have been reported in 31% of an unselected population with advanced NSCLC treated with this regimen [28]. When the use of the bevacizumab was limited, only to patients with nonsquamous NSCLC histology, the occurrence dropped to 2.3% [28, 29]. Cetuximab is an IgG1 monoclonal antibody to EGFR and has shown activity in colon, head and neck, and NSCLC. Dyspnea related to infusion is the main pulmonary adverse event, although serious interstitial pneumonitis with a pathological pattern of bronchiolitis obliterans with organizing pneumonia has been reported [30]. Rituximab targets CD20+ B lymphocytes and is indicated for lymphoma therapy. Lung toxicity, in terms of interstitial pneumonitis and alveolar hemorrhage, is rare and occurs in less than 0.03% of treated patients. The underling pathogenesis is not clear but cytokine release has been proposed, since rituximab leads to complement activation, B-lymphocytes cytolysis and release of tumor necrosis factor [10]. Trastuzumab is a monoclonal antibody to EGFR-2 (HER2). It was recently approved for the treatment of metastatic breast cancer patients with overexpression of this receptor. Infusion-related symptoms occur in 15% of patients. More serious respiratory adverse events with rapidly progres­ sive pulmonary infiltrates and respiratory failure are reported in 0.4% of patients [31, 32].

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Supportive Care Drugs Chemotherapy regimens are dose limited by their adverse effects on bone marrow and myelosuppression. Colonystimulating growth factors (G-CSF) (i.e., filgrastim and ­pegfilgrastim) are of great importance in the supportive care of cancer patients. They are effective in reducing the nadir and duration of neutropenia by permitting the optimum dose intention when necessary. Pulmonary injury has been described with the use of marrow stem-cell growth factors [33]. Since in all the reports the pulmonary symptoms started during or after neutropenia recovery, it appears that the ­proposed mechanism of toxicity is mediated by neutrophilic invasion into the lungs and release of cytokines. Capillary leak syndrome and ALI are the pathological patterns ­displayed. Since most cases have been reported as recurrent exacerbation of chemotherapy-related pulmonary toxicity by G-CSF, it is possible that the stem-cell growth factors may strengthen the lung toxicity of several chemotherapeutic agents. Given the importance of neutrophils on the onset of toxicity, high-risk patients must be under close monitoring and should discontinue G-CSF administration as soon as the leukocyte count rises to 1,000 cells/mL [33].

Diagnosis and Therapy Diagnosis of therapy-induced pulmonary toxicity is an ­exclusion-based multistep procedure. Due to the lack of ­specific clinical, imaging, and pathological findings, chest images, hematology, serology and laboratory tests, bronchoscopy with lavage examination, and finally lung biopsy in selected patients must be performed but can only be suggestive of the diagnosis. The latest is based on exclusion of other factors of respiratory distress in cancer patients, ­predominately pulmonary infections. Time of the onset of symptoms, shortly after the initiation of anticancer therapy can be helpful. In some cases, we can prevent the occurrence of pulmonary toxicity. When toxic effects are dose dependent, restriction of total cumulative doses under a safe threshold (i.e.,  bleomycin <400  mg) can limit the risk [9]. If hyper­ sensitivity reactions during infusion are common (i.e., taxanes and monoclonal antibodies), proper premedication with antihistamines, corticosteroids, and H2 inhibitors can be used [11]. Diuretic treatment offers little help in capillary leak syndrome therapy, while on the contrary, the use of low doses of corticosteroids before and shortly after drug administration can delay toxicity. High doses of corticosteroids (prednisone 60–100  mg) are effective in the cases of therapy-induced pneumonitis without fibrogenic formation [3, 9]. Supportive care measurements including mechanical ­ventilation, IV

A.G. Charpidou and K.K. Syrigos

­ uids, and vasopressors are indicated in severe cases with fl ­circulation collapse.

References 1. Vahid B, Marik P (2008) Pulmonary complications of novel antineoplastic agents for solid tumors. Chest 133: 528–538. 2. Dimopoulou I, Efstathiou E, Samakovli A et al (2004) A prospective study on lung toxicity in patients treated with gemcitabine and carboplatin: Clinical, radiological and functional assessment. Ann Oncol 15: 1250–1255. 3. Charpidou AG, Gkiozos I, Tsimpoukis S et  al (2009) Therapyinduced toxicity of the lungs: an overview. Anticancer Res 9(2): 631–639. 4. Reed JC (2006) Proapoptotic multidomain Bcl-2/Bax-family ­proteins: mechanisms, physiological roles, and therapeutic opportunities. Cell Death Differ 13: 1378–1386. 5. Charpidou A, Blatza D, Anagnostou E et al (2008) Review: EGFR mutations in non-small cell lung cancer clinical impications. In Vivo 22(4): 529–536. 6. Madani I, De Ruyck K, Goeminne H et al (2007) Predicting risk of radiation induced lung injury. J Thorac Oncol 2(9): 864–874. 7. Bradley JD, Graham MV, Winter KW (2005) Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol 61: 318–328. 8. Meadors M, Floyd J, Perry MC (2006) Pulmonary toxicity of ­chemotherapy. Semin Oncol 33(1): 98–105. 9. Sleijfer S (2001) Bleomycin-induced pneumonitis. Chest 120: 617–624. 10. Dimopoulou I, Bamias A, Lyberopoulos P et al (2006) Pulmonary toxicity from novel antineoplastic agents. Ann Oncol 17: 372–379. 11. Syrigou E, Syrigos K, Saif MW (2008) Hypersensitivity reactions to oxaliplatin and other antineoplastic agents. Curr Allergy Asthma Rep 8(1): 56–62. 12. Alsamarai S, Charpidou AG, Matthay RA et al (2009) Pneumonitis related to docetaxel: case report and review of the literature. In vivo 23: 635–637. 13. Semb KA, Aamdal S, Oian P (1998) Capillary leak syndrome appears to explain fluid retention in cancer patients who receive docetaxel treatment. J Clin Oncol 16: 3426–3432. 14. Hanna N, Neubauer M, Yiannoutsos C et al (2008) Phase III study of cisplatin, etoposide and concurrent radiation with or without consolidation docetaxel in patients with inoperable stage III nonsmall-cell lung cancer: Hoosier oncology Group and U.S Oncology. J Clin Oncol 26(35): 5755–5760. 15. Takahashi T, Higashi S, Nishiyama H et al (2006) Biweekly paclitaxel and gemcitabine for patients with advanced urothelial cancer ineligible for cisplatin-based regimen. Jpn J Clin Oncol 36: 104–108. 16. Vander Els NJ and Miller V (1998) Successful treatment of gemcitabine toxicity with a brief course of oral corticosteroid therapy. Chest 114: 1779–1781. 17. Arrieta O, Gallardo-Rinco D, Villarreal-Garza C et al (2009) High frequency of radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with concurrent radiotherapy and gemcitabine after induction with gemcitabine and carboplatin. J Thorac Oncol 4: 845–852. 18. Sohn JH, Mon VW, Lee CG et al (2007) Phase II trial of irinotecan and cisplatin with early concurrent radiotherapy in limited-disease small-cell lung cancer. Cancer 109: 1845–1850.

11  Pulmonary Toxicity of Therapy 19. O’Brien ME, Ciuleanu TE, Tsekov H et  al (2006) Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with small-cell lung cancer. J Clin Oncol 24: 5441–5447. 20. Yague XH, Soy E, Merino BQ et al (2005) Interstitial pneumonitis after oxaliplatin treatment in colorectal cancer. Clin Transl Oncol 7: 515–517. 21. Nagaria NC, Cogswell J, Choe JK et al (2005) Side effects and good effects from new chemotherapeutic agents: case 1. Gefitinibinduced interstitial fibrosis. J Clin Oncol 23: 2423–2424. 22. Herbst RS, Prager D, Hermann R et al (2005) TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced nonsmall-cell lung cancer. J Clin Oncol 23: 5892–5899. 23. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353: 123–132. 24. Ohnishi K, Sakai F, Kudoh S et al (2006) Twenty-seven cases of drug-induced interstitial lung disease associated with imatinib. Leukemia 20: 1162–1164. 25. Socinski MA, Novello S, Sanchez JM et  al (2006) Efficacy and safety of sunitinib in previously treated, advanced non small cell lung cancer: preliminary results of a multicenter phase II trial. J Clin Oncol 24(18 suppl): 364s (Abstract 7001).

105 26. Duran I, Siu LL, Oza AM et al (2006) Characterization of the lung toxicity of the cell cycle inhibitor temisirolimus. Eur J Cancer 42: 1875–1880. 27. Rothenburger M, Teerling E, Bruch C et al (2007) Calcinurin inhibitor-free immunosuppression using everolimus (certican) in maintenance heart transplant recipients: 6 months’follow-up. J Heart Lung Transplant 26: 250–257. 28. Sandler A, Gray R, Perry MC et  al (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355: 2542–2550. 29. Reck M, von Pawel J, Zatloukal P et  al (2009) Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAiL. J Clin Oncol 27: 1227–1234. 30. Chua W, Peters M, Loneragan R et al (2009) Cetuximab- associated pulmonary toxicity. Clin Colo Cancer 8: 118–120. 31. Vahid B and Mehrotra A (2006) Trastuzumab (herceptin)-­associated lung injury. Respirology 11: 655–658. 32. Tripathy D, Slamon DJ, Cobleigh M et  al (2004) Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol 22: 1063–1070. 33. Azoulay E, Attalah H, Harf A et  al (2001) Granulocyte colonystimulating factor on neutrophil-induced pulmonary toxicity: myth or reality? Chest 120: 1695–1701.

Chapter 12

Management of Respiratory Symptoms in People with Cancer David C. Currow and Amy P. Abernethy

Dyspnoea

Incidence, Prevalence, and Trajectory of Dyspnoea

Definitions Dyspnoea is a complex somato-psychic experience mediated by complex interactions at several levels of the peripheral and central nervous system [1]. Like many chronic symptoms, dyspnoea is a constant reminder of the underlying pathology and its imposition on the person; intensity, and degree of unpleasantness vary. The underlying pathological causes of the sensation of breathlessness are usually multifactorial with superimposed psychological aspects to the subjective sensation. The ever-present sense of impending doom heightens anxiety as a person struggles to breathe. At the most primal level, severe dyspnoea is a direct and constant threat to a person’s very existence. Fears about dyspnoea are at the forefront of people’s minds as cancer is diagnosed and as the disease progresses, especially when primary or secondary lung lesions are identified. Increasing dyspnoea has been identified in two relatively small studies as an independent risk factor for mortality in people with advanced cancer: one with the relative risk of death more than double the rest of the population (hazard ratio 2.04; 95% confidence interval [CI], 1.26–3.31; p < 0.01) [2]; the other linking poorer performance status and higher physical symptom scores with poorer survival [3]. The correlation between perceived symptoms and objective measures of respiratory function are very poor although, predictably, an increase in PaCO2 or decrease in PaO2 or pH [4] is likely to result in worsening breathlessness. With space occupying lesions, mechanical receptors in the chest wall may be activated in addition to vagal receptors in the airways and lungs.

D.C. Currow (*) Palliative and Supportive Services, Flinders University, Adelaide 5041, South Australia e-mail: [email protected]

In a sample of the general population (n = 8,396), 9% of ­people are troubled by substantial breathlessness on a daily basis across the community [5]. Superimpose cancer on this baseline community prevalence of breathlessness, together with worsening control of comorbid illnesses, and both the incidence and intensity of breathlessness increase markedly. The National Hospice Study in the USA estimated that more than 50% of people with advanced cancer have substantial dyspnoea [6], which is in keeping with another study of more than 900 people with cancer [7]. In a consecutive cohort of more than 5,000 people referred to a regional palliative care service where data collection routinely occurred at every clinical encounter, the number of people with some report of dyspnoea increased from 35% 3 months before death to 50% at the last clinical encounter before death [8], closely reflecting other longitudinal data [9, 10]. In parallel, there was an increase in severe breathlessness (³7 on a 0–10 numerical rating scale) from 10 to 26% in the same time period, despite continued access to a specialised palliative care service and symptom control interventions. In people with cancer, the estimates of the number of ­people troubled by the symptom vary widely. These varying estimates are likely to reflect the different points in the ­trajectory of functional decline when dyspnoea is measured, and differing underlying cancers and comorbidities. Not ­surprisingly, primary lung is the cancer most frequently associated with breathlessness [11]. Even in the setting where it is expected that a person can be cured of their cancer, breathlessness can still be a substantial problem. Breathlessness is likely to preexist for many people given the associations between tobacco smoke, chronic obstructive pulmonary disease, ischaemic heart ­disease and lung cancer. The treatment of primary lung cancer with surgery or radiotherapy will diminish vital capacity and often translate to long-term breathlessness on exertion or even at rest as a result. In a person with progressive cancer, unlike most other symptoms (with the exception of fatigue), dyspnoea often

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worsens as functional status declines and death approaches despite efforts to optimise symptom control [12]. For the majority of people in this situation, reversible causes of breathlessness will not be found, although they should be sought in the overall clinical context of the person. In addition to fatigue, worsening cachexia may be associated with worsening dyspnoea. Other neuromuscular factors that may contribute to the sensation of breathlessness include phrenic or recurrent laryngeal nerve (RLN) palsies. Physical restriction of breathing effort can occur with lung entrapment (as seen with mesothelioma or following an empyema) or malignant infiltration of the chest wall (carcinoma en cuirasse). Factors contributing to dyspnoea that require complex investigations, burdensome interventions or have a marked lag time between starting definitive therapy and gaining symptomatic benefit will become less relevant the closer a person is to death. Not only will reversible causes not be found for many people near the end of life, but also a cardiorespiratory pathology will not be evident either.

Defining the Goals of Care There is a need to generate a careful balance between disease modifying therapy for primary or metastatic cancers and the need to palliate symptoms. Whether the aim of therapy is to cure, prolong life or palliate, breathlessness needs to be addressed in parallel with other therapies. Symptom reduction and optimising function (physical, social, and emotional) are the key goals of supportive care, and patients will be the only judge of whether their breathlessness is being adequately managed.

Assessment Reversible Causes As with any symptom, the best treatment is to reverse the underlying cause of the illness whenever possible. Although direct causes of worsening breathlessness can be identified, this is in the minority of patients. Causes directly linked with the cancer itself include pleural effusions, large and intermediate airway obstruction, and lung volume loss due to surgery, radiotherapy or permanent occlusion of proximal airways, or worsening tumour burden especially in the setting of multiple pulmonary metastases including lymphangitis carcinomatosis. Anaemia, whether as a result of systemic therapy, chronic disease, or other causes, should always be explored as a potentially reversible cause. Mild anaemia is unlikely to account for

D.C. Currow and A.P. Abernethy

significant dyspnoea, and any treatment of anaemia should be followed by careful monitoring to establish whether a transfusion actually improved the person’s breathlessness. Intermittent exacerbations of chronic obstructive pulmonary disease, asthma, ischaemic heart disease, chronic and intermittent arrhythmias, and thromboembolic diseases should be sought as reversible causes of suddenly worsening breathlessness. The peak disease incidences for cancer and most of these comorbidities overlap. Optimising the clinical management of any such factors may help ameliorate the sensation of breathlessness, although reversal of clinical signs will not always translate into improved symptom control.

Dimensions of Breathlessness Breathlessness is multidimensional. As such, the comprehensive assessment of breathlessness requires each clinician to assess the dimensions that have been identified as being important [13] – the physical sensation (both intensity and how unpleasant the sensation is) [1], the anxiety and other psychological consequences [7, 10], the existential questions generated by continuing dyspnoea [14], and the social impact of breathlessness [15]. Each dimension needs to be assessed in order to have an adequate picture of breathlessness in a person. An important question for a clinician to ask is what has the person themselves encountered by way of breathlessness during life – in themselves or in people they have seen. Linked intimately with this question is the exploration of what they expect to experience and specifically what fears they have about future breathlessness or the fear of suffocation. Giving voice to these questions allows clinicians to reassure a person that symptoms will be addressed actively and that every effort will continue to be made to reduce suffering and avoid the sensation of suffocation. The other crucial aspect of assessment is to consider the effect that breathlessness has on caregivers. Again, care­ givers have specific needs in providing care for people where breathlessness is a dominant symptom [15, 16]. The role of caring for someone with chronic disabling breathlessness is in itself very confronting to caregivers, and the ability to be able to take on and continue the role needs careful assessment by clinicians, given the identified burdens perceived by caregivers in this setting [17].

Measuring Breathlessness A distinction needs to be made between measures of breathlessness for research and day-to-day clinical evaluation.

12  Management of Respiratory Symptoms in People with Cancer Table 12.1  Modified medical research council (MRC) dyspnoea scale Grade Description of symptom 0 “I only get breathless with strenuous exercise” 1 “I get short of breath when hurrying on the level or walking up a slight hill” 2 “I walk slower than people of the same age on the level because of breathlessness or have to stop for breath when walking at my own pace on the level” 3 “I stop for breath after walking about 100 yards or after a few minutes on the level” 4 “I am too breathless to leave the house” or “I am breathless when dressing” Note: This modified MRC scale uses the same descriptors as the ­original MRC scale in which the descriptors are numbered 1–5

Objective measures of the function required to induce ­dyspnoea include tests such as the 6-min walk test. For many people, especially in the face of advancing disease or significant comorbid disease burden, even a 6-min walk test will be beyond their ability, and this is in itself a telling clinical finding. In the clinical setting, it is important to distinguish between breathless and leg fatigue as the rate-limiting factor in functional assessments [18]. Although there are functional tests for people unable to tolerate a 6-min walk test, the clinical application of these is extremely limited. Given the subjective nature of breathlessness, the cornerstone of measurement is subjectivity. Such measures must include both the intensity and how unpleasant the sensation is [1]. Unidimensional categorical scales, such as Likert scales or the Borg scale, and numerical rating or visual analogue scales all have relevance for measuring breathlessness and its impact on the person’s life. Both the Medical Research Council dyspnoea scale (Table  12.1) and the Cancer Dyspnoea Scale can be used to explore breathlessness from a patient’s viewpoint. The latter has the advantage of including anxiety, effort, and discomfort [19]. A combination of categorical and continuous measures is likely to be able to be used in rating most people. Numerical or analogue rating scales are abstract, and for some people categorical scales may be much easier to use reproducibly [20]. Most importantly, clinicians need to consistently use at least one measure of physical impairment and of subjective discomfort routinely in clinical practice, and use the same scales for longitudinal assessments with each patient.

Symptomatic Treatment of Refractory Dyspnoea Exploring any reversible causes for dyspnoea should occur at the same time as initiating therapy for the symptom itself in people with advanced cancer. With reversible causes

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o­ ptimally addressed (and this would include diuretics for cardiac failure or corticosteroids for reversible bronchoconstriction), all efforts should focus on the symptomatic relief of the sensation of breathlessness. Options include pharmacological interventions (and oxygen is considered within this category) and nonpharmacological interventions. Recent systematic reviews have been done in each of these areas [20–24].

Systemic Opioids The mechanisms of action through which opioids relieve dyspnoea include a central effect. A recent randomised controlled trial comparing naloxone (a centrally acting opioid antagonist) with normal saline explored the exercise abilities in people with moderate-to-severe chronic obstructive pulmonary disease that were not on exogenous opioids. Without affecting exercise tolerance, when randomised to the naloxone arm (i.e., when endogenous opioids were blocked), people had more dyspnoea for the same workload. This landmark study strongly defines the effects of endogenous opioids and suggests that exogenous opioids can have a role without necessarily compromising respiratory function [25]. Opioids are the gold standard pharmacological intervention for the symptomatic treatment of dyspnoea. When administered regularly in low doses and carefully titrated for chronic administration, there are no data to suggest that respiratory depression is a significant clinical issue. Data from the acute care setting where relatively larger doses of opioids are given to people who are opioid naïve cannot be extrapolated to the chronic setting [26]. A systematic review by Jennings et al. [21] confirms that in the palliative setting opioids demonstrated efficacy in reducing breathlessness. The direction and magnitude of the findings in this study were confirmed by an adequately powered, cross-over, randomised, placebo-controlled trial of 20 mg sustained release oral morphine daily in people with refractory breathlessness, mostly from COPD [27]. More recently, a systematic review of controlled trials in people only with cancer confirmed that systemic opioids reduced the subjective sensation of breathlessness [23]. Viola approached the same patient population and again demonstrated that systemic opioids (morphine, Dihydrocodeine) have benefit in the relief of breathlessness despite slightly different eligibility criteria for the studies included [22]. All three systematic reviews reflect the diversity of approaches in the clinical studies that have been done. The Jennings study makes a clearer distinction between single-dose studies and steady-state studies. Importantly, the systematic reviews by Jennings, Viola, and Ben-Aharon each conclude that, to date, there are no data to support a role for nebulised opioids for refractory dyspnoea [21–23].

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The magnitude of symptomatic benefit experienced by patients from the pooled data was of the order of 8 mm on a 100-mm visual analogue scale (overall pooled effect size, −0.31; 95% CI, −0.50 to −0.13; p = 0.0008), which is both statistically and clinically significant given the progressive nature of this breathlessness and the fact that baseline scores were of the order of 50 mm [21]. This does include singledose studies that may move the estimate away from a net clinical benefit (in a similar way to early single-dose trials of opioids for pain). In the safety measures reported, there was no evidence of respiratory depression or obtundation. Optimal dosing and titration studies are still awaited for both people who are opioid naïve and for people already on opioids for other indications such as pain. To date, a starting dose of between 10 and 20 mg of sustained release morphine in 24  h in divided doses is reasonable. Further work also needs to ensure the safety of these medications in everyday practice, but, to date, evidence of toxicity in steady-state is minimal. Constipation remains the most constantly reported effect of taking regular opioids and should be treated expectantly.

Nonopioid Medications A wide range of psychotropic medications (anxiolytics ­[benzodiazepines, buspirone], phenothiazines [promethazine], selective serotonin reuptake inhibitors) have been used to try and relieve refractory breathlessness. Again, measured endpoints and single vs. steady-state studies make comparisons difficult, but in systematic reviews, the only medication that may have a role is oral promethazine as a second-line agent, if the patient is unable to tolerate opioids or has not responded to them [22]. Again, optimal dosing has not been defined. Other agents did not have supporting phase III trials, although phase II data suggest the need for further studies of buspirone and selective serotonin uptake inhibitors. Despite widespread use, the benefit of a range of benzodiazepines has yet to be established in relieving breathlessness, especially if used for extended periods of time. The largest study of benzodiazepines in dyspnoea in the terminal stages of life (last hours and days) cannot be extrapolated into ­clinical practice for people who have better performance [28]. If there is a clear component of anxiety, benzodiazepines may have a role in acutely breaking the cycle of anxiety while other treatments are introduced. Apart from its diuretic effects, several small studies have explored the role of nebulised frusemide. Although it has been demonstrated to protect against bronchoconstriction, it also appears to affect the perception of breathlessness in people who do not have bronchoconstriction. This ­intervention

D.C. Currow and A.P. Abernethy

has not been studied in people with cancer; however, in ­people with chronic obstructive pulmonary disease, it appears to signi­ ficantly lessen breathlessness after exercise when compared with placebo in a blinded trial [29] and change the perception of breathlessness in healthy volunteers when challenged with breath holding or loaded breathing [30]. A systematic review has not provided conclusive ­evidence for inclusion in practice at this time [31].

Oxygen Oxygen is often prescribed for palliative benefit when a person is noted to be breathless, especially if there has been an acute change in their condition [32, 33]. While levels of oxygenation are being established, it is reasonable for ambulance, emergency room, and ward staff to do this. Having introduced oxygen in the acute setting, what is its role in the ongoing care of people with chronic breathlessness? A systematic review of five studies of people with cancer and breathlessness (n = 134) does not support symptomatic benefit from oxygen in people who were not hypoxaemic (SMD = −0.09, 95% CI −0.22 to 0.04; p = 0.16) [24]. Indeed, there is evidence that patients are very discerning about the net benefit offered by domiciliary oxygen balancing the symptomatic benefit with the burden of administration and concerns about being dependent on a machine [34]. In an adequately powered, parallel arm, randomised, doubleblind study of oxygen compared to medical air for 1 week, there was no difference across the population (n = 241) in relief of breathlessness nor quality of life. Both arms showed benefit over baseline of a similar magnitude, suggesting that flow of gas may be a key to reducing the sensation of breathlessness. People with the most severe breathlessness appeared to derive more benefit, and more so from oxygen than medical air, but the study was not powered for subgroup analyses [27]. Given the ability of patients to define benefit, it is reason­ able to consider properly constructed n-of-1 studies so that any benefit can be quantified and the clinician and patient agree on the long-term strategy regarding oxygen.

Heliox28 Heliox28 is a mixture of 72% helium and 28% oxygen and potentially reduces the work of breathing by providing a lower density gas than nitrogen by generating less resistance to movement through small airways. A phase II study comparing Heliox28 with oxygen and with medical air suggested symptomatic and functional improvements in favour of

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Heliox28, but not significantly greater than oxygen. It is questionable whether this benefit is of sufficient magnitude to justify the added expense of Heliox28, and indeed whether phase III data should be sought.

Nonpharmacological Management of Dyspnoea Given the multidimensional construct of breathlessness, it is to be expected that a range of interventions may be required to optimally treat the symptom. An increasing number of clinical trials identify nonpharmacological interventions that benefit people with refractory dyspnoea, including psychosocial support and optimising breathing techniques.

chronically by a number of substances can produce a chronic cough. Like most other symptoms, there may be a protective component to a cough, but for many people, a chronic cough interrupts their social interactions and essential functions such as sleep. Work is currently underway to understand better the underlying mechanisms of cough. Functional MRI demonstrates the involvement of both the cortex and the brainstem in cough. Although asthma and gastro-oesophageal reflux disease are associated with some people having a chronic cough, the role of upper airway sensitization (especially involving the transient receptor potential vanilloid-1 ­receptor) may better explain the reason that some people experience this troublesome symptom and others do not [36, 37].

Assessment Breathlessness Clinics Breathlessness clinics that focus on breathing techniques, relaxation, coping strategies including activity pacing and counselling have shown benefits for people with cancer. Weekly sessions for 3–8 weeks have been shown to provide benefit well after the sessions have concluded. Data from a randomised trial support this model [35], but availability of this nurse-led resource remains limited (and predominantly focused in the UK).

Breathing Techniques A forward leaning position in which the person’s weight is supported by their arms appears to help relieve breathlessness by more effectively using the muscles of respiration. This includes better use of the diaphragm and less reliance on accessory and abdominal muscles. Pursed lip breathing is expiration that lasts at least 4 s and reduces dynamic airway collapse by providing gentle back pressure to small airways. Both of these techniques require a motivated and cognitively capable patient who is physically well enough to learn and practice these techniques.

Cough Cough is frequently encountered in people with cancer involving the lung, especially when larger airways are affected by malignancy. Upper or lower airways irritated

Reversible or modifiable causes for cough need to be sought. The three most commonly encountered causes that are potentially modifiable include asthma or chronic bronchitis, swallowing disorders particularly in this cohort of people where age remains a risk factor for dysphagia to ­liquids or gastro-oesophageal reflux disease. There are data to support the use of inhaled corticosteroids or ipratropium in reducing cough in people with airways disease. There are limited data to support the use of proton-pump inhibitors in reducing cough in people with gastro-oesophageal reflux disease [38]. It is also important to determine whether the cough remains a protective mechanism (excess secretions) or is serving no physiological benefit.

Symptomatic Treatment There is no gold standard symptomatic therapy for cough. In the palliative setting, nebulised saline may help reduce the viscosity of mucous. Encouraging more effective use of coughing is the aim for many therapies, where excess mucous secretion is the major cause for coughing [39]. Cough suppressants often employ opioid-based compounds, but blinded trials have not shown benefit over ­placebo or the characteristics of a subpopulation who may benefit from the intervention. Codeine or its derivatives are used in modest doses, but there is a very high placebo response rate in the blinded studies that have been conducted and a significant period effect given that the natural history of cough is that it resolves for most people [39].

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Pleural Effusions Pleural effusions are frequently encountered in the setting of cancer. This discussion will be limited to people who have previously been diagnosed with cancer and now have a ­pleural effusion. The symptom burden of the effusion needs to be weighted carefully against the burden of intervention. For example, in someone with widespread cancer and a small unilateral ­effusion, one could argue that further investigation is unlikely to improve comfort or function. Conversely, in someone who has been offered definitive treatment for their cancer and is now presenting with an effusion for the first time, it will be imperative to establish the nature and likely cause(s) of the effusion. Importantly, up to 50% of people who have an ­effusion drained will not have an improvement in their breathlessness or exercise tolerance after drainage [40]. The nature of pleural fluid is important as likely causes are explored. The distinction proposed four decades ago for categorising effusions into transudates and exudates using Light’s criteria [41] still has clinical application – one or more of three criteria will make the diagnosis of an exudate: pleural/serum protein >0.5; pleural/serum lactate dehydrogenase (LDH) >0.6; and/or pleural fluid LDH >0.66 of the upper limit of normal. The major caveat in using these is when someone is on diuretics as there is a risk of underdiagnosing transudates in favour of exudates [42]. Raised pleural fluid cholesterol levels are associated with exudates independently of diuretic use [43]. The differential diagnosis for frequently encountered causes of transudates includes cardiac failure, hepatic failure, or other low-albumin states. The most frequently encountered causes of exudates include malignancy, pneumonia, pulmonary embolism, or, in some parts of the world, tuberculosis. Gram stain and culture of pleural fluid should occur in suspected para-pneumonic causes, and adenosine deaminase and gamma interferon estimates in people with suspected tuberculosis. The treatment of pleural effusions needs to distinguish between diagnostic drainage and the relief of symptoms. Symptomatic relief needs to take account of the person’s overall functional status. Someone with a poor level of function where nothing else can change the course of the illness may require a far more circumspect approach than someone for whom this was the only site of symptomatic disease who is otherwise functioning without compromise. The size of the effusion should be carefully evaluated before intervention – only effusions that are causing symptoms should be considered for intervention. Small effusions are unlikely to cause a significant symptom burden in all but people with the most severe respiratory compromise creating a difficult ­benefit/burden equation to balance before intervening in this extremely unwell cohort.

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In people well enough to tolerate it, a pleurodesis should be performed. Although there is continuing debate in the literature as to the optimal sclerosant, talc has been most studied and appears to offer longer periods of benefit for symptomatic pleural effusions, especially with the use of larger particle diameter talc [44]. Whether the sclerosant should be introduced thorascopically or with the insertion of an intercostal chest drain is open to debate and will often be dictated by local resources and experience [40]. Thorascopically performed pleuradeses appear to have lower rates of effusion recurrence and have the advantage of being able to physically breakdown septa that cause loculation in many effusions, but with the disadvantage of requiring general anaesthetic with selective lung intubation on the contralateral side. In people with excellent performance status, this is the intervention of choice for pleurodesis [45]. Pleuroscopy is less invasive (a single entry point) and can be done under conscious sedation rather than general anaesthetic. At the time of pleuroscopy, a sclerosant can be introduced if necessary. The other therapy gaining popularity is small bore tunnelled intercostal catheters that can be implanted in people on an outpatient basis and can be emptied by community nurses or family members using a vacuum-sealed attachment (PleuRxR) in the long term. This appears to have a similar rate of “auto-pleurodesis” at 1 month as intercostal drainage, without the need for inpatient care at the time that a formal pleurodesis was done. In people with poor performance status and limited life expectancy, a trial of recurrent thoracentesis or the insertion of small bore tunnelled intercostal catheters are treatments of choice. This needs to be judged within the context of a ­person’s overall systemic function. Although fibrinolytics have been used to reduce loculation in para-pneuomonic exudates and systematically analysed [46, 47], their role in malignant pleural effusions has been defined by a small number of case series with no comparative effectiveness data available [48]. The administration of methyprednisolone into the pleural cavity did not change the time to reaccumulation nor dyspnoea scores [49].

Haemoptysis Like dyspnoea, the fear of bleeding from the respiratory tract is a constant concern for many people with cancer involving their lungs. Up to 20% of all people with cancer involving, the lung will have haemoptysis at some stage during their illness – either as a presenting complaint or subsequently [50]. Differential causes that need to be considered include thromboembolism to the lungs and probleeding states such

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as coagulopathies or thrombocytopaenia. Anticoagulants, nonsteroidal antiinflammatories, and antiplatelet agents should be reviewed carefully. The rate of bleeding should be considered in three categories – mild, moderate, or severe. Episodes of mild bleeding warrant investigation for any reversible causes of a probleeding state. They also are an opportunity to have a conversation about the small but real risk of an increased volume of bleeding at some point in the future. Exhaustive investigations in this setting are not warranted. Most low-level bleeding stops spontaneously. Moderate bleeding is an area where the threshold for aggressive investigations may well be met, even if the functional status is very poor. Beyond coagulation and platelet studies, it may be worth seeking to visualise the large ­airways and coagulate any bleeding points seen with photocoagulation or local instillation of adrenaline [50]. If a lesion cannot be visualised, then a select group of patients with persistent bleeding should be considered for selective angiography to identify and potentially treat the bleeding point. In reality, for all the people with haemoptysis, few will qualify for angiography. Other potential therapies for moderate haemoptysis include external beam radiotherapy to a known tumour deposit. It appears that high-dose endobronchial radiotherapy may offer little benefit over external beam radiotherapy and may have higher rates of catastrophic bleeding [51]. Systemically, the use of tranexamic acid regularly for up to 5 days while clot organises over the bleeding source is also an option. This medication is contraindicated in people who have a history of thromboembolism or a recent history of bleeding in the urinary tract or other sites. In severe, large volume bleeding, although many textbooks and authorities talk of emergency orders, the reality is that these happen very rarely, and when they do occur, there is rarely sufficient time to respond with sedating medication before the person dies. Such events are distressing for all involved – the patient, their family and friends, and the staff providing care. Important nursing considerations continue to include the availability of linen that is not white – green or red towels will help mask the extent of blood loss.

Hoarse Voice The diagnosis of exclusion is damage to the recurrent laryngeal nerve (RLN), itself a branch of the vagus. Given the descent of both laryngeal nerves into the thorax, damage can occur from the tumour or local therapies such as radiotherapy. The left RLN wraps under the arch of the thoracic aorta and the right side around the right subclavian artery. Mediastinal, thoracic, or head and neck malignancies can cause damage to the nerve.

Patients are most likely to present with a change in the character or volume of their voice. The major clinical concerns are about the ability to protect the airway when the vocal cords cannot appose adequately. The risk of aspiration and poor cough is a deadly combination. Bilateral damage (unlikely in this clinical setting) will cause aphonia and often difficulty in breathing. Treatment for unilateral damage most frequently now includes injection of collagen into the paralysed cord to improve adduction of the cord. Patient reassurance is a key since hoarse voice can be very noticeable.

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114 16. Currow DC, Ward AM, Clark K, et al. Caregivers for people with end-stage lung disease: characteristics and unmet needs in the whole population. Int J Chron Obstruct Pulmon Dis. 2008;3(4):753–762. 17. Booth S, Silvester S, Todd C. Breathlessness in cancer and chronic obstructive pulmonary disease: using a qualitative approach to describe the experience of patients and carers. Palliat Support Care. 2003;1(4):337–344. 18. Wilcock A, Maddocks M, Lewis M, et  al. Symptoms limiting ­activity in cancer patients with breathlessness on exertion: ask about muscle fatigue. Thorax. 2008;63(1):91–92. 19. Tanaka K, Akechi T, Okuyama T, et al. Development and validation of the Cancer Dyspnoea Scale: a multidimensional, brief, self-­rating scale. Br J Cancer. 2000;82(4):800–805. 20. Bausewein C, Farquhar M, Booth S, et al. Measurement of breathlessness in advanced disease; a systematic review. Respir Med. 2007;101(3):399–410. 21. Jennings AL, Davies AN, Higgins JPT, et al. A systematic review of the use of opioids in the management of dyspnoea. Thorax. 2002;57:939–944. 22. Viola R, Kiteley C, Lloyd NS, et al. The management of dyspnea in cancer patients: a systematic review. Support Care Cancer. 2008;16(4):329–337. 23. Ben-Aharon I, Gafter-Gvili PM, Leibovici L, et al. Interventions for alleviating cancer-related dyspnea: a systematic review. J Clin Oncol. 2008;28(14):2396–2404. 24. Uronis HE, Currow DC, McCrory DC, et al. Oxygen for relief of dyspnoea in mildly- or non-hypoxaemic patients with cancer: a syste­matic review and meta-analysis. Br J Cancer. 2008;98(2): 294–299. 25. Mahler DA, Murray JA, Waterman LA, et al. Endogenous opioids modify dyspnoea during treadmill exercise in patients with COPD. Eur Respir J. 2009;33:771–777. 26. Currow DC, Abernethy AP, Frith P. Morphine for management of refractory dyspnea. BMJ. 2003;327:1288–1289. 27. Abernethy AP, McDonald CF, Frith PA, et al. Effect of palliative oxygen versus medical (room) air in relieving breathlessness in patients with refractory dyspnea: a double-blind randomized controlled trial (NCT00327873). Lancet 2010 (In press). 28. Navigante AH, Cerchietti LC, Castro MA, et  al. Midazolam as adjunct therapy to morphine in the alleviation of severe dyspnea perception in patients with advanced cancer. J Pain Symptom Manage. 2006;31(1):38–47. 29. Ong K-C, Kor A-C, Chong W-F, et al. Effects of inhaled furosemide on exertional dyspnea in chronic obstructive pulmonary disease. Am J Resp Crit Care Med. 2004;169(9):1028–1033. 30. Nishino T, Ide T, Sudo T, et al. Inhaled furosemide greatly alleviates the sensation of experimentally induced dyspnea. Am J Respir Crit Care Med. 2000;161(6):1963–1967. 31. Newton PJ, Davidson PM, Macdonald P, et  al. Nebulized furosemide for the management of dyspnoea. Does the evidence support its use? J Pain Symptom Manage. 2008;36(4):424–441. 32. Stringer E, McParland C, Hernandez P. Physician practices for ­prescribing supplemental oxygen in the palliative care setting. J Palliat Care. 2004;20(4):303–307.

D.C. Currow and A.P. Abernethy 33. Abernethy AP, Currow DC, Frith PA, et  al. Prescribing palliative oxygen: a clinician survey of expected benefit and patterns of use. Palliat Med. 2005;19:165–172. 34. Currow DC, Fazekas B, Abernethy A. Oxygen use – patients define symptomatic benefit discerningly.’ J Pain Symptom Manage. 2007; 34(2):113–114. 35. Corner J, O’Driscoll M. Development of a breathlessness assessment guide for use in palliative care. Palliat Med. 1999;13(5):375–384. 36. Millqvist E, Bende M. Role of the upper airway in patients with chronic cough. Curr Opin Allergy Clin Immunol. 2006; 6(1):7–11. 37. Pavord ID, Chung KF. Management of chronic cough. Lancet. 2008;371(9621):1375–1384. 38. Chang AB, Lasserson TJ, Gaffney J, et  al. Gastro-oesophageal reflux treatment for prolonged non-specific cough in children and adults. Cochrane Database Syst Rev. 2005;(2):CD004823. 39. Wee B. Chronic cough. Curr Opin Palliat Care. 2008;2:105–109. 40. Khaleeq G, Musani AI. Emerging paradigms in the management of malignant pleural effusions. Resp Med. 2008;102:939–948. 41. Light RW, MacGregor MI, Luchsinger PC, et al. Pleural effusions: the diagnostic separation of transudates and exudates. Ann Intern Med. 1972;77(4):507–513. 42. Light RW. Diagnostic principles in pleural disease. Eur Respir J. 1997;10:476–481. 43. Porcel JM, Vives M, Vincente de Vera MC, et al. Useful tests on pleural fluid that distinguish transudates from exudates. Ann Clin Biochem. 2001;38(6):671–675. 44. Maskell NA, Lee YC, Gleeson FV, et  al. Randomized trials describing lung inflammation after pleurodesis with talc of varying particle size. Am J Respir Crit Care Med. 2004;170(4): 377–382. 45. Shaw P, Agarwal R. Pleurodesis for malignant pleural effusions. Cochrane Database of Syst Rev 2004;(1):CD002916. 46. Tokuda Y, Matsushima D, Stein GH, et al. Intrapleural fibrinolytic agents for empyema and complicated parapneumonic effusions: a meta-analysis. Chest. 2006;129(3):783–790. 47. Cameron R, Davies HR. Intrapleural fibrinolytic therapy versus conservative management in the treatment of adult parapneumonic effusions and empyema. Cochrane Database System Rev. 2008;(2): CD002312. 48. Davies CW, Traill ZC, Gleeson FV, et al. Intrapleural streptokinase in the management of malignant multiloculated pleural effusions. Chest. 1999;115(3):729–733. 49. North SA, Au HJ, Halls SB, et al. A randomized, phase III, doubleblind, placebo-controlled trial of Intrapleural instillation of methylprednisonolone acetate in the management of malignant pleural effusion. Chest. 2003;123(3):822–827. 50. Kvale PA, Simoff M, Prakash UB. Lung cancer. Palliative care. Chest. 2003;123(1 Suppl):284S–311S. 51. Ung YC, Yu E, Falkson C, et  al; The role of high-dose-rate brachytherapy in the palliation of symptoms in patients with nonsmall-cell lung cancer: a systematic review. Brachytherapy. 2006;5(3):189–202.

Part V

Endocrine and Metabolic

Chapter 13

Endocrine and Metabolic Symptoms of Cancer and Its Treatment Rony Dev

Tumor Lysis Syndrome Tumor Lysis Syndrome (TLS), a potentially life-threatening complication for patients with cancer, has been subclassified into either laboratory TLS or clinical TLS. Laboratory TLS is characterized by the rapid development of two or more of the following abnormalities – hyperuricemia, hyperkalemia, hyperphospatemia, hypocalcemia, and azotemia – which occur in cancer patients most often 28–72 h after the initiation of chemotherapy or radiation; however, spontaneous cases have been reported [1]. Clinical manifestations of TLS include renal failure (glomerular filtration rate £60 ml/min) and organ damage leading to cardiac arrhythmias or seizures. Predisposing factors for TLS include neoplasms with high growth rates, patients with a large tumor size or burden, high white blood cell count (>50,000/mm3), cancers highly sensitive to chemotherapy or radiation, and patients with extensive bone marrow involvement [2]. Comorbidities that increase the risk for developing TLS include elevated uric acid level prior to treatment, preexisting renal insufficiency, obstructive uropathy, and advanced age [2]. Patients with hematological malignancies including high-grade lymphomas (i.e., Burkitt’s lymphoma) and acute or chronic leukemias are more likely to have complications of TLS. In adults with solid tumors, TLS is a rare complication in chemosensitive tumors including bulky small cell lung cancer and metastatic germ cell carcinoma. In children, TLS is more frequently associated with malignancies that have an increased proliferative fraction, large tumor burden, widely metastatic disease, or increased sensitivity to chemotherapy. The pathogenesis of TLS involves the acute release of intracellular products into the systemic circulation secondary to the destruction of cancer cells after chemoradiotherapy. Uric acid, calcium phosphate, or hypoxanthine may precipitate in the renal tubules resulting in acute renal failure. Other R. Dev (*) Department of Palliative Care and Rehabilitation Medicine, University of Texas MD Anderson Cancer Center, Symptom Control and Palliative Medicine, Houston, TX 77030, USA e-mail: [email protected]

hemodynamic changes resulting in decreased glomerular flow have also been postulated to contribute to renal failure. Early recognition of TLS and identification of patients at high risk are essential to prevent complications. Prophylactic measures should be ideally initiated 48  h prior to tumor-­ specific therapy. The first approach for the prevention of TLS involves vigorous intravenous volume expansion, which ­promotes urinary excretion of uric acid and phosphate [3]. In addition, administration of sodium bicarbonate in order to alkalinize the urine above a pH of 7 to prevent uric acid nephropathy has been historically recommended [4], but is controversial. Alkalinization may prevent hyperuricemia; however, it can exacerbate hyperphosphatemia that may result in calcium phosphate precipitation in renal tubules. Prophylactic drug therapy includes allopurinol (300–800 mg daily) that blocks the activity of xanthine oxidase in the liver, preventing the conversion of hypoxanthine and xanthine to uric acid which decreases the risk of uric acid crystallization in the kidneys [5]. Alternative prophylactic drug therapy includes rasburicase, a recombinant urate-oxidase enzyme, which converts uric acid to a compound more urine soluble, allantoin [6]. Rasburicase is contraindicated in patients with B6PDH deficiency, metahemoglobinemia, patients at risk for hemolytic anemia, and pregnant or lactating females. Clinical TLS is an emergency with the potential to result in the death of a patient. Aggressive hydration and diuresis, plus allopurinal or rasburicase for hyperuricemia, is recommended for the treatment of established TLS [7]. No research evaluating a direct comparison between rasburicase and allopurinol has been performed in adult patients with TLS. In pediatric patients with TLS and hyperuricemia, rasburicase has shown better results [8].

Tumor Fever Normal human body temperature displays a circadian rhythm, which is lower in the early morning, at 36.1°C or less and rises to 37.4°C or higher in the afternoon. Elevation of a patient’s body temperature results from either hyperthermia

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or pyrexia (fever). Hyperthermia represents a failure of the thermal regulatory control system that normally balances heat loss with heat production. In pyrexia, thermoregulation mechanisms are intact, but the hypothalamic set-point for body temperature is increased by either exogenous or endogenous pyrogens. A person’s response to fever varies with age. Older patients, secondary to inadequate thermoregulatory mechanisms may develop hyperthermia, which makes them susceptible to complications of arrhythmias, heart failure, or changes in mental status, while children may develop febrile convulsions. In patients with cancer, the major causes of fever include infections, drugs, transfusion of blood products, graft-versushost disease, or secondary to the tumor itself (also known as paraneoplastic fever) [9]. Paraneoplastic fever has previously been considered to be a more frequent complication of patients with primary malignancies such as renal cell carcinomas or lymphomas; however, data suggest that it may occur in cancers from various primary sites [10]. Currently, the exact etiology of tumor fever is unknown but potential causes include hypersensitivity reactions, pyrogen or cytokine production, or secondary to tumor necrosis. In cancer patients, other etiologies of fever that must be excluded include infections, drug withdrawal (i.e., opioids or benzodiazepines), bowel or bladder obstruction, neuroleptic malignant syndrome, or tumor embolization. Other comorbidities associated with fever include venous thrombosis, connective tissue disorders, and bleeding in the central nervous system [9]. Establishing a diagnosis underlying the febrile response is critical since it may impact management of symptoms and response to therapy. Obtaining a thorough history, medication review, and completion of a whole body examination is impor­tant when assessing a patient with fever. Blood, urine, and sputum cultures as well as radiographic imaging may be indicated to complete the initial evaluation. In debilitated cancer patients, a fever may lead to increased metabolic demands and dehydration. Symptoms commonly associated with a fever include fatigue, myalgias, diaphoresis, and chills. Interventions for the management of fever include treatment of the underlying cause, hydration with parenteral fluids or hypodermoclysis, and nonspecific palliative measures to alleviate symptoms. Antibiotics are effective in the palliation of symptoms associated with fever secondary to infection. Site-specific symptoms such as cough secondary to pneumonia or localized pain due to an underlying abscess may be ameliorated by appropriate antibiotic therapy. Neutropenic (granulocyte count <500) fever requires prompt initiation of broad-spectrum antibiotic therapy. For patients with neutropenia, a single temperature elevation above 38.5°C or three measurements above 38°C in 24  h would be defined as fever [9]. Without rapid treatment within 48  h, the mortality rate is as high as 70% of patients with neutropenic fever. Recommendations [11] for the treatment

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of neutropenic fever are rapidly changing and clinicians are advised to obtain appropriate consultation. The ideal management of paraneoplastic fever is treatment of the underlying neoplasm. If antineoplastic therapy is not available or ineffective, nonsteroidal antiinflammatory drugs (NSAIDs) are the drugs of choice for the palliation of symptoms. Naproxen has been favored by some clinicians to treat tumor fever. A structurally different NSAID may be substituted to treat paraneoplastic fever if initial treatment loses its effectiveness. Aspirin and acetaminophen may also be used to control tumor fever. Aspirin should be used with caution in cancer patients with thrombocytopenia and patients with Hodgkin lymphoma; also, aspirin is not recommended in pediatric patients because of the risk of Reye syndrome. Nonspecific palliative treatments for fever include increasing fluid intake, removing excess clothing or linens, and bathing/ sponging with tepid water [12].

Sweats and Hot Flashes Sweating by promoting transdermal heat loss is an integral mechanism to managing core body temperature. Fever secondary to underlying disease and other nondisease states including warm environmental temperature, menopause, or exercise can also result in sweating. Hot flashes and sweats are a common symptom in cancer survivors as well as cancer patients with advanced disease. Research suggests that moderate-to-severe sweating occurs in roughly 14–16% of advanced cancer patients receiving palliative care [13]. The underlying physiological mechanism of sweating is complex and treatment options include hormonal agents, nonhormonal drug treatments, and various integrative therapies [14]. Hot flashes characterized by the vasomotor instability of menopause are complicated by sweating and occur in twothirds of postmenopausal women with a history of breast cancer and three-quarters of men with locally advanced or metastatic prostate cancer treated with medical or surgical orchiectomy. Tumor, cancer treatment, or comorbidities can result in sweating in cancer patients. Hodgkin lymphoma, pheochromocytoma, and neuroendocrine tumors including carinoid cancers are often associated with sweating. Medical comorbidities including fever, menopause, male castration, drugs, and abnormalities of the hypothalamus can also contribute. Drugs associated with sweats include tamoxifen, aromatase inhibitors, opioid therapy, tricyclic antidepressants, steroids, hormonal therapies, as well as a number of cytotoxic agents. Treatment of the underlying cause of sweats and hot flashes is appropriate when effective therapy is available. Antineoplastic therapy, if effective, can control sweating in patients with tumor recurrence or progression of disease.

13  Endocrine and Metabolic Symptoms of Cancer and Its Treatment

If curative treatment is not available, a number of palliative interventions may be attempted to improve quality of life. If not contraindicated, estrogen replacement may control hot flashes in postmenopausal women. However, evidence suggesting an increased risk of breast cancer associated with the use of hormonal replacement therapy has arisen. A large, randomized, placebo-controlled trial evaluating estrogen plus progestin in healthy postmenopausal women was stopped prematurely secondary to detection of a 1.26-fold increased risk for breast cancer in women receiving hormonal replacement [15]. No clear increased risk was evident with unopposed estrogen therapy [16]. Other interventions including megestrol acetate (i.e., 20  mg twice daily), selective serotonin reuptake inhibitors (SSRIs), and intramuscular depot medroxyprogesterone ­acetate have undergone testing and are promising treatment options for hot flashes in women with a history of breast cancer. Other pharmacologic interventions for the treatment of hot flashes that have not been well studied include androgens, gabapentin, selective serotonin norepinephrine inhibitors, alpha adrenergic agonists (e.g., methyldopa, clonidine), beta-blockers, and veralipride. Nonpharmacological interventions that improve the management of hot flashes include the use of loose-fitting clothing, fans to circulate cool air, stress management techniques (i.e., relaxation and slow, deep breathing exercises), and self-hypnosis, using cooling suggestions. All been shown to be effective for controlling hot flashes in approximately 50% of cases in pilot studies. More research is needed. Herbs and dietary supplements including soy phytoestrogen, vitamin E, and black cohosh are often used to control sweating and hot flashes. Vitamin E (400 IU twice daily) has modest benefit compared to placebo. In well-designed randomized, controlled trials, both soy phytoestrogen supplements and black cohosh have been shown to be no better than placebo. Other alternative therapies used to control hot flashes but not well studied include flaxseed, dong quai, milk thistle, red clover, licorice, and chaste tree berry, which need further research to determine efficacy. Table 13.1  Types of hypercalcemia associated with cancer Type Frequency (%) Bone metastasis Local osteolytic hypercalcemia Humoral hypercalcemia of malignancy

20

Common, extensive

80

Minimal or absent

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As with women, men with prostate cancer undergoing androgen deprivation therapy may have complications of sweats and hot flashes that can diminish their overall quality of life. Treatment is similar to women and includes treating the underlying cause and if ineffective, palliation with the following: estrogens, progesterone, SSRIs, gabapentin (300 mg three times daily), cyproterone acetate, and antiandrogens.

Hypercalcemia Approximately 20–30% of patients with cancer have complications of hypercalcemia at some time during the course of their illness. Hypercalcemia is responsible for a significant number of hospitalizations and results in distressing symptoms in patients with cancer. Hypercalcemia is an indicator of poor prognosis with the exception of patients with breast cancer or multiple myeloma. In a study in 1990, 50% of cancer patients with hypercalcemia died within 30 days [17]. Treatment with bisphosphonates may be decreasing the incidence and improving the outcome for cancer patients. Hypercalemia results in nonspecific clinical symptoms – “bones, stones, abdominal groans, and psychic moans”. Symptoms include anorexia, nausea, abdominal pain, muscle weakness, fatigue, and boney tenderness. Severe complications of hypercalcemia include dehydration, nephrolithiasis, acute pancreatitis, acute renal failure, and altered mental status including coma. The calcium level itself correlates poorly with symptoms, while the rapidity with which calcium rises is closely associated with the development of symptoms. Hypercalcemia associated with cancer can be classified into four types based on the underlying pathophysiology (Table 13.1) [18]. Elevated calcium (Table 13.2) is a frequent electrolyte abnormality in patients with lung, breast, and head and neck tumors as well as leukemia and multiple myeloma. Bone metastasis is not a prerequisite for the deve­ lopment of hypercalcemia.

Causal agent

Typical tumors

Cytokines, chemokines, PTHrP PTHrP

Breast cancer, multiple myeloma, lymphoma Squamous cell cancer (e.g., of head and neck, esophagus, cervix, or lung), renal cancer, ovarian cancer, endometrial cancer, HTLV-associated lymphoma, breast cancer Lymphoma (all types)

1,25(OH)2D-secreting <1 Variable 1,25(OH)2D lymphomas Ectopic hyperparathyroidism <1 Variable PTH Variable PTH, parathyroid hormone; PTHrP, PTH-related protein; 1,25(OH)2D, 1,25-dihydroxyvitamin D; HTLV, human T-cell lymphotrophic virus Source: From Stewart [18] Copyright © 2005 Massachusetts Medical Society. All rights reserved

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Table 13.2  Severity of hypercalcemia Serum calcium Hypercalcemia level (mg/dL)

Serum calcium level (mmol/L)

Mild Moderate Severe

(2.6–2.9) (3.0–3.4) (³3.5)

(10.5–11.9) (12.0–13.9) (³14.0)

Total calcium ranges from 9 to 10.5  mg/dL (2.2– 2.6 mmol/L) can be found in the either a free ionized state or bound to other molecules including albumin. Mathematical formulae to correct total calcium concentrations are often used to correct for hypoalbuminemia but have been found to be unreliable [19]. Serum ionized calcium concentrations should be measured in cancer patients and are more accurate. Corrected calcium formula (mg/dL ) = ((4.0 − albumin ( g/dL )) × 0.8) + serum total calcium (mg/dL ) In the overall management of cancer patients with hypercalcemia, clinicians need to consider the clinical condition of the patient as well as their goals of care and quality of life. Hydration with intravenous saline is essential to reverse the decreased glomerular filtration rate and impaired renal calcium excretion. Furosemide can also promote calcium excretion by inhibiting the Na/K/Cl transporter in the loop of Henle; however, diuretics are not recommended in cancer patients who are volume depleted. Basic supportive-care measures include: removal of calcium in vitamin supplements and from parenteral feeding solutions, and discontinuation of medications that may lead to hypercalcemia (e.g., calcitriol, vitamin D, lithium, and thiazides). Bisphosphonates, including pamidronate and zoledronate, are first-line medical therapy and work by blocking osteoclastic bone resorption. Bisphosphonates should be given intravenously since they are poorly absorbed when given orally. Common adverse effects include fever, nausea, vomiting, opthamolgic complications (i.e., anterior uveitis, scleritis, and conjunctivitis), renal toxicity in 6–10% of patients, [20], and osteonecrosis of the jaw – up to 10% of patients with breast cancer or multiple myeloma [21]. Second-line medications include glucocorticoids (useful in lymphoma patients with elevated 1,25(OH)2 vitamin D) and calcitonin, which results in rapid but transient reduction in calcium levels. Also, close monitoring of electrolytes is warranted with replacement of phosphorous orally if serum phosphorous is less than 3 mg/dL (0.96 mmol/L). Intravenous phosphorous replacement should be avoided unless phosphorous is critically low <1.5  mg/dL (0.48 mmol/L) since it can cause seizures, hypocalcemia, renal failure, and arrhythmias. Certain hypercalcemic patients with malignancies that are refractory to standard therapy or have contraindications may be considered for dialysis.

Hypernatremia Hypernatremia results from impaired water intake resulting in a deficit of water relative to sodium. Diminished intake of water results from dysfunction of the thirst center or osmoreceptors and may occur in tumor infiltration of the lateral hypothalamus, craniopharyngiomas, primary or metastatic breast and lung cancers. Central or nephrogenic diabetes insipidus may also lead to hypernatremia. Tumor invasion of  the hypothalamic pituitary axis or the osmocenter may impair antidiuretic hormone (ADH) secretion resulting in central diabetes insipidus. A lack of response to ADH in the kidneys results in nephrogenous diabetes insipidus, such as  may occur with ifosfamide, resulting in hypernatremia [22]. Amphotericin-induced nephrotoxicity, tumor-related obstructive uropathy, and light chain kidney disease in patients with multiple myeloma may contribute to the development of hypernatremia in cancer patients.

Siadh and Hyponatremia Hyponatremia is a common electrolyte abnormality that can occur in patients with cancer by various mechanisms. Hyponatremia can result from volume depletion secondary to hemorrhage, diarrhea, intractable vomiting, drainage of ascites or pleural effusion, or a salt wasting nephropathy. In addition, increase in total body salt and water content can result in hyponatremia, which is clinically manifested as peripheral edema or ascites. In this setting, other common clinical scenarios resulting in hyponatremia include druginduced congestive heart failure, liver disease, severe hypoalbuminemia, nephritic syndrome, and veno-occlusive disease. Also, hyponatremia is associated with chemotherapeutic agents, particularly cisplatin and carboplatin [23], cyclophosphamide, vincristine, and vinblastine [24]. The SIADH secretion is also a common cause of hyponatremia in cancer patients and has been reported to complicate various types of malignancies including lung cancer, primary and metastatic malignancies of the brain, hematological malignancies, skin tumors, gastrointestinal cancer, gyn­ ecological cancer, breast and prostate cancer. Cancer patients with complications of SIADH clinically appear euvolemic and do not have significant edema. Essential features of SIADH include decreased effective osmolality (<275 mOsm/ kg of water), urinary osmolality >100 mOsm/kg of water, and urinary sodium >40 mmol/L [25]. Supplemental features of SIADH include plasma uric acid <4 mg/dL, blood urea nitrogen <10 mg/dL, and fractional sodium excretion >1% [25]. Ectopic secretion of arginine vasopressin (AVP) by tumor cells results in hyponatremia secondary to the retention of

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13  Endocrine and Metabolic Symptoms of Cancer and Its Treatment

free water despite relative serum hypotonicity [26]. Inappropriate release of AVP by tumor cells does not respond to serum tonicity resulting in the absorption of free water at the collecting-duct level resulting in worsening hypotonicity and concentrated urine [27]. Hyponatremia has been associated with chemotherapy including both cisplatin and carboplatin [23]. Chemother­ apeutic agents are believed to cause damage to the renal tubules, resulting in an inability to retain sodium and increased urinary sodium loss, renal salt wasting syndrome (RSWS) [28]. Clinically, patients with RSWS appear hyponatremic with euvolemia, and an elevated spot urine sodium level ­suggests RSWS. The treatment of RSWS, rather than water restriction, is sodium supplementation. Clinical manifestations of hyponatremia are related to how quickly sodium has declined rather than the actual measured sodium. Hyponatremia may be asymptomatic or be life-threatening. Most symptomatic patients will have a serum sodium less than 120 mEq/L but symptoms may also occur when sodium is <129  mEq/L [27]. In acute hyponatremia, the clinical presentation is secondary to cerebral edema and includes nausea, vomiting, headaches, seizures, coma, respiratory arrest, and death secondary to herniation if hyponatremia is not treated. In hyponatremia developed slowly, symptoms may be less severe or more subtle. Rapidly correcting chronic hyponatremia in patients with minimal symptoms may result in the disastrous complication of osmotic demyelination syndrome (ODS), so clinicians must carefully assess the risks and benefits of therapy prior to aggressive treatment. Symptomatic patients with altered mental status, seizures, respiratory depression, or coma require emergent correction of hyponatremia with 3% saline infusion. A number of approaches and formulas have been developed to determine free water excess, sodium deficit; however, these formulas may be too complicated and not entirely reliable. One simple approach to correcting hyponatremia is to infuse 1 cm3/kg body weight of 3% NS per hour, which will lead to a rise of 1 mEq/L serum sodium per hour [26]. Treatment should be stopped when the following endpoints have been reached: resolution of symptoms, serum sodium level is 120  mEq/L or above, or an increase of 8 mEq/L per day has been reached [26]. During treatment, hourly monitoring is critical to prevent overcorrection. Relowering of serum sodium with an infusion of D5W has been recommended for the treatment of overcorrection to reduce the risk of ODS [29]. The clinical manifestations of ODS as a consequence of overcorrection of hyponatremia include quadriparesis or quadriplegia, pseudobulbar palsy, and altered mental status. In severe cases, locked-in syndrome, coma, and death may occur after correction of hyponatremia [30]. Risk of ODS is related to the chronicity of hyponatremia as well as the severity. Most cases of ODS occur in patients with chronically

severe hyponatremia, <120 mEq/L; however, in the setting of malnourished patients, ODS has occurred with higher serum sodium levels which may be relevant to patients with cancer cachexia [31]. Rates of correction as low as 8 mEq/L/24 h have been associated with ODS and most guidelines recommend limiting the correction of sodium to 8 mEq/L/24 h to minimize the risk of developing ODS [26]. Novel therapy for hyponatremia includes the AVPreceptor antagonists, conivaptan, lixivaptan, and tolvaptan, which are being currently studied. Conivaptan blocks both V1a and V2 receptors and has been approved in the USA for the treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. Studies examining AVP-receptor antagonists reveal that they stimulate free water excretion and improve plasma sodium concentration in patients with hyponatremia secondary to SIADH [32].

Hypomagnesemia Hypomagnesemia is a frequent complication in hospitalized patients and may be more prevalent in patients with cancer. In addition to gastrointestinal or urinary magnesium losses, malnutrition and decreased dietary magnesium intake may facilitate the development of hypomagnesemia. Magnesium plays a pivotal role as a cofactor for about 300 cellular enzymes, participates in cellular energy metabolism, and is critical to the stabilization of membrane structures, mRNA translation and transcription, and DNA replication. In addition, hypomagnesemia may increase or protect against the development of cancer. Magnesium supplementation for patients with hypomagnesemia, such as chronic alcoholic patients, may reduce the incidence of some malignancies [33]. Approximately 60% of magnesium in the body is stored in the bone, 38% in soft tissues, and <2% is in the extracellular fluid compartment. Serum levels typically ranges from 1.8 to 2.5 mEq/L, unfortunately they do not reflect the total body stores of magnesium. Serum magnesium below 1.2 mg/ dL may cause nonspecific symptoms including neurologic and cardiovascular abnormalities, which may often be overlooked. Neurologic symptoms include muscle weakness, tremors, hyperreflexia, dizziness, apathy, seizures, or coma. Chovstek’s or Trousseau’s signs may be noted on physical examination. Patients with hypomagnesemia are at risk for arrhythmias including atrial fibrillation, multifocal atrial tachycardia, supraventricular tachycardia, or ventricular tachycardia, and ventricular fibrillation. Causes of hypomagnesemia can be categorized as gastrointestinal or renal loss, extracellular to intracellular fluid shifts, or transdermal losses. Gastrointestinal losses could be due to diarrhea, dietary deficiency, familial magnesium

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­ alabsorption, gastrointestinal fistulas, inflammatory bowel m disease, laxative abuse, surgical resection, or excessive vomiting. Renal causes of low magnesium include alcoholism, diabetes, diuretics, hypoparathyroidism, hyperthyroidism, hyperadlosteronism, SIADH, excessive vitamin D, ketoacidosis, hypercalcemia/hypophosphatemia, and other tubular defects. Fluid shifts that result in hypomagnesemia include acidosis, frequent blood transfusions, hungry bone syndrome, refeeding syndrome, and in cases of acute pancreatitis. Transdermal losses include excessive sweating or massive burns. In cancer patients, drugs that can lead to hypomagnesemia include cisplatin, interleukin-2, cyclosporine, enzataurin, tacrolimus, pegylated liposomal doxorubicin, carboplatin, gallium nitrate, deoxyspergualin, and drugs targeting the epidermal growth factor receptor (EGFR) including cetuximab and panitumumab [34]. Other drugs often used in cancer patients that may precipitate hypomagnesemia include aminoglycoside antibiotics, amphotericin B, pentamidine, gentamicin, and diuretics [35]. Magnesium can be replaced either orally as magnesium oxide or as a gluconate or parenterally as magnesium sulfate. If hypomagnesemia is mild (level >1.2  mEq/L) and the patient is asymptomatic, oral replacement is feasible. Symp­ tomatic hypomagnesemia should be treated with intravenous magnesium supplementation; standard dosage is 2–4  g of 50% magnesium sulfate diluted in saline or dextrose over 1 h. Administration faster than 1 h may result in bradycardia, heart block, or hypotension. Hypomagnesemia may worsen despite ongoing replacement in which case stopping chemotherapy for a few weeks may be helpful [34]. Levels of magnesium typically return to normal 6 weeks after termination of chemotherapy.

Cushing’s Syndrome Patients with Cushing’s syndrome develop elevated serum cortisol levels secondary to either a corticotropin (ACTH) producing pituitary tumor, excessive cortisol secretion by either an adrenal adenoma or carcinoma, or by ectopic secretion of ACTH by a nonpituitary tumor. Chronic exposure to excess glucocorticoids in Cushing’s syndrome results in a large spectrum of symptoms, none of which are pathognomonic, including progressive central obesity involving the face, neck, trunk, and abdomen with sparing of the extremities; glucose intolerance with symptoms of polydipsia and polyuria; proximal muscle weakness; hypertension; psychological disturbances; hyperpigmentation (increased ACTH only), easy bruisability, skin atrophy, and striae; bone pain or osteoporosis; and oligomenorrhea or amenorrhea. The presence of androgen excess in women

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with adrenal cancer or ACTH-stimulated hyperandrogenism can cause virilisation, hirsutism, increased libido, and acne. Since symptoms are nondiagnostic, Cushing’s syndrome must be confirmed by laboratory work-up. Initially, a history excluding exogenous glucocorticoid intake must be sought, including a careful review of medications (all glucocorticoids, megestrol acetate, inhaled or topical steroids). PseudoCushing’s syndrome with elevations in cortisol levels can occur in patients with bacterial infections, severe obesity, psychological distress, or rarely chronic alcoholism. Initial laboratory work-up as suggested by the 2008 Endocrine Society Guideline [36] consists of at least two first-line tests – two measurements of urine free cortisol, two measurements of late-night salivary cortisol, 1-mg overnight dexamethasone suppression test, or the longer low dose (2 mg/day over 48 h) dexamethasone suppression test. For patients with normal results, follow-up testing in 6 months is recommended; however, if patients have normal results but exhibit clinical symptoms highly suggestive of Cushing’s syndrome or one abnormal test, an evaluation by an endocrinologist is advised [36]. After the confirmation of hypercortisolism, the next step is to measure serum ACTH levels to differentiate between ACTH-dependent (pituitary or nonpituitary ACTH-secreting tumors) and ACTH-independent (adrenal source). Patients with ACTH-independent Cushing’s syndrome are identified by a low-plasma ACTH concentration [<5  pg/ml (1.1 pmol/L)] and subsequently will need a thin-section CT to evaluate for an adrenal mass. Adrenal carcinomas are typically larger than adenomas and distinguished by evidence of necrosis, hemorrhage, and calcification on the CT scan [37]. MRI may provide additional information and ACTH-independent patients with bilateral adrenal micro­ nodular or macronodular hyperplasia on imaging may require further work-up. The majority of patients with ACTH-dependent hypercortisolism have pituitary corticotroph adenoma (Cushing’s ­disease). Intermediate ACTH concentrations between 5 and 20  pg/ml require corticotrophin-releasing hormone (CRH) testing. Patients with Cushing’s disease respond by secreting ACTH and cortisol within 45 min after CRH administration. The remainder of ACTH-dependent patients (ACTH levels >20 pg/ml) should have a high-dose dexamethasone suppression test and a CRH stimulation test to distinguish between Cushing’s disease and ectopic ACTH-secreting tumors. If testing is consistent with Cushing’s disease, a pituitary MRI should be obtained. If a lesion >6 mm is detected, no further testing is warranted; however, if the imaging on MRI is unclear (<6 mm), petrosal sinus sampling is recommended [38]. Transsphenoidal microadenectomy is the treatment of choice for patients with Cushing’s disease. For a patient not cured by transsphenoidal resection of the pituitary tumor or in whom fertility is a prominent concern, pituitary irradiation is the next treatment option. Adrenalectomy followed

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13  Endocrine and Metabolic Symptoms of Cancer and Its Treatment

by lifelong glucocorticoid and mineralocorticoid supplementation or cytotoxic chemotherapy for locally invasive pituitary tumors or other carcinomas, which have metastasized to the central nervous system, are alternative treatment options. Surgical excision is the optimal treatment for ectopic ACTH syndrome. With tumors that are nonresectable, treatment to control symptoms of hypercortisolism with adrenal enzyme inhibitors including ketoconazole, metyrapone, and etomidate is appropriate. Mitotane can also be used as medical adrenalectomy in patients with indolent tumors. For patients with primary adrenal disease, treatment is directed at removal of the adrenal gland(s). In patients with inoperable, residual, or recurrent disease, mitotane may provide palliation [39].

for infection or organ dysfunction should be initiated. Surreptitious use of insulin or other hypoglycemic agents should be considered in patients without a history of diabetes. In patients with cancer, the diagnosis of tumor-associated hypoglycemia may be difficult, and evaluation of insulin, C-peptide, and insulin-like growth factor I and II levels may be useful [40]. An initial treatment includes the administration of glucose via standard regimens in order to normalize mental status and improve consciousness. After a patient has been stabilized, treatment is directed at the underlying malignancy, either curative or palliative. For insulinomas and tumors associated with NICTH, surgical excision may be curative. Palliative treatment in concert with an endocrinologist may provide symptomatic relief and depending on the tumor, include treatment with prednisone with or without somatostatin analogs [40].

Hypoglycemia of Malignancy Hypoglycemia associated with malignancy is relatively rare. The three main etiologies include: the most common cause is nonislet cell tumor hypoglycemia (NICTH) [40], the most well known is hypoglycemia due to insulin secretion by islet cell pancreatic tumors [41], and any advanced metastatic carcinoma that has infiltrated the liver or adrenal glands resulting in hypoglycemia [42]. The initial evaluation for hypoglycemia involves careful evaluation for other possible causes of hypoglycemia. After a thorough work-up excluding other causes, curative or palliative treatment of hypoglycemia of malignancy can be initiated. Insulinomas, well-known but relatively rare tumors, almost exclusively occur in the pancreas. Approximately 90% of insulinomas are benign, and the production of insulin by beta-cell tumors leads to hypoglycemia. Surgical treatment is often curative [43]. Hypoglycemia associated with NICTH involves a variety of tumors including mesenchymal, epithelial, and hematopoietic in origin, the most common being fibrosarcoma, mesotheliomas, leiomyosarcomas, hepatomas, lung cancers, gastric malignancies, and pancreatic exocrine tumors [43]. The secretion of insulinlike growth factor II, which is capable of activating insulin receptors, results in hypoglycemia in NICTH [44]. Metastatic cancer infiltrating the liver or adrenal glands may result in hypoglycemia secondary to tissue destruction or another yet undefined mechanism. Clinical findings in cancer patients with hypoglycemia include altered consciousness, obtundation, or bizarre behavior and are not different from hypoglycemia secondary to nonmalignant causes. Since hypoglycemia secondary to malignancy is quite rare, a thorough evaluation for other causes should be initiated. In diabetic patients, medications and oral intake should be reviewed. An evaluation

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124 15. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principle results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288(3):321–333. 16. Li CI, Malone KE, Poster PL, et  al. Relationship between long duration and different regimens of hormone therapy and risk of breast cancer. JAMA 2003;289(24):3254–3263. 17. Ralston SH, Gallager SJ, Patel U, et al. Cancer associated hypercalcemia: morbidity and mortality: clinical experience in 126 treated patients. Ann Intern Med 1990;112:499–504. 18. Stewart A. Hypercalcemia associated with cancer. NEJM 2005; 352(4):373–379. 19. Ladenson JH, Lewis JW, McDonald JM, et al. Relationship of free and total calcium in hypercalcemic conditions. J Clin Endocrinol Metab 1978;48:393–397. 20. Layman R, Olson K, Van Poznak C. Bisphosphonates for breast cancer. Hematol Oncol Clin North Am 2007;21(2):341–367. 21. Woo SB, Hellstein JW, Kalmar JR. Systematic review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144(10): 753–761. 22. Klastersky J. Side effects of ifosfamide. Oncology 2003;65 (Suppl 2):7–10. 23. Cao L, Prashant J, Sumoza D. Renal salt wasting in a patient with cisplatin-induced hyponatremia. Am J Clin Oncol 2002;25:344–346. 24. Hammond IW, Ferguson JA, Kwong K, Muniz E, Delisle F. Hyponatremia and syndrome of inappropriate anti-diuretic hormone reported with the use of Vincristine: an over representation of Asians? Pharmacoepidemiol Drug Saf 2002;11(3):229–234. 25. Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med 2007;356(20):2064–2072. 26. Verbalis JG, Goldsmith SR, Greenberg A, et al. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med 2007;120:S1–S21. 27. Yeong-Hau LH, Shapiro JI. Hyponatremia: clinical diagnosis and management. Am J Med 2007;120:653–658. 28. Vassal G, Rubie C, Kalifa C, et al. Hyponatremia and renal sodium wasting in patients receiving cisplatinum. Pediatr Hematol Oncol 1987;4:337–344. 29. Soupart A, Decaux G. Therapeutic recommendations for management of severe hyponatremia: current concepts on pathogenesis and prevention of neurologic complications. Clin Nephrol 1996;46:149–169.

R. Dev 30. Rabinstein AA, Wijdicks EF. Hyponatremia in critically ill neurological patients. Neurologist 2003;9(6):290–300. 31. Laureno R. Central pontine myelinolysis following rapid correction of hyponatremia. Ann Neurol 1983;13:232–242. 32. Palm C, Reimann D, Gross P. The role of V2 vasopressin antagonists in hyponatremia. Cardiovasc Res 2001;51:403–408. 33. Wolf FL, Maier JA, Nasulewics A, et al. Magnesium and neoplasia : from carcinogenesis to tumor growth and progression or treatment. Arch Biochem Biophys 2007;458:24–32. 34. Saif MW. Management of hypomagnesemia in cancer patients receiving chemotherapy. J Support Oncol 2008;6:243–248. 35. Mouw DR, Latessa RA, Hickner J. Clinical inquiries. What are the causes of hypomagnesemia? J Fam Pract 2005;54:174–176. 36. Nieman LK, Biller BM, Findling JW, et  al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93:1526–1540. 37. Blake MA, Kalra MK, Seeney AT, et al. Distinguishing benign from malignant adrenal masses: multi-detector row CT protocol with 10-minute delay. Radiology 2006;238:578–585. 38. Oldfield EH, Chrousos GP, Schulte HM, et al. Preoperative lateralization of ACTH-secreting pituitary microadenomas by bilateral and simultaneous inferior petrosal venous sinus sampling. N Engl J Med 1085;312:100–103. 39. Luton JP, Cerdas S, Billaud L, et al. Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 1990;322:1195–1201. 40. Nayar MK, Lombard MG, Furlong NJ, et al. Diagnosis and management of nonislet cell tumor hypoglycaemia. Endocrinologist 2006; 16(4):227–230. 41. Service FJ, Hypoglycemic disorders. N Engl J Med 1995;91: 505–510. 42. de Groot JW, Rikhof B, van Doorn J, et al. Non-islet cell tumour induced hypoglycaemia: a review of the literature including two new cases. Endocr Relat Cancer 2007;14:979–993. 43. Le Roith D. Tumor-induced hypoglycemia. N Engl J Med 1999;341: 757–758. 44. Daughaday WH, Trivedi B. Measurement of derivatives of proinsulin-like growth factor-II in serum by radioimmunoassay directed against the E-domain in normal subjects and patients with nonislet cell tumor hypoglycemia. J Clin Endocrinol Metab 1992;75: 110–115.

Part VI

Reproductive

Chapter 14

Sexual Problems in Patients with Cancer Andreas Meißner, Charalampos Mamoulakis, Grada J. Veldink, and Jean J. M. C. H. de la Rosette

Introduction Advances in the diagnostic and treatment modalities applied in the field of oncology during the last decades have led to the prolongation of overall and cancer-specific survival in patients with many different types of tumors [1]. Consequently, quality of life (QoL) preservation has emerged as an important additional issue in oncologic patients. There is no doubt that sexuality is considered a factor of capital importance, closely related to QoL, which can only be fully and satisfactorily developed and maintained if the body and soul of a human being are in harmony. Consequently, it is crucial to consider both the somatic and the psychosocial oncologic effects [2]. Both medically and socially speaking, the diagnosis “­cancer” catapults the affected person abruptly from a previously healthy to a severely ill human being and leads to profound consequences in all aspects, including the relationship with a partner and sexual life. Sexuality may be affected by both the disease and the necessitated treatment. Concretely, the degree of harm is defined by the type of cancer and the treatment implemented. Nevertheless, another important factor is the individual’s psychological resources defined by his/ her ability to develop specific coping mechanisms, which in turn is highly associated to the type and degree of the environmental support, level of education, and the situation before the disease.

Common Mechanisms Leading to Sexual Problems in Cancer Patients Sexual problems in cancer patients can be caused by the anatomical or functional organ impairment due to the presence of the tumor or may result from the treatment applied (surgical

A. Meißner (*) Academic Medical Center, Department of Urology, University of Amsterdam, Amsterdam, 1105 AZ, The Netherlands e-mail: [email protected]

procedure, chemotherapy, irradiation), which may be very aggressive, harming not only the tumor cells but also healthy adjacent or remote tissues and body structures such as nerves and blood vessels. Furthermore, the problems can also be psychological in nature through different body feeling, changing in neurotransmitters and central nervous system deregulation. In addition, psychosocial problems may arise with numerous consequences for the patient and the partner. This specific type of problem has received a central scientific interest since the late 1980s. There is much variety in reactions ranging from tension within the couple and misunderstanding to strengthening of their relationship to fight as a union against the illness. Therefore, the partner should always be observed and included in all discussions and decisions on patients’ treatments concerning sexuality. To get one step further, it could be claimed that sexuality impairment in terms of cancer should always be considered as a problem of the couple rather than a unique problem of the patient [3]. A definition of sexuality is generally hard to give. Simply speaking, human sexuality is a kind of attitude (experience and expression) driven by the common intuitive tendency for reproduction, which is highly individualized through control by superior psychocognitive centers developed variably among people on the basis of their different built-in characteristics and experiences. For practical reasons, the integrated function of sexuality may be schematically subdivided into the following series of consecutive-interrelated events following the human sexual response cycle [4]: • Sexual desire • Arousal with erection in males and lubrication in females • Orgasm with ejaculation in males and culmination in females • Resolution Sexual problems in oncologic patients may stem from the impairment of each one of these events in separate or in any combination and some examples are given below. Fertility impairment is beyond our scope and will be discussed elsewhere in this book. Sexual desire or arousal may be compromised via different mechanisms such as general somatic pain and fatigue due to

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_14, © Multinational Association for Supportive Care in Cancer Society 2011

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cancer itself or therapy, deregulation of the hypothalamic– pituitary–gonadal axis via hormonal manipulations (e.g., in metastasized prostate or breast cancer) including surgical castration (e.g., in metastasized prostate cancer, bilateral ­testicular, and ovarian cancer), and pain during or after intercourse (dyspareunia) following vaginal reconstruction after radical uterus extirpation (e.g., in cervical or muscle-invasive bladder cancer). Postoperative pain may eliminate sexual feelings, while sensitivity may be lost after surgery, irradiation, or chemotherapy, compromising nerves. Furthermore, symptomatic treatment, for example, against vomiting, depression [5], epileptic seizures, or pain, can have an additional direct or indirect effect on sexual function. For example, pain medication such as morphine can lower testosterone production significantly [6] and sleep medication can disturb nocturnal erections. Erectile dysfunction (ED) may also be caused by hormonal manipulations (e.g., in metastasized prostate cancer) or by operations or irradiation in the small pelvis potentially damaging penis innervation and blood supply (e.g., radical prostatectomy, external beam irradiation for localized prostate cancer). Disorders of ejaculation may also appear (anejaculation after radical prostatectomy or retrograde ejaculation after retroperitoneal lymph node dissection). On the other hand, female patients are often unable to achieve orgasm, experience dyspareunia due to insufficient lubrication after irradiation or vaginismus (painful contraction of the pelvic floor muscles and vagina). Apart from the somatic mechanisms briefly mentioned above, psychological mechanisms are also crucial. The patient experiences difficulties accepting and coping with a potentially life-threatening problem. This psychological burden has also consequences on the patient’s social role, which often gets limited since the patient is or feels unable to run a normal life overwhelmed by the so-called experiential problems (rapid mood changes, anxiety for the future, etc.), even with financial consequences in the extreme cases. Under this psychological pressure, sexuality may be set aside. This fact is often complicated further by the changed body image [7]. Breast amputation, orchiectomy, and abdominal radical operations for rectal-, bowel-, or muscle-invasive bladder cancer, with stoma formation can lead, for example, to a completely different body shape (Fig.  14.1), while chemotherapy can diminish hair growth. Changed body image in turn results in self-confidence deprivation and lowering of self-esteem driven by thoughts of the loss of sexual attractiveness. On the other hand, the partner’s sympathy may result in goodintended avoidance of seeking physical contact, which may be, though, often misinterpreted by the patient as rejection or neglect, erroneously attributed to the loss of attractiveness. In conclusion, sexuality impairment in terms of cancer has an underlying multidimensional and multifactorial

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Fig. 14.1  Changed body shape due to exenteration

pathophysiology. It stems from a combination of distinct but interrelated problems (physical, psychological, relational, social, existential [8], and experiential), secondary to the disease, that may ruin the relationship of the couple. Therefore, cancer should be considered an abrupt psychological trauma rather than a purely somatic, life-threatening disease. The psychotraumatic consequences are revealed repeatedly and unexpectedly in time, provoked by numerous situations or events, which the patient tries desperately to avoid and finally lead to a true posttraumatic stress disorder. This also holds true for the partner [9, 10]. Therefore, it is crucial to overcome the barriers of avoidance and provide support to the affected couple by starting talking about the potential sexual problems that may accompany the underlying disease.

In Which Cancers Should Hidden Sexual Problems be Suspected? In general, sexual problems are most likely present in cases where the external or internal genitals are involved (prostate, testicular, penile, breast, uterine, ovarian, and cervical cancer) because sexual function is directly compromised [11, 12]. Sexuality may either be harmed immediately or eventually and insidiously over time during the disease course such as, for example, ED after irradiation of the small pelvis or indirectly due to psychological imbalance. It has been shown that QoL is still relatively good during the period of chemotherapy, but worsens after 3 and 6 months compared to baseline, mainly in the sexual and physical domains [13]. Nevertheless, there may be an extensive variability among different patients regarding the degree of physical/ psychological impairment and the consequent sexual

14  Sexual Problems in Patients with Cancer

d­ ysfunction, so that no clear correlation can be detected. On the other hand, sexual dysfunction cannot be predicted well by somatic or treatment aspects and therefore the psychological component should be taken into account [14] as well as the degree of sexual functioning prior to the diagnosis and treatment initiation. It is of utmost importance not only to prescribe medication or apply sex therapy but also to unmask the main problem of the couple, familiarize them with it, and give solutions, which most of the time are individualized and multimodal.

Trying to Unmask Sexual Problems: Talking about Sex The first and most important step is to start talking about sex (feelings, changes due to cancer, and emerging problems). Ideally, it should be done very early during the disease course by the responsible physician or surgeon if an operation likely to compromise sexual organs has been planned [15]. Specialized nurses play an important role too [16] because they are often in a more intensive and regular contact with the patients during postoperative, chemotherapy, and irradiation periods. At our institution, for example, specialized “stoma nurses” are involved acting as andrological consultants as well (Table 14.1). The form of the interview should be free and open with enough space for questions and emotional expression. Positive feelings may develop if the couple realizes that the disease prognosis might not be that ominous and QoL is still important. Joint partners’ efforts against the disease may strengthen their relationship. Therefore, encouraging revealing the sexual problems and seeking help can further motivate patients toward life, which in turn influences positively their sexuality and vice versa. On the other hand, even terminal ill patients still have both the right and the wish for QoL and therefore sexual contacts. As people realize that their life approaches the end, they often experience a stronger need for more intensive relationships especially with their partners getting positive feelings out of it. The differentiation between intimacy and sex is important to be stressed and clarified during the talk because the meaning of these terms is often confused and misunderstood. The patients’ partners often suffer more by lack of intimacy than absence of sex. Therefore, it is important to legitimate intimacy not followed necessarily by sex. However, the limitations should be understood and accepted by both partners. This precludes conflicts and potential resulting distance in the future. All these issues should be addressed but not necessarily during the initial interview. It is important to unmask the

129 Table 14.1  Possible functions of an (andrological) consultant An initial interview to draw conclusions by clarifying: • The problem and how it is experienced • The related emotions • The major concerns that may be confounded by less important issues • The level of communication between patient and partner • The level of knowledge on proper sexual function A more intensive talk after drawing conclusions in order to: • Ensure presence of couple’s motivation to follow treatment • Try to find an individual solution Collection of an adapted anamnesis consisting of: • A medical part on the – General health state – Surgery of the small pelvis – Use of medication • Since when and in which qualities of their sexual function the patient and his partner are – Satisfied with – Dissatisfied with • How big is the problem growing from this? • What are the personal sexual wishes of patient and partner and to let them talk about frankly? • What could be a desirable and acceptable solution for them? • How far are they ready to go for a solution? • What kind of therapy has been done up to now? Treatment initiation: • Support the patient and his partner with audio-visual information about use of intracavernous autoinjection therapy and penis vacuum pump in order to achieve sufficient erection and see if this is a possible option for them • Determine the dosage and teach how to inject intracavernously • Educate the handling with the pump • Instruct small exercises as house work to activate perfusion of the penis • Initiate a conversation between the partners at home how they personally see their sexual live together and how they can/want to proceed and work on it Teamwork: • Close cooperation with andrologist and sexologist in a multidisciplinary network with interdisciplinary case discussions on a regular base in order to accompany the patient from different angles at the same time

couples’ fears and try to motivate them toward QoL in order to facilitate treatment success. Unfortunately, however, this target cannot be reached in every case.

Limitations in Treatment Application For therapeutic success, it is crucial to take into account the patient’s actual activity potential as well as the priority that sexual desire has been assigned by the couple especially prior to the onset of the disease. The malignant disease and

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treatment may lead to such a somatic impairment that daily activities can be very much limited and therefore sexual activity is also physically impossible. The psychological distress may also be so intense that it definitely prevents patients from even thinking of being sexually active. The situation is even worse in cases where sexual life has been already impaired for unrelated reasons before the disease onset or in cases that sex has been assigned a low priority in the couple’s list of activities. Nevertheless, in the ideal case, sexual surrender can be increased.

Giving Professional Help and Treatment In an ideal setting, the couple has access to an interdisciplinary network consisting of a specialized gynecologist for the female patient and of an andrologist backed up by an andrological consultant for the male patient, together with a sexologist, psychologist or psychiatrist, and a specialized physiotherapist, working closely with the oncologic surgeons, medical oncologists, radio-oncologists, and general practitioners. Under this setting, multimodality therapy is guaranteed. When cancer patients are transferred for sexual problems, it is mostly due to physical rather than psychological complaints, which are easier described by the patient and conceived by the doctor. It depends on the examiner’s skills to find out the degree to which the psychological component has to be handled. Sexual problems may already preexist long before the diagnosis of cancer [17]. Such problems should be detected for the treatment to have chances to be successful. Preinterventional ED is unlikely to improve afterward, but it is important to start as early as possible with supportive treatment in order to preserve the existing erection status. Open talk is strongly recommended. However, in the beginning at least, it may be very hard for the patient to speak freely about sexual feelings and prior expectation fulfillment. Especially in the case of a newly diagnosed cancer and treatment initiation, variable feelings may appear such as shame or fear, diminishing sexual interactions, and desire and longing for aid or comfort by the partner. Therefore, it is important to support the couple, showing that the problems are seriously taken into account and try to convince them that their situation and reactions could be expected under such extreme circumstances. Due to the cause-effect variability and the interindividual variation of complaints, the solution sought should be most of the times individualized based on the various sexological, psychological, and medical approaches available in the current treatment armamentarium.

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Practical (Technical) Solutions Somatic problems should be at least initially treated with conventional somatic medicine. If the patient’s problem turns out to consist of more levels, the treatment should be adapted accordingly. The issue becomes complicated if the somatic problem is irreversible such as abrupt loss of menstruation due to cancer therapy, or permanent such as in stoma patients, aggravated by fecal or urinary incontinence. In such cases, coping strategies have to be developed so that the situation is accepted by the patient, which is often very hard to achieve.

Males In cases of the symptomatic lack of testosterone, which is not intended as a hormonal ablation in prostate cancer treatment, hormonal substitution of testosterone could be used to improve desire, erections, and well-being. According to the actual ISA, ISSAM, EAU, EAA, and ASA recommendations [18], this is a safe and valid treatment. There are three phosphodiesterase type 5 inhibitors (PDE5i) on the market for the treatment of ED, namely sildenafil, tadalafil, and vardenafil. Since they only work as amplifiers, their action requires a degree of remaining nerve function and uncompromised blood supply to the penis, after radical prostatectomy, for example. In the case of postoperative ED, which is difficult to measure [19], it is important to instruct the patient how to use the medications and start treatment early. If postoperative treatment initiation is delayed, there is a risk of penile cavernous bodies’ fibrotic degeneration. Before switching from one member of the group to another or to other options, the medications should be taken long enough to rule out failure or that side effects do not fade out with time. Administering a daily dosage prevents pressure for sexual action on a certain time slot. However, prophylactic penile rehabilitation has recently been shown not to be as efficient as originally believed based on basic research [20, 21]. If PDE5i are not considered a therapeutic option due to failure, side effects, or contraindications, intracavernous autoinjection therapy is another but invasive option. To achieve erection, the patient has to inject a certain amount of alprostadil (prostaglandin E1) leading to relaxation of the smooth muscle cells or a combination of papaverin and phentolamin (alpha-blocker) shortly before intercourse, which makes it necessary to include the injection procedure in the sexual foreplay. Potential side effects include pain at the site of injection and priapism (unintended, painful erection for more than 4 h in duration), which represents a urologic emer-

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gency due to possible irreversible cavernosal damage, and Peyronie disease, i.e., plaque formation in the corpora cavernosa leading to an abnormal curvature of the penis. A more patient-friendly solution with fewer side effects is the socalled medicated urethral system for erection (MUSE). Using a specially constructed applicator, the patient introduces an alprostadil-containing pellet into the distal part of his urethra. This option is, however, less effective and causes a burning sensation of the penis and urethra; therefore it has almost been abandoned. As a third-line therapy, vacuum pump devices are available. An erection is achieved through negative pressure applied to the penis, which is maintained by means of an elastic band at the penile base for a maximum of 30  min. Daily use of the device is possible. The success rate can be up to 70–94%. If it works, the technique represents a good and noninvasive option, given that the patient together with his partner accepts such an artificial way of producing erections. Potential side effects include pain during the application and cold penis. The implantation of a penile prosthesis (semirigid or inflatable) can be satisfying for both the patient and his partner. However, it is considered as an end option because it is invasive and irreversible, and the use of new, coated prostheses has dropped the incidence of infection dramatically.

Females For stoma-carrying and breast cancer patients, special lingerie has been developed. Relaxing exercises of the pelvic floor can be initiated in cases of dyspareunia and a vaginal lubricant can be used in case of a dry vagina, which can make sex easier and more satisfying for both partners. Therapy of the underlying anxiety can also be of help.

Conclusion Preservation of sexual function in cancer patients represents an important issue, which can be a driving force to fight against the disease. Sexuality may, however, be compromised. It is very important that the sexual problems of the patient are detected also with the aid of the partner. For the therapy, the different levels of imbalance have to be taken into account and treated by an interdisciplinary specialized group ideally consisting of an andrologist in case of a male or a gynecologist in case of a female patient, a sexologist, a psychologist or psychiatrist, and specialized physiotherapist in pelvic floor exercises.

References 1. Capocaccia R, Gavin A, Hakulinen T, Lutz JM, Sant M. Survival of cancer patients in Europe, 1995–2002: The EUROCARE 4 study. Eur J Cancer. 2009 Apr;45(6):901–1094. Epub 2009 Jan 24. 2. Zebrack BJ, Foley S, Wittmann D, Leonard M. Sexual functioning in young adult survivors of childhood cancer. Psychooncology. 2010 Aug;19(8):814–22. 3. Gilbert E, Ussher JM, Hawkins Y. Accounts of disruptions to sexuality following cancer: the perspective of informal carers who are partners of a person with cancer. Health (London). 2009 Sep;13(5): 523–41. 4. Masters WH, Johnson VE. Human Sexual Response. Bantam, 1981 ISBN 978-0553204292; 1st ed. Boston: Little, Brown, 1966. (Lippincott Williams & Wilkins Publishers. ISBN 0316549878). 5. Schweitzer I, Maguire K, Ng C. Sexual side-effects of contemporary antidepressants: review. Antidepressants Aust N Z J Psychiatry. 2009 Sep;43(9):795–808. 6. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, Kaur G, Bruera E. Hypogonadism and sexual dysfunction in male cancer survivors receiving chronic opioid therapy. J Pain Symptom Manage. 2003 Nov;26(5):1055–61. 7. Gurevich M, Bishop S, Bower J et al. (Dis)embodying gender and sexuality in testicular cancer. Soc Sci Med. 2004 May;58(9): 1597–607. 8. Lee V. The existential plight of cancer: meaning making as a concrete approach to the intangible search for meaning. Support Care Cancer. 2008 Jul;16(7):779–85. Epub 2008 Jan 16. 9. Kangas M, Henry JL, Bryant RA. Predictors of posttraumatic stress disorder following cancer. Health Psychol. 2005 Nov;24(6): 579–85. 10. Rourke MT, Hobbie WL, Schwartz L, Kazak AE. Posttraumatic stress disorder (PTSD) in young adult survivors of childhood of cancer. Pediatr Blood Cancer. 2007 Aug;49(2):177–82. 11. Eeltink C, Batchelor D, Gamel C. Kanker en seksualiteit; veranderingen en gevolgen van de behandeling. Handboek voor verpleegkundigen. Amsterdam: Internetuitgeverij van Haaster, 2006. 12. National Cancer Institute (2009). Sexuality and Reproductive Issues (PDQ®) Health Professional Version http://www.cancer.gov/cancer topics/pdq/supportivecare/sexuality/HealthProfessional/allpages/ print. 13. Saevarsdottir T, Fridriksdottir N, Gunnarsdottir S. Quality of life and symptoms of anxiety and depression of patients receiving cancer chemotherapy: longitudinal study. Cancer Nurs. 2010 Jan-Feb;33(1): E1–10. 14. Den Oudsten BL, Van Heck GL, Van der Steeg AF, Roukema JA, De Vries J. Clinical factors are not the best predictors of quality of sexual life and sexual functioning in women with early stage breast cancer. Psychooncology. 2010 Jun;19(6):646–56. 15. Kaufmann S, Al-Najar A, Boy S, Hamann MF, Naumann CM, Fritzer E, Jünemann KP, van der Horst C. Erectile dysfunction after radical prostatectomy: patient information, contact persons, postoperative proerectile therapy. Urologe A. 2010 Apr;49(4): 525–9. 16. Southard NZ, Keller J. The importance of assessing sexuality: a patient perspective. Clin J Oncol Nurs. 2009 Apr;13(2):213–7. 17. Pinkawa M, Fischedick K, Gagel B, Piroth MD, Asadpour B, Klotz J, Borchers H, Jakse G, Eble MJ. Impact of age and comorbidities on health-related quality of life for patients with prostate cancer: evaluation before a curative treatment. BMC Cancer. 2009 Aug 24;9:296. 18. Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morales A, Morley JE, Schulman C, Thompson IM, Weidner W, Wu FC. Investigation, treatment, and monitoring of late-onset hypogonadism

132 in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. Eur Urol. 2009 Jan;55(1):121–30. Epub 2008 Aug 30. 19. Mulhall JP. Defining and reporting erectile function outcomes after radical prostatectomy: challenges and misconceptions. J Urol. 2009 Feb;181(2):462–71. Epub 2008 Dec 13. 20. Shindel AW. 2009 update on phosphodiesterase type 5 inhibitor therapy part 1: recent studies on routine dosing for penile ­rehabilitation,

A. Meißner et al. lower urinary tract symptoms, and other indications. J Sex Med. 2009 Jul;6:1794–808. 21. Hatzimouratidis K, Moysidis K, Bekos A, Giakoumelos A, Hatzichristou D. What is adequate management to preserve erectile function after unilateral nerve-sparing radical pro­ statectomy? J Endourol. 2008 Sep;22(9):2029–31; discussion 2033.

Chapter 15

Sterility, Infertility, and Teratogenicity Hele Everaus

Introduction The recent advances and success of cancer therapy, particularly for childhood cancer and patients who had cancer during their reproductive age, significantly increased the demand for selecting the most fertility-friendly approaches for cancer treatment. Cancer itself and different modalities of cancer treatment, including chemotherapy and radiotherapy (RT), are known to have significant deleterious effects on human fertility, both in men and women. As long as cancer treatments cannot be exclusively targeted to tumor cells, damage to the reproductive system will remain an important aspect of cancer morbidity. Male and female germ cells vary in their sensitivity to the mutagenic effects of chemotherapy and RT, depending on their stage of maturation and the agent used. No increase in genetic defects or congenital malformations was detected among children conceived to parents who have previously undergone chemotherapy and RT. In female cancer patients, miscarriage and congenital malformations are not increased following chemotherapy. With improved survival rates among young patients with cancer, recent bench-to-bedside translation of new techniques to preserve fertility, increased awareness of choices for the preservation of fertility, and options for family planning are now being offered to patients who have received a cancer diagnosis. Concerns about fertility are similar for men and women. Their opportunities for intervention differ considerably. Four main challenges are related to the preservation of fertility in people with cancer: the improvement of patient-specific, life-preserving treatments; the identification and reduction of the harm that cancer treatment poses to fertility; the expansion of safe and effective options for fertility treatment; and the creation of symptom management plans for patients who lose endocrine function from the gonads as

H. Everaus (*) Department of Hematology-Oncology, Tartu University Hospital, Tartu 51014, Estonia e-mail: [email protected]

a consequence of cancer treatment [1]. The goal is to provide and develop methods of fertility preservation.

Direct Effect of Cancer on Human Reproduction Cancer, in particular, genital cancer, has impact on human reproduction through a direct effect on the gonads as well as through effects on endocrine glands. The direct effect is clear when the malignant tumor involves the genital system – ovaries and uterus in the female and testicles in the male. Different mechanisms can participate in the induction of adverse effects by cancer itself on human fertility. Cancer evokes a systemic response of the body. This response can be mediated by cytokines. Stress associated with a cancer diagnosis can impair fertility through disturbances at the hormonal levels [2]. Systemic effects, such as fever, have also been ­implicated adversely affecting semen parameters. An immunological mechanism can be involved as there have been found to be  disturbances in the balance between subpopulations of  T-lymphocytes, which can be the cause of dyspermia in  Hodgkin disease patients [3]. There is evidence of a shared etiology for the malignant process and reduced fertility in testicular cancer as part of the testicular dygenesis syndrome [4].

The Effect of Cancer Treatment on Female Fertility Chemotherapy Chemotherapeutic drugs are interrupting the vital cell ­processes and arresting the normal cellular proliferation cycle. The chemotherapy-related risks are connected to the patient’s age, the specific chemotherapeutic agents used, and

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the cumulative dosage administered [5]. Women over 38 years of age have a higher incidence of complete ovarian failure and permanent infertility in comparison with younger women [6]. The ovaries of younger women can tolerate greater doses. Patients with early-stage breast cancer who do not receive chemotherapy and whose baseline fertility is within the normal range have a relatively small treatment-related threat to fertility. Patients with breast cancer who have tumors larger than 1 cm, cancer that is metastatic to lymph nodes, or hormone-receptor-negative disease often undergo chemotherapy [7]. These patients face a greater threat to fertility [8]. Chemo­therapeutic agents used for the treatment of breast cancer include cyclophosphamide, fluorouracil, doxorubicin, paclitaxel, and docetaxel. Alkylating agents (AA), including cyclophosphamide, are toxic to the ovaries [9]. AA have a severe effect on human fertility. Ovarian fibrosis and follicular and oocyte depletion occur [10]. According to Meirow [11], AA are associated with the greatest risk among all chemotherapeutic agents for inducing ovarian failure. The following agents have been shown to be gonadotoxic: busulfan, melphalan, cyclophosphamide, and procarbazine. Cisplatin and analogs cause ovarian failure and chromosomal damage. Vinca alkaloids induce aneuploidy. Damaged oocytes could produce malformed fetuses. Antimetabolites – insufficient data are available on the effects of antimetabolites on female germ cells. Anthracycline antibiotics – adriamycin and bleomycin are female-specific mutagens. Etoposide induces pericentric lesions and aneuploidy in oocytes [12]. The addition of adjuvant endocrine therapy in patients older than 40 years was more likely to result in permanent chemotherapy-related amenorrhea [13].

Premature Ovarian Failure The risk of premature ovarian failure (POF) must be considered in female patients with malignant lymphoma receiving three or more cycles of chemotherapy including AA. Regarding the teratogenic effects of chemotherapy, studies that have monitored pregnancies in women exposed to chemo­ therapy before conception have not registered increased rates of miscarriage or congenital abnormalities in comparison with the general population.

High-Dose Chemotherapy in Bone Marrow Transplantation Bone marrow transplantation has come into widespread use  in last 30 years in the treatment of oncohematological

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­ alignancies. The conditioning regimens used for BMT m include high-dose chemotherapy, with or without whole body irradiation. It has been reported that there is an extremely high risk of persistent ovarian failure in women who undergo BMT [14]. Growth and sexual development are impaired in children, and sterility is common in adults [15].

Radiotherapy From several malignant conditions that affect young women, including melanoma, cervical cancer, leukemia, lymphoma, and ovarian cancer, breast cancer is of the highest incidence [16]. Standard regimens of radiation therapy for breast cancer are not associated with significant ovarian toxicity. Internal scatter radiation can reach the pelvis and ovaries. In vitro fertilization and egg harvesting should not be performed during radiation treatment, and pregnancy should be prevented [17]. Gonadal damage depends on the cumulative dose, the irradiation field, and the patient’s age. Older women are at greater risk of damage [15]. Women who are older than 40 years of age when undergoing treatment have a smaller pool of remaining oocytes and require only 5–6 Gy to produce permanent ovarian failure. Exposure of the ovaries to high radiation doses, as is the case for treatment of cervical and rectal cancer, and with craniospinal RT for central nervous system malignancies can cause mutagenic, embryotoxic, embryolethal, and teratogenic effects [18]. The same effects can happen when pelvic lymph nodes are irradiated for lymphomas and with total body irradiation (TBI) before bone marrow transplantation. In these cases, it is recommended that, when possible, the gonads should be shielded, the radiation field restricted, or when possible the ovaries should be surgically relocated away from the radiation field (oophoropexy) [18]. The radiation dosage necessary for loss of ovarian function has been examined in many studies. Chiarelli [19] has demonstrated the percentage of women who suffered from infertility correlated with increasing ­dosages of abdominal pelvic irradiation: Treatment doses of 20–35 Gy caused a 22% rate of infertility, and doses >35 Gy caused a 32% rate of infertility. Survivors who received hypothalamic/pituitary radiation doses of 30  Gy or higher or ovarian/uterine radiation doses higher than 5  Gy and those who were treated with lomustine or cyclophosphamide were less likely to have ever been pregnant [20]. Radiation effects on the uterus and subsequent pregnancy outcomes are also known [21]. Irradiation of the uterus is associated with infertility, spontaneous pregnancy loss, and intrauterine growth retardation [22]. Irradiation can cause irreversible changes in the uterine musculature, blood flow, and ­hormonal-resistant endometrium insufficiency [23].

15  Sterility, Infertility, and Teratogenicity

Physiological sex steroid replacement therapy may improve uterine characteristics in some patients after irradiation at a young age. Patients who have undergone RT have increased rates of obstetric complications compared to the general population: spontaneous abortions (38% vs 12%), preterm labor (62% vs 6%), and low-birth-weight infants (62% vs 6%) [24]. There is advice of delaying pregnancy for a year after the completion of RT.

Measures to Protect Fertility At diagnosis, plans for fertility preservation must take into consideration the individual patient’s priorities in conjunction with the recommended treatment strategy. Several options are available for women with cancer who wish to preserve their germ line. Patients may elect to delay cancer treatment in order to undergo one cycle of hormone stimulation, followed by cryopreservation of either a mature oocyte or an embryo [25]. Cryopreservation of mature oocytes is considered ­experimental [26]. Around 100 children have been born worldwide from this option [27]. Oocyte cryopreservation should only be performed in centers with the necessary expertise [28].

Cryopreservation of Mature Oocytes (After Gonadotropin Stimulation) Oocyte banking is more problematic than cryopreservation of sperms or embryos [21]. The first obstacle is the sensitivity of oocytes to chilling. Cooling and exposure to cryoprotecting agents (CPAs) may aggravate the high incidence of aneuploidy in human oocytes. Exposure to CPAs causes hardening of the zone pellucida, so all oocyte cryopreservation protocols involve intracytoplasmic sperm injection (ICSI) as a precaution. Fertilization has to be carried out about 3–5 h after thawing while the oocyte remains fertile. The disadvantage of the method is that cancer patients may not have more than one opportunity for oocyte harvesting before undergoing potentially sterilizing treatment. The success of the method is depending on the total number of eggs harvested (less than ten oocytes give very low chances of pregnancy). To date, more than 4,300 oocytes have been cryopreserved and more than 80 children have been born. The overall live birth rate per cryopreserved oocyte is about 2%, which is much lower than that with IVF using fresh oocytes. Pregnancy rates were one-third to one-fourth of the success rates seen with unfrozen oocytes [29].

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Cryopreservation of Immature Oocytes After In Vitro Maturation (Without Gonadotropin Stimulation) Oocytes are recovered for in vitro maturation (IVM) from fresh tissue or follicular aspirates before the dominant follicle emerges during the mid-follicular phase of the menstrual cycle. Cryopreservation difficulties include the different optimal times of equilibration for the oocyte and its smaller cumulus cells. Oocytes can be recovered from unstimulated ovaries as well as from children, and if harvesting is less expensive and risky, it can be repeated frequently. The procedure still needs further advances in cryotechnology.

Gonadotropin-Releasing Hormone Analog Treatment Multiple small studies have evaluated the utility of gonadotropin-releasing hormone analog (GnRH-a) treatment for the preservation of ovarian function during cytotoxic therapy. Rendering the ovarian follicular development quiescent by suppression of gonadotropins has been proposed to protect women from damage by cytotoxic therapy. One controversy is whether the ovary can be protected during the cancer treatment by using GnRH-a to create a temporary menopause [30]. Blumenfeld et al. in small studies have demonstrated that GnRH agonists are well tolerated and might protect long-term ovarian function [31]. He has reported beneficial effects of GnRH therapy on ovarian function in 55 lymphoma patients receiving chemotherapy. Meirow et al. [32] were not able to demonstrate a protective effect of GnRH after ablative chemotherapy and RT in patients undergoing bone marrow transplantation. Randomized controlled trials are currently underway internationally to evaluate the efficacy of treatment with GnRH-a. There is a possibility that GnRH agonist therapy concomitant with cytotoxic chemotherapy might reduce the efficacy of chemotherapy for breast cancer [33]. The American Society of Clinical Oncology points out that there is insufficient evidence regarding the safety and effectiveness of GnRH-a and other means of ovarian suppression on female fertility preservation [28]. Fertility preservation in patients with hormone receptorpositive breast cancer receiving systemic chemotherapy requires careful consideration. The association between ­pregnancy after breast cancer and an increased risk of recurrence has not been demonstrated [34]. As estrogen-receptor-­ positive breast cancer is hormonally driven, ovarian stimulation and the exposure to estrogens and progestins may be contraindicated.

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GnRH-a have been tested in women of reproductive age; however, the ovarian-protective effect of these agents has not been proved in studies in humans [35]. Recent data suggest that estrogens may have an indirect mitogenic effect on hormone receptor-negative cancers [36]. Hormone stimulation may have unfavorable effects in both patients with hormone receptor-positive disease and hormone receptor-negative ­disease. There is therefore the need for fertility preservation techniques that do not require hormonal exposure.

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To screen ovarian tissue for the presence of metastatic disease before transplantation, different techniques have been used: preoperative imaging, histologic analysis with immunohistochemical staining, polymerase chain reaction (PCR) amplification, and real-time PCR [41]. In vitro follicle maturation can be the safer option. Immature follicles are recovered from cryopreserved tissue and grown in vitro. The oocyte is matured in vitro and used for in vitro fertilization. So far this technique has been successful in animal models. Experiments involving human tissue are in progress [42].

Sex Steroids Small observational studies suggest that oral contraceptives may help preserve ovarian function when given during chemo­ therapy [6]. However, the results are controversial. One possible explanation for the varying results might be that the oral contraceptives do not suppress the gonads completely.

Ovarian Tissue Cryopreservation In some centers, the harvesting of ovarian tissue has been started for autotransplantation [30]. Ovarian tissue cryopreservation is an investigational method of fertility preservation. Ovarian tissue is removed laparoscopically and frozen. At a later date, the ovarian tissue is thawed and reimplanted. Ovarian tissue cryopreservation has been performed in humans for less than a decade. The first ovarian transplant procedure was reported in 2000 [37]. Ovarian tissue can be transplanted orthotopically to the pelvis or heterotopically to subcutaneous areas such as the forearm or lower abdomen [38]. Studies have reported restoration of ovarian endocrine function after both types of transplantation [39]. Ovarian tissue can be obtained without additional hormonal stimulation. Oocytes may be aspirated from the ovary, matured in vitro, and then cryopreserved for later use [36]. Individual follicles or strips of ovarian cortical tissue can be cryopreserved for future use in either in  vitro follicle ­maturation or tissue transplantation. There are five reports of live births in women with cancer who underwent autologous transplantation of cryopreserved ovarian tissue [40]. Transplantation of ovarian tissue is associated with a risk of reintroducing cancer cells from the transplanted tissue. This is why it is considered as a last option for the preservation of fertility in patients with cancer. Patients with leukemia are at increased risk for this adverse event [39]. Ovarian tissue screening to detect malignant cells should be performed to minimize the risk of tumor transfer with the ovary.

Embryo Cryopreservation Is the Most Effective Approach The human embryo is very resistant to damage caused by cryopreservation. The postthaw survival rate of embryos is in the range of 35–90%, while implantation rates are between 8% and 30%. However, this approach requires in vitro fertilization and a participating male partner. This option is not acceptable to prepubertal or adolescent girls [43]. Oocytes are fertilized in  vitro and cryopreserved after fertilization. A small percentage of cancer survivors have yet returned to utilize their embryos [44]. Women with very early-stage or low-grade gynecological cancer may be able to preserve fertility by having limited surgery, for example, conservation of the uterus and contralateral ovary for women with ovarian cancer or radical trachelectomy (preservation of the uterus despite removal of most of the cervix) for cervical cancer. It has been estimated that nearly 50% of women diagnosed with cervical carcinoma under the age of 40 are eligible for radical trachelectomy, a procedure in which the cervix is resected but the uterus is spared [45]. Ovarian transposition (oophoropexy – surgically moving ovaries as far as possible from the radiation field) can be offered when pelvic radiation is used for cancer treatment. The procedure can be done laparoscopically if laparotomy is not needed for the primary treatment of the tumor [46]. Lateral transposition of the ovaries to remove them from the field of pelvic irradiation is an option that preserves ovarian function in about half of the women treated for cervical cancer or Hodgkin disease [47]. Natural cycle in  vitro fertilization, in which follicles are aspirated without exposure to exogenous hormone stimulation, is also an emerging option. Still the success rate associated with this technique is low [48]. For women becoming infertile because of cancer treatment, an option would be the use of donor oocytes to have a child either through a pregnancy or gestational surrogacy when a patient who has had cancer would like to become pregnant by means of any ­fertility

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preservation option, and a clinical investigation should be ­performed to be sure that the patient is disease free. Attempts to preserve or restore fertility in women receiving chemotherapy for cancer have been less successful than analogous effects in men. For patients with partners, cryopreservation of in vitro fertilized mature egg is effective and is available at most cancer centers. Suppression of ovarian function by luteinizing hormone-releasing hormone (LHRH) agonists or contraceptives seems to be a promising way of preventing Premature Ovarian Failure and infertility, but no large randomized trial has been reported. Treatment-induced involuntary infertility is a major concern in cured cancer patients. At present, there is no epidemiological proof that there is an increased percentage of malformations in children born after their parents have had cancer treatment. Chemotherapy during the first trimester of a pregnancy would indicate the necessity of termination; but in most cases, where it does not increase the risk of malformation [18], it may result in preterm deliveries and slightly increases the risk of prenatal complications. Fertility options for women are unfortunately still problematic. Women who do not require urgent treatment may undergo a cycle of in  vitro fertilization before cancer treatment and cryopreservation of embryos, but the chance of a pregnancy with future use is still limited [27]. Women with breast cancer can utilize new protocols that may limit exposure of cancer cells to high estrogen levels by adding [44] aromatase inhibitors or tamoxifen to the ovarian stimulating drugs. Fertility preservation options in females depend on the patient’s age, type of treatment, diagnosis, whether she has a partner, the time available, and the potential that the cancer has metastasized to her ovaries. The possibility that fertility preservation interventions and/or subsequent pregnancy may increase the risk of cancer recurrence has been most concerning in breast cancer and the gynecologic malignancies. In recent studies, it has been demonstrated that there are no conclusive data at present that suggest only deleterious effects, such as an increased risk for relapse, due to subsequent pregnancy in women with a history of breast cancer. Regarding the miscarriage rate, studies that have monitored pregnancies in women exposed to chemotherapy before conception were unable to detect any increased rates of miscarriage or congenital abnormalities in comparison with the general population. The optimal timing of a subsequent pregnancy after cancer is unclear and depends on the patient’s prognosis, age, and personal situation. Meirow and Schiff [49] postulated that patients who recover from ovarian failure after high-dose chemotherapy or RT treatments should not delay childbearing for too many years. These patients should try to conceive after a disease-free interval of a few years, but not less than 6–12 months after the treatment, due

to the possible toxic effects of the therapy on growing oocytes. The delay of 2–3 years after the cancer therapy is recommended, so that the period associated with the greatest risk of recurrence has passed before a pregnancy. In patients with hormone-positive breast cancer, tamoxifen and GnRH-a do not cause permanent amenorrhea, but this treatment can last up to 5 years, during which time a pregnancy is contraindicated [50].

The Effect of Cancer Treatment on Male Fertility Several factors can negatively affect male fertility – disruptions of the hypothalamic–pituitary–gonadal axis, damage to the germinal epithelium, and depression related to the diagnosis of cancer [51]. Recent studies have demonstrated that the integrity of sperm DNA is altered before the initiation of treatment in patients with Hodgkin lymphoma or testicular cancer [52, 53]. Testicular cancer is associated with abnormalities of spermatogenesis [2]. Testicular cancer particularly compromises fertility as growth factors produced by the cancer may alter the spermatogenesis. Often, it is necessary to remove the affected testis which may decrease the production of sperm. Prostate cancer surgery can induce erectile dysfunction. Radiation therapy is toxic to developing sperm, even at low doses. High-dose ­pelvic irradiation used for the therapy for prostate, rectal, and testi­ cular cancers may permanently damage testicular function and contribute to erectile dysfunction [54]. Damage to sperm DNA for up to 2 years after completion of therapy has been reported in patients undergoing radiation therapy and chemotherapy for testicular cancer and systemic therapy for Hodgkin lymphoma [53]. It is important to counsel patients concerning contraceptive use and cryopreservation of sperm before the initiation of therapy [55]. Infertility is a major concern for young men of reproductive age undergoing chemotherapy, RT, or surgery. Malignancy is also associated with an increased catabolic state, malnutrition, an increase in stress hormones, and a decrease in pituitary gonadotropin levels, which can also have an impact on fertility [56].

Effects of Oncological Surgery Bladder neck or prostate resection, bilateral retroperitoneal lymphadenectomy, or extensive pelvic surgery might cause anejaculation as a result of retrograde flow of semen in to the urinary bladder.

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Modified nerve-sparing surgical procedures have reduced this adverse outcome. Improved surgical techniques in the treatment of bladder and prostate cancer avoid damaging the nerve fibers. Seventy to eighty percent of men with radical prostatectomy or radical cytoprostatectomy maintain sexual function [57].

Chemotherapy Most cytotoxic forms of chemotherapy are not tumor specific and target rapidly dividing cell types. Spermatogenesis is extremely vulnerable to the damaging effects of systemic therapies. Olgiospermia or azoospermia develops often. As cytotoxic treatment targets tissues with a high growth fraction, the spermatogenesis can be impaired after treatment for cancer. Following cancer chemotherapy, most men develop low levels of sperm (oligospermia) or no sperm (azoospermia). In addition, the cells in the testes that produce testosterone, called Leydig cells, may also be affected by chemotherapy, resulting in low or lack of testosterone production. These conditions may persist for long periods of time and may be permanent. The effect of chemotherapy on the testes depends on the type of drugs and dose and schedule of treatment. Some chemotherapy drugs are more likely to cause sterility, while there tends to be a much lesser long-term toxicity with the newer forms of chemotherapy. The classes of chemotherapy drugs that are more likely to cause sterility are as follows.

Alkylating Agents The AA (nitrogen mustard, cyclophosphamide, chlorambusil, busulfan, procarbazine) are major causes of late-testicular toxicity. AA cause depletion of the germinal epithelium in the testes and aplasia of germinal cells, resulting in severe oligospermia or azoospermia within 90–120 days of treatment [58] with poor long-term recovery [2]. Long-term infertility due to treatment with AA may be expected in more than 50% of the patients at a cumulative dose of cyclophosphamide > 6 g/m2, and procarbazine > 4 g/m2. AA are mutagenic in all stages of maturation of male human germ cells, however, do not cause transmissible chromosomal translocations or aneuploidy in stem cells [59]. The majority of men receiving procarbazine-containing regimens for the treatment of lymphomas are rendered permanently infertile [60]. Platinum compounds – platinum compounds (cisplatin, carboplatin, and oxaliplatin) are major causes of damage to the

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testis. Long-term infertility due to therapy may be expected in more than 50% of the patients who receive a cumulative dose of cisplatin > 0.6 g/m2. Vinca alkaloids – arrest ­sper­mato­genesis. Antimetabolites – 5-fluorouracil, 6-­mercaptopurine cause ­chromosomal aberrations. Topoisomerase interactive agents are cytotoxic to all spermatogonial stages. Combination ­chemotherapy, the MOPP regimen, used for Hodgkin disease, can cause azoospermia in 90% of men up to 4 years after ­therapy and an increased frequency of aneuploidy for up to years after treatment. Current treatment of HD in children includes chemotherapy with ABVD, which appears to be less gonadotoxic.

Radiation Effects Radiation therapy that is used to treat several malignant conditions is toxic to developing sperm even at low doses [61]. Therapy for prostate, rectal, and testicular cancers can require high-dose pelvic irradiation, which may permanently damage testicular function and also contribute to erectile dysfunction [61]. Ionizing radiation has adverse effects on gonadal function in men of all ages. The severity of the damage is depending on the dose, the treatment field, and the fractionation schedule [62]. Doses of more than 4 Gy can cause permanent damage of spermatogenesis [63]. The lowest sperm counts are demonstrated 4–6 months after treatment is completed. Return to pretreatment levels occurs in 10–24 months [64]. TBI as a conditioning regimen for stem cell transplantation causes permanent gonadal failure in approximately 80% of men [65]. Recovery of spermatogenesis takes place from surviving stem cells (type A spermatogonia) and is dependent on the dose of radiation. Complete recovery takes place within 9–18 months following radiation with 1 Gy or less, 30 months for 2–3 Gy, and 5 years or more for doses of 4 Gy and above [60]. Testicular radiation with doses higher than 20 Gy is associated with Leydig cell dysfunction in prepubertal boys, while Leydig cell function is usually preserved with doses of as much as 30 Gy in sexually mature males [66]. Exposing the testes to ionizing radiation at a dose lower than 6  Gy causes disturbances of spermatogenesis and altered spermatocytes with recovery periods dependent on dose; doses higher than 6 Gy cause permanent infertility by killing off all stem cells [67]. For patients with testicular germ cell cancer, using modern radiation techniques (radiation doses to the para aortic field <30 Gy) and testis shielding providing testis scatter radiation (<30 Gy), radiation-induced impairment of fertility is very unlikely [68]. Sperm counts are typically lowest at 4–6 months posttreatment; return to pretreatment levels usually occurs in 10–24 months, with longer periods required for recovery after higher doses [69].

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It has to be taken into account that men who regain spermatogenesis after cancer treatment have low sperm counts and motility and an increased rate of chromosomal abnormalities [70]. These effects are dose dependent and persist for up to 3 years after RT. Contraception for a period of 1–3 years is recommended after testicular irradiation.

testicular biopsy, serum hormone analysis, and semen analysis. When male infertility is the result of abnormal ­hormone production, the use of hormone manipulation may lead to the return of sperm production [71].

Fertility Preservation in Male Cancer Patients Long-Term Sterility Sterility is an inability of a man to fertilize an egg or reproduce. Sterility is caused by poor function or failure of the ­testes. Damage to the testes from radio- or chemotherapy is a common cause of sterility among cancer patients – some type of surgery to treat prostate, bladder, testicular, and colon cancers can also produce sterility by affecting glands and nerves. Age is an important factor that contributes to recovery of the reproductive function. Older patients are more likely to experience long-term sterility. Patients who undergo chemotherapy treatment for testicular cancer, Hodgkin disease, and childhood lymphomas are likely to experience long-term sterility. Men treated for acute lymphoblastic leukemia may also experience some damage, but most appear to recover their reproductive function. Testicular cancer now has a cure rate of more than 80% with combination chemotherapy composed of cisplatin, etoposide, and bleomycin. However, approximately 25% of patients have azoospermia for 2–5 years or more after treatment. Additional research with survivors of testicular cancer reveals conflicting results regarding the impact of treatment or reproductive ability. Although one study demonstrates 68% exhibit testicular dysfunction, another study showed that the release of hormones from the brain compensates for the loss of testosterone production in the testes. Therefore, the response to treatment seems to vary between individuals.

Hodgkin Disease Many men with Hodgkin disease have testicular deficiencies before treatment. Eight per cent of patients had azoospermia and only 30% had normal sperm counts. Thus, 70% demonstrated semen abnormalities before the onset of treatment. Additional, patients with Hodgkin lymphoma are treated with procarbazine – containing chemotherapy regimens that cause sterility in the vast majority. Survivors of HD typically progress through puberty ­normally. Although some will have long-term testicular ­dysfunction as measured by LH and FSH levels, many will not experience this side effect of treatment. For men, gonadal toxicity can be evidenced by the following three ­measurements:

Preservation of fertility in male cancer patients has been increasingly successful during the last three decades.

Sperm Cryopreservation The best option for the preservation of male fertility is cryopreservation of sperm before treatment. Cryopreservation of human sperm has been reported for up to 28 years. This is possible with no apparent capacity for fertilization [72]. Semen cryobanking before chemotherapy, RT, and surgery affecting the reproductive system is a widely available option that yields good results and provides a reasonable chance of establishing a pregnancy after cancer therapy [73]. Traditionally, the banking of at least three semen samples, with an abstinence period of at least 48 h between the samples, has been recommended. Completion of the process usually requires 5–8 days. Additional samples and longer abstinence periods (72–96 h) to achieve higher total sperm counts might also be considered [74]. The prepubertal testis does not produce mature spermatozoa. However, it contains the diploid stem germ cells from which haploid spermatozoa will ultimately be derived, so that testicular tissue could be harvested before chemotherapy and cryopreserved [75, 76]. After the patient is cured, the tissue will be thawed and the stored germ cells could be reimplanted into the patient’s own testes, where they would initiate normal spermatogenesis in the seminiferous tubules. The procedure is known as germ cell transplantation [77, 78]. Alternatively, the stored cells could be matured in  vitro until fertilization can be achieved by the use of ICSI. The most important issue with autotransplantation is the risk of reintroducing malignant cells after retransplantation. The risk is greater with hematological cancers as the testes can be sanctuary sites for leukemia cells [79]. The technique of IVM of stem cells circumvents the risk of reintroducing malignant cells. According to ESMO recommendations [80], all patients at risk for infertility who have not completed childbearing should discuss germ cell storage options with the medical team. Available interventions for male fertility preservation are unlikely to delay cancer treatment. Semen cryopreservation of at least three samples with 48 h abstinence intervals is recommended for men [80]. For azoospermic men, testicular

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sperm extraction may be an option for fertility preservation. Prepubertal males may participate in clinical research of testicular tissue spermatogonial stem cell storage. No studies support the effectiveness of male gonadal protection by means of hormonal manipulations during chemotherapy and RT.

Children with Cancer Childhood cancer includes hematological malignancies, sarcomas, central nervous system processes, renal cancer, and bone cancer. Treatment regimens for childhood cancers are toxic and there is a high risk to the fertility of young patients. The patients have increased risk of secondary malignancies [81]. The majority of childhood cancers are managed with a combination of chemotherapy and radiation therapy. These treatments alter the function of the hypothalamic–pituitary–gonadal axis. Direct damage to the ovaries by affecting folliculogenesis or inducing POF can be produced as well [82].

Gonadal Dysfunction The degree of gonadal damage depends on the type and total doses of chemotherapy used and dosage of RT received. AA, such as nitrogen mustard, procarbazine, and cyclophosphamide are the most damaging to the gonads. Thirty per cent of prepubertal boys had evidence for gonadal dysfunction with total cyclophosphamide doses > 400  mg/kg (12  g/m2) compared to no effect on prepubertal girls. Midpubertal and sexually mature boys frequently had gonadal dysfunction even with total doses as low as 100  mg/kg (3  g/m2). When girls receive chemotherapy during or after puberty, they are affected more severely but are still less sensitive than boys. Girls having abdominal irradiation for Hodgkin disease or Wilms tumor (i.e., ovaries in the radiation field) have a 50% incidence of ovarian failure if both ovaries are in the field and the dose is > 1,500 cGy. The rate is higher if AA are also used. A major concern is early menopause [83]. In a large study, the average age at menopause was 31 years in women treated with abdominal irradiation and AA combined. Radiation to the gonads can also affect fertility [84]; 200–300 cGy to the testes causes 100% aspermia with no recovery after as many as 40 months of follow-up. This is important for boys receiving testicular radiation for testicular germ cell tumors or testicular disease from acute lymphoblastic leukemia, abdominal irradiation for advanced Hodgkin disease, or TBI with bone marrow transplant. The testes are especially vulnerable as germinal epithelium can be seriously damaged, permanently affecting

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s­ permatogenesis. The direct toxic effects of chemotheraphy and RT are dose dependent.

Monitoring of Late Effects Ovary Girls who receive AA or abdominal or pelvic RT should monitor their menstrual histories yearly after therapy. Elevated LH and FSH and low estradiol may indicate ovarian failure if menses do not occur and if signs of POF are present. Hormone replacement therapy is necessary for girls who do not go through puberty or who have evidence of POF.

Testes In boys, who receive AA or testicular or pelvic RT, it would be necessary to check baseline LH, FSH, and testosterone once they reach the age of 12 years and then as needed. Puberty is rarely affected. Large doses of alkylators and RT doses > 3,500  cGy are likely to affect Leydig cells. Sperm analysis represents the criterion standard regarding fertility, although elevated gonadotropins and small testes are indicators of potential infertility [85]. Options for fertility preservation in pediatric patients generally overlap those that are available for adults. Children under chemotherapy can receive GnRH agonists, however, that have little protective effect. Cryopreservation of sperm before the initiation of therapy remains the best method of preserving fertility in postpubertal boys. In the case a young patient is not able to provide a semen sample, electroejaculation or surgical sperm extraction can be performed [86]. Adolescent girls are not considered to be candidates for assisted reproductive technology [40]. Oophoropexy to move the ovaries away from direct toxic effects of the radiation target can be performed in girls. Children with cancer and their families have not typically been offered options for ferti­lity preservation. However, such options are available for this patient population.

Teratogenic Effects of Cancer Treatments Studies indicate that chemotherapy and RT treatments can be mutagenic to human germ cells [18]. Genetic damage of the human germ cell might influence fertilization, increase the rate of abortions, or cause malformations in children conceived by men or women previously exposed to cancer treatment. The potential teratogenic effect of cancer treatment depends

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15  Sterility, Infertility, and Teratogenicity

upon the developmental stage of the fetus at the time of ­exposure. The developmental stages are divided into the preimplantation and early postimplantation periods, the embryonic period or major organogenesis period (third to eighth week postconception) during which most of the organs develop [87], and the fetal period (ninth completed gestational week to term). During the predifferential period, the conceptus is most resistant to teratogenic insult [88]. Any embryonic damage occurring at this point would most likely lead to death of the conceptus. During organogenesis, damage of any developing organ would most likely lead to major malformation. During the fetal period, the damage is less extensive. The risk of teratogenesis following cancer treatment appears to be significantly lower than is commonly appreciated [18]. Most drugs reach the fetus in significant concentrations after maternal administration as the placenta is not an effective barrier. Of the chemotherapeutic agents examined, cisplatin [89] and cyclophosphamide [90] cross the placenta easily, while epirubicin has limited transplacental passage [91]. An estimate of 10–20% of fetuses exposed to chemotherapy during the first trimester would have major malformations [92]. The risk of anomalies after administration of chemotherapy in the second and third trimesters is probably not greater than the background rate. However, there can be a greater risk of stillbirth, fetal growth restriction, premature birth, and maternal and fetal myelosuppression [93]. Concerning the teratogenic effects of individual agents, the antimetabolites methotrexate and aminopterin have been associated with birth defects more frequently. AA are less teratogenic than antimetabolites [94]. Vinca alkaloids are potent teratogens in animals, although most cases of human exposure resulted in normal infants [94]. Taxanes and platinum compounds are relatively safe to administer beyond the first trimester. Delayed effects of in utero exposure to chemotherapeutic agents are basically undefined. A major concern is intellectual and neurological functions or long-term development following in utero exposure to maternal cancer and its associated treatment. It is recommended that if treatment cannot be delayed and is given in the first trimester (especially if folate antagonists are used), then termination of the pregnancy is recommended [18]. There are no data on pemetrexed, gemcitabine, and vinorelbine. Few pregnant women have been exposed to targeted agents. Trastuzumab caused oligohydramnios in four and abnormal implantation in one out of seven pregnant women, while rituximab only caused transient neonatal lymphopenia in four reported cases. Imatinib was associated with low birth weight and premature delivery in 29 reported cases. In view of the lack of data and past experience with the antiangiogenic agent thalidomide, administration of targeted agents modulating angiogenesis (bevacizumab, sunitinib, sorafenib) should be avoided in pregnant women [80]. To decrease the risk of anomalies to the fetus, chemotherapy should be delayed (if possible) until the second trimester.

However, chemotherapy started in the second and third ­trimesters may increase the risk of stillbirth, fetal growth restriction, premature birth, and maternal and fetal myelo­ suppression.

Mutagenic Effect of Rt Radiation has direct mutagenic effects on germ cells in relation to dose. High dose may lead to dominant lethal effects, point mutations, and chromosomal abnormalities [95]. Radiation is also carcinogenic. Classic effects of radiation on developing mammals are embryonic death, gross congential malformations, and intrauterine growth retardation. During the first 2 weeks post fertilization, the embryo is highly sensitive to the lethal effects of irradiation and is insensitive to the teratogenic effects of radiation [95]. In weeks three to ten post fertilization, radiation may be teratogenic and cause growth retardation. Very high doses (at least 1.0 Gy) may be lethal to the embryo. The central nervous system develops throughout gestation, and may therefore be sensitive to radiation at all stages of pregnancy. High doses of ionizing irradiation, mainly in therapeutic doses, were found to induce skeletal, eye, and brain anomalies in the human fetus. The main defects were microcephaly and mental retardation, microphthalmia, cataract, iridal defects, and skeletal anomalies [18]. There is concern about the carcinogenic effects of irradiation on the developing embryo and fetus. Several epidemiological studies have demonstrated an increased risk of childhood leukemia and other childhood tumors [18]. The overall additional risk is estimated to be about 40%. It is recommended to avoid high-dose irradiation during pregnancy as it may induce central nervous system, eye and skeletal anomalies, impaired growth, and mental retardation. At any point during the pregnancy, maternal exposure (to the abdomen) of less than 0.10–0.20 Gy does not seem to cause teratogenic effects, although in utero exposure to radiation causes 40% increased risk of childhood leukemia and other tumors. If there was very early or low dose exposure to radiation, these do not justify termination of the pregnancy [18]. Studying the teratogenicity of cancer chemotherapy is usually based on animal models. However, the chemotherapy doses used in humans are often lower than the minimum teratogenic doses applied in animals. Therefore, it is difficult to extrapolate data from animal models to humans [96]. Cytotoxic drugs are often used in multidrug regimens, which make it difficult to estimate the exact effect of each drug. Due to the rarity of pregnancy-associated cancer, there is little expertise in the field. There is a critical need for multicenter cooperation to facilitate better epidemiological studies and improved long-term follow-up.

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Conclusion

References

Reproductive health after cancer is increasing in importance as the number of cancer survivors multiplies and the length of their survival also improves. Interventions that prevent or reverse the reproduction problems will greatly improve the quality of life of patients. There is a tremendous demand for the provision of reproductive care for survivors of cancer treatment including fertility options, management of pregnancy, and other needs such as contraception and sexual dysfunction. Such demand is without doubt increasing every day with more successful outcomes of cancer treatment and availability of new effective modalities to satisfy fertility and reproductive needs. A large minority of male and female cancer survivors have unmet needs related to reproductive health, even when treated in a comprehensive cancer center. Although fertilitysparing treatment is allowing more patients to have children after cancer, the gains are minimal compared with the elevated rates of childlessness among cancer survivors. As Cvancarova et al. [97] points out, the need for more effective fertility preservation for girls and young women is particularly pressing. Controlling cancer is necessary but not sufficient to ensure a satisfying quality of life for our patients. Current evidence suggests that pregnancy does not appear to be detrimental, but individualized counseling regarding prognosis and risk of relapse based on their age and pathological features of the cancer is required before patients can make informed decisions regarding future childbearing. There is a growing recognition of the importance of deve­ loping “survivorship plan.” Multidisciplinary teams ­including reproductive medicine specialists and gynecologists would be needed. The keys to successful preservation of fertility are to mitigate the risks whenever possible and to initiate planning for fertility treatment as soon as possible in order to prevent unnecessary delays in cancer treatment. Reasonable, evidence-based recommendations regarding the effect of cancer treatment on human fertility are needed to counsel patients during their cancer diagnosis, treatment, and follow-up, including the various options for fertility preservation. During the last three decades, oncologists have seen explosive developments of prophylactic and therapeutic techniques to prevent posttreatment infertility in cancer patients. Although many problems still remain, in particular for female cancer patients, the risk of posttreatment infertility can be minimized if the responsible physician is aware of this progress. Adequate pretreatment counseling of young patients, based on today’s knowledge about the technical possibilities, is the part of good clinical practice.

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15  Sterility, Infertility, and Teratogenicity 24. Hawkins MM, Smith RA. Pregnancy outcomes in childhood cancer survivors: probable effects of abdominal irradiation. Int J Cancer. 1989;43:399–402. 25. Agarwal SK, Chang RJ. Fertility management for women with ­cancer. Cancer Treat Res. 2007;138:15–27. 26. Practice Committee of the Society for Assisted Reproductive Technology; Practice Committee of the American Society for Reproductive Medicine, Essential elements of informed consent for elective oocyte cryopreservation: a practice committee opinion. Fertil Steril. 2007;88:1495–1496. 27. Roberts JE, Oktay K. Fertility preservation: a comprehensive approach to the young woman with cancer. J Natl Cancer Inst Monogr. 2005;34:57–59. 28. Lee SJ, Schover LR, Patridge AH, Patrizio P, Wallace WH, Hagerty K, Beck LN, Brennan LH, Oktay K. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol. 2006;24:2917–2931. 29. Oktay K, Cil AP, Bang H. Efficiency of oocyte cryopreservation a meta-analysis. Fertil Steril. 2006;86:70–80. 30. Seli E, Tangir J. Fertility preservation options for female patients with malignancies. Curr Opin Obstet Gynecol. 2005;17(3): 299–308. 31. Blumenfeld Z. Preservation of fertility and ovarian function and minimalization of chemotherapy associated gonadotoxicity and premature ovarian failure: the role of inhibin A and B as markers. Mol Cell Endocrionol. 2002;187:93–105. 32. Meirow D, Badaan S, Ligumski M, Lewis H. Sperm production and reproductive performance in male mice treated with the immunosuppressive drug used for inflammatory bowel disease, 6-meraptopurine. Fertil Steril. 2000;74:S80. 33. Oktay K, Sonmezer M, Oktem O, Fox K, Emons G, Bang H. Absence of conclusive evidence for the safety and efficacy of gonadotropinreleasing hormone analogue treatment in protective against chemotherapy-induced gonadal injury. Oncologist. 2007;12:1055–1066. 34. Ives A, Saunders C, Bulsara M, Semmens J. Pregnancy after breast cancer: population based study. BMJ. 2007;334:194. 35. Meistrich M, Shetty G. Hormonal suppression for fertility preservation in males and females. Reproduction. 2008;136:691–701. 36. Gupta PB, Kuperwasser C. Contributions of estrogen to ER-negative breast tumor growth. J Steroid Biochem Mol Biol. 2006;102: 71–78. 37. Oktay K, Karlikaya GG, Aydin BA. Ovarian cryopreservation and transplantation: basic aspects. Mol Cell Endocrinol. 2000;169(1–2): 105–108. 38. Oktay K, Buyuk E, Davis O, et al. Fertility preservation in breast cancer patients: IVF and embryo cryopreservation after ovarian stimulation with tamoxifen. Hum Reprod. 2003;18:90–95. 39. Oktay K, Buyuk E. Ovarian transplantation in humans: indications, techniques and the risk of reseeding cancer. Eur Jobstet Gynecol Reprod Biol. 2004;113(suppl 1):545–547. 40. Jeruss JS, Woodruff TK. Preservation of fertility in patients with cancer. N Engl J Med. 2009;360:902–911. 41. Meirow D, Hardon I, Dor J. Searching for evidence of disease and malignant cell contamination in ovarian tissue stored from hematologic cancer patients. Hum Reprod. 2008;19:1069–1075. 42. Telfer EE, McLaughlin M, Ding C, Thong KJ. A two-step serumfree culture system supports development of human oocytes from primordial follicles in the presence of activin. Human Reprod. 2008;23:1151–1158. 43. Maltaris T, Sulfert R, Fishl F, Schaffrath M, Pollow K, Koelbe H, Dittrich R. The effect of cancer treatment on female fertility and strategies for preserving fertility. Eur J Obstet Gynecol Reprod Biol. 2007;30:148–155. 44. Oktay K, Buyuk E, Libertella N, et  al. Fertility preservation in breast cancer patients: a prospective controlled comparison of

143 o­ varian stimulation with tamoxifen and letrozole for embryo ­cryopreservation. J Clin Oncol. 2005;23:4347–4353. 45. Sonoda Y, Abu-Rustum NR, Gemignani ML, Chi DS, Brown CL, Poynor EA, Barakat RR. A fertility-sparing alternative to radical hysterectomy: how many patients may be eligible? Gynecol Oncol. 2004;95(3):534–538. 46. Visvanathan DK, Cutner AS, Cassoni AM, Gaze M, Davies MC. A  new technique of laparoscopic ovariopexy before irradiation. Fertil Steril. 2003;79(5):1204–1206. 47. Gershenson DM. Fertility-sparing surgery for malignancies in women. J Natl Cancer Inst Monogr. 2005;(34):43–47. 48. Hirt R, Davy C, Guibert J, Olivennes F. Pregnancy after in  vitro fertilization – intra cytoplasmic sperm injection obtained with a modified natural cycle in a BRCA1 mutation carries. Fertil Steril. 2008;90(4):1199.e25–1199.e28. 49. Meirow D, Schiff E. Appraised of chemotherapy effects on reproductive outcome according to animal studies and clinical data. J Natl Cancer Inst Monogr. 2005;34:21–25. 50. Goodwin PJ, Ennis M, Pritehard KI, Trudea M, Hood N. Risk of menopause during the first year after cancer diagnosis. J Clin Oncol.1999;17:2365–2370. 51. Brannigan RE. Fertility preservation in adult male cancer patients. Cancer Treat Res. 2007;138:28–49. 52. O’Flaherty C, Vaishua F, Hales BF, Chan P, Robaire B. Characterization of sperm chromatin quality in testicular cancer and Hodgkin lymphoma patients prior to chemotherapy. Hum Reprod. 2008;23:1044–1052. 53. Tempest HG, Ko E, Chan P, Robaire B, Rademaker A, Martin RH. Sperm aneuploidy frequencies analyzed before and after chemotherapy in testicular cancer and Hodgkin lymphoma patients. Hum Reprod. 2008;23:251–258. 54. Rowley MJ, Leach DR, Warner GA, Heller CG. Effect of graded doses of ionizing radiation on the human testis. Radiat Res. 1974;59: 665–678. 55. Nalesnik JG, Sabanegh ES Jr, Eng TY, Buchholz TA. Fertility in men after treatment for stage 1 an 2A seminoma. Am J Clin Oncol. 2004;27:584–588. 56. Agrawal A, Said TM. Implications of systemic malignancies on human fertility. Reprod Biomed Online. 2004;9:673–679. 57. Puschek E, Philip PA, Jeyendran RS. Male fertility preservation and cancer treatment. Cancer Treat Rev. 2004;30:173–180. 58. Byrne J, Mulvihill JJ, Myers MH, et  al. Effects of treatment on ­fertility in long-term survivors of childhood or adolescent cancer. N Engl J Med. 1987;317:1315–1321. 59. Witt KL, Bishop JB. Mutagenicity of anticancer drugs in mammalian germ cells. Mutat Res. 1996;355:209–234. 60. Howell A, Cuzik J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS. Result of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years adjuvant treatment for breast cancer. Lancet. 2005;365:60–62. 61. Nakayama K, Milbourne A, Schover LR, Champlin RE, Ueno NT. Gonadal failure after treatment of hematologic malignancies: from recognition to management, for health-care providers. Nat Clin Pract Oncol. 2008;5:78–89. 62. Wallace WH, Shalet SM, Crowne EC, Morris-Jones PH, Gattamaneni HR. Ovarian failure following abdominal irradiation in childhood: natural history and prognosis. Clin Oncol (R Coll Radiol). 1989;1:75–79. 63. Centola GM, Cisar M, Knab DR. Establishment and morphologic characterization of normal human endometrium in vitro. In Vitro. 1984;20(6):451–462. 64. Gordon W Jr, Siegmund K, Stanisic TH, McKnight B, Harris IT, Carroll PR, et al. A study of reproductive function in patients with seminoma treated with radiotherapy and orchidectomy (SWOG-8711).

144 Southwest Oncology Group. Int J Radiat Oncol Biol Phys. 1997;38:83–94. 65. Socié G, Salooja N, Cohen A, Rovelli A, Carreras E, Locasciulli A, Korthof E, Weis J, Levy V, Tichelli A; Late Effects Working Party of the European Study Group for Blood and Marrow Transplantation. Nonmalignant late effects after allogeneic stem cell transplantation. Blood. 2003;101(9):3373–3385. Epub 2003 Jan 2. 66. Soloway CT, Soloway MS, Kim SS. Sexual, phsychological and dyadic qualities of the prostate cancer couple. BJU Int. 2005;95(6): 780–785. 67. Schover LR. Sexuality and Fertility after Cancer. Wiley, New York, 1997. 68. De Santis M, Albrecht W, Höltl W. Impact of cytotoxic treatment on long-term fertility in patients with germ-cell cancer. Int J Cancer. 1999;83(6):864–865. 69. Simon B, Lee SJ, Partridge AH Preserving fertility after cancer. CA Cancer J Clin. 2005;55(4):211–228. 70. Martin RH, Hildebrand K, Yamamoto J, et  al. An increased ­frequency of human sperm chromosomal abnormalities after radiotherapy. Mutat Res. 1986;174:219–225. 71. Gradishar WJ, Schilsky RL. Effects of cancer treatment on the reproductive system. Crit Rev Oncol Hematol. 1988;8(2)153–171. 72. Feldschuh J, Brassel J, Durso N, Levine A. Successful sperm ­storage for 28 years. Fertil Steril. 2005;84:1017. 73. Sanger WG, Olson JH, Sherman JK. Semen cryobanking for men with cancersriteria change. Fertil Steril. 1992;58:1024–1027. 74. Shin D, Lo KC, Lipshultz LL. Treatment options for the infertile male with cancer. J Natl Cancer Inst Monogr. 2005;34:48–50. 75. Wallace WH, Anderson RA, Irvine DS. Fertility preservation for young patients with cancer: who is at risk and what can be offered? Lancet Oncol. 2005;6:209–218. 76. Ginsberg JP, Carlson CA, Link K, Hobbie WL, Wigo L, Wu X, Brinster RL, Kolon TC. An experimental protocol for fertility preservation in prepubertal boys recently diagnosed with cancer: a report of acceptability and safety. Human Reprod. 2010;25(1):37–41. 77. Brinster RL, Zimmermann JW. Spermatogenesis following mall germ-cell transplantation. Proc Natl Acad Sci USA. 1994;91: 11298–11302. 78. Orwig KE, Schalatt S. Cyropreservation and transplantation of ­spermatogonia and testicular tissue for preservation of male fertility. J Natl Cancer Inst Monogr. 2005;34:51–56. 79. Frederickx V, Michiels A, Goossens E, De Block G, Van Steirteghem AC, Tournaye H. Recover, survival and functional evaluation by transplantation of frozen-thawed mouse germ cells. Hum Reprod. 2004;19:948–955.

H. Everaus 80. Pentheroudakis G, Pavlidis N, Castiglione M. Cancer, fertility and pregnancy; ESMO Clinical Recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;54:iv 178-iv 181. 81. Marina N. Long-term survivors of childhood cancer: the medical consequences of cure. Pediatr Clin North Am. 1997;44:1021–1042. 82. Chemaitilly W, Mertens AC, Mitby P. Acute ovarian failure in the childhood cancer survivor study. J Clin Endocrinol Metab. 2006;91:1723–1728. 83. Byrne J. Infertility and premature menopause in childhood cancer survivors. Med Pediatr Oncol. 1999;33(1):24–28. 84. De Bruin ML, Van Dulmen-den Broeder E, Van den Berg MH, Lambalk CB. Fertility in female childhood cancer survivors. Endocr Dev. 2009;15:135–158. 85. Edgar AB, Morris EM, Kelhar CJ, Wallace HB. Long-term follow-up of survivors of childhood cancer. Endocr Dev. 2009;15:159–180. 86. Schmiegelow ML, SOmmer P, Carlsen E, Sonnsen JO, Schmigelow K, Müller JR. Penile vibratory stimulation and electroejaculation before anticancer therapy in two pubertal boys. J Pediatr Hematol Oncol. 1998;20:429–430. 87. Sadler TW (ed). Langmans in Medical Embryology. 7th edition. Williams & Wilkins, Baltimore, 1995. 88. Schardein JL. Chemically Induced Birth Defects. 2nd edition. Marcel Dekker, New York, 1993. 89. Koc ON, McFee M, Reed E, Gerson SL. Detection of platinum-DNA adducts in cord blood lymphocytes following in utero platinum exposure. Eur J Cancer 1994;30A:716–717. 90. D’Incalci M, Sesa L, Coumbo N. Transplacental panage of cyclophosmamide. Cancer Treat Rep. 1982;66:1681–1682. 91. Gaillard B, Leng J, Grellet J. Transplacental passage of epirubicin. J Gynecol Obstet Biol Reprod. 1995;24:63–68. 92. Caligiuri MA, Mayer RJ. Pregnancy and leukemia. Semin Oncol. 1989;16:388. 93. Garcia L, Valcarcel M, Santiago-Borrero IJ. Chemotherapy during pregnancy and its effect on the fetus-myelosuppression: two-case reports. J Perinatol. 1999;19:230–233. 94. Doll RC, Ringenberg OS, Yarbo JW. Antineoplastic agents and pregnancy. Semin Oncol. 1989;16:337–346. 95. Brent RL. Utilization of developmental basic science principles in the evaluation of reproductive risks from pre- and postconception environmental radiation exposures. Teratology. 1999;59:182–204. 96. Pereg D, Koren G, Lishner M. Cancer in pregnancy: gaps, challenges and solutions. Cancer Treat Rev. 2008;34:302–312. 97. Cvancarova M, Samuelsen SO, Magelssen H. Reproduction rates after cancer treatment: experience from the Norwegian Radium Hospital. J Clin Oncol 2009;27:334–343.

Chapter 16

Menopause Symptoms Debra L. Barton and Sherry L. Wolf

Introduction The menopause transition is triggered by senescence of ­ovarian follicular function resulting in decreased estrogen and progesterone production. It is fully ushered in with follicular depletion. This usually occurs at a mean age of 51 years, although for cancer survivors due to treatment effects, it can happen at a much younger age [1, 2]. According to the last state of the science meeting on menopause symptoms at the National Institutes of Health, symptoms clearly associated with menopause include hot flashes, night sweats, vaginal dryness, with or without dyspareunia, and perhaps sleep disturbance [3]. According to the panel, symptoms with limited or insufficient evidence to associate their cause with menopause include mood disorders, cognitive changes, pain, fatigue, joint and muscle aches, urinary symptoms, and libido [3]. Like all life’s experiences, natural menopause is associated with psychosocial events and psychological meaning. It signifies the end of child bearing years; it is a time when children are grown and beginning independent lives; it can be accompanied by increased job demands and stresses; it may require care of parents and is accompanied by sometimes subtle but apparent changes in body image [4]. For cancer survivors, menopause can occur prematurely as a result of cancer treatment including the need for bilateral oophorectomy as well as chemotherapy that can impact follicular life [5, 6]. This menopause is also associated with meaning which may be slightly different than with natural menopause. It can be a reminder of the cancer diagnosis and may be associated with more distress since it can occur years before the woman’s peer group experiences this phenomenon. There is also the potential for more severe sequelae due to the number of years a woman may live with estrogen depletion.

D.L. Barton (*) Department of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA e-mail: [email protected]

There are also endocrine-related treatments that are associated with menopause symptoms. Examples of these are tamoxifen and hot flashes, as well as aromatase inhibitors (AIs) with bone loss, arthralgias and myalgias, and hot flashes (though to a lesser extent than tamoxifen) [7–9]. In addition to sharp decreases in estrogen and progesterone, menopause related to cancer treatment may also signify decreases in other hormones such as androgens. It is not known to what extent other ovarian function is disturbed by chemotherapy. In postmenopausal women, the ovarian stroma is a source of androgen production [10]. When a woman has had a bilateral oophorectomy, her testosterone concentrations can be half of that of women experiencing natural menopause [11]. One descriptive study found that women who had a bilateral oophorectomy were more likely to experience moderate, severe, and daily hot flashes compared to women experiencing natural menopause [12]. It is not clear whether, or how much, androgen production is decreased postchemotherapy, nor what impact androgen deprivation may have on hot flashes, bone changes, or vaginal health when coupled with estrogen deprivation. Decreases in androgen may well be a contributor to the plethora of menopausal symptoms experienced by female cancer survivors, and this needs further study. Since the gold standard of treatment for bothersome menopausal symptoms, estrogen replacement therapy, is contraindicated for many female cancer survivors with hormone sensitive cancers, other treatment options are critically needed. There has been a fair amount of research evaluating nonestrogenic interventions for a variety of menopausal symptoms over the past decade or so. This evidence base will be presented in this chapter, along with a brief description, (including what is known of the physiology) of the symptoms of hot flashes/night sweats, osteoporosis, and vaginal atrophy. Each section will conclude with evidence-based practice recommendations. Evidence-based practice consists of treatment recom­ mendations based on the best available evidence which ­integrates both patient characteristics as well as provider expertise. Things that providers need to consider in developing

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_16, © Multinational Association for Supportive Care in Cancer Society 2011

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symptom management recommendations with their patients include their own experience with patients’ symptom expressions and responses to interventions, the specific attributes of a patient’s symptom expression, a patient’s preferences for types of interventions, including lifestyle factors, as well as various types of evidence, from randomized controlled ­trials to pilot data to case studies. All these elements have a role in the final decision of what types of interventions should be used first line and second line to manage a patient’s symptoms. Sleep disturbances, though an important symptom, will not be addressed in this chapter as it is covered in Chap. 39 of this book.

Hot Flashes and Night Sweats Definition and Incidence Hot flashes are a sensation of heat that often begins in the neck and the face and can encompass the entire body, particularly the chest [1, 13]. The warmth may or may not be accompanied by sweating and red skin. Night sweats are periods of perspiration, mild to profound, that occur during one’s sleep which can disrupt the sleep cycle. Hot flashes are the most prevalent symptom of menopause, experienced by up to 75% of women, having a significantly negative impact on daily activities [1]. Women with a history of breast cancer are thought to experience more severe symptoms and can experience symptoms for longer periods of time due to endocrine-related treatment for cancer [5, 14].

Physiology The physiologic mechanisms that cause or perpetuate a hot flash are not definitively known, however, more about hot flash physiology is being uncovered. It has been shown that core body temperature rises as much as 10 min before a hot flash begins [15]. In addition, it is thought that hot flashes are triggered by central nervous system activity resulting in an imbalance of serotonin and norepinephrine [16, 17]. Further, it is believed that estrogen withdrawal results in changes in the hypothalamus, which causes less flexibility in the body’s ability to respond to temperature changes [18, 19]. This is referred to as a narrowed thermoregulatory zone. Therefore, one hypothesis about hot flash perpetuation is that as a person is confronted with stress, environmental conditions, or other factors that increase core body temperature or further upset neurotransmitter balance, a hot flash can ensue.

D.L. Barton and S.L. Wolf

Evidence-Based Prevention and Treatment There have been many clinical trials done, which provide a consistent evidence base for the use of many nonest­ rogen based pharmacologic as well as nonpharmacologic interventions.

Pharmacologic Treatment Options There are a variety of pharmacologic agents that have been found to reduce hot flashes in phase III placebo-controlled ­trials. Classes of agents found effective include antidepressants; selective serotonin reuptake inhibitors (SSRI); and ­serotonin/norepinephrine reuptake inhibitors (SNRI), i.e., venlafaxine (75  mg/day extended release), paroxetine (10  mg/day or 12.5  mg CR), fluoxetine (20  mg/day), and ­citalopram (10 or 20 mg/day); anticonvulsants, i.e., gabapentin (300 mg TID) and pregabalin (75 mg BID); and anticholinergics, i.e., clonidine (0.1  mg/daily) [20–22]. Newer agents with similar mechanisms of action, such as desvenlafaxine (an SNRI) and escitalopram (an SSRI), have been evaluated in pilot trials or in noncancer populations and have shown ­efficacy for hot flashes. Although not fully evaluated in cancer survivors, it is likely that these agents would also be efficacious in managing hot flashes for this population. Of the antidepressants found beneficial, the mechanism of action has included serotonin modulation. Venlafaxine and paroxetine have been found to reduce hot flashes by about 55–60% in phase III trials, while citalopram and fluoxetine have been found to reduce hot flashes by about 50% in similarly designed trials. The antidepressant, sertraline, although also a serotonin modulator, did not prove to be quite as helpful (less than 40% reduction) in reducing hot flashes as other agents in its class have been found to be [23]. It is not clear why this might be so. Interestingly, pilot trials investigating the efficacy of other types of antidepressants, such as dopamine, and pure norepinephrine modulators, such as bupropion and desipramine, respectively, were found to reduce hot flashes only 20–30%, which is consistent with a placebo effect [24, 25]. A second class of agents, anticonvulsants (gabapentin and pregabalin), were found to reduce hot flashes by 60% and 50%, respectively, in phase III trials. Finally, clonidine, either orally or transdermally, provides about a 40% reduction in hot flashes [20]. Side effect profiles related to the doses found effective for hot flashes with these agents are relatively mild and well ­tolerated. For the antidepressants, the most common side effects include nausea, appetite increase or decrease, and dry mouth [20, 26]. Theoretically, SSRIs can be accompanied by sexual function changes such as lack of orgasm. However,

16  Menopause Symptoms

long-term studies at the low doses used for hot flash management have not been done to describe the actual effects on sexual function from these agents when used for hot flashes. The anticonvulsants are associated with a few more side effects such as drowsiness, dizziness, trouble concentrating, trouble sleeping, blurred vision, and coordination troubles. Gabapentin can also cause changes in albumin/total protein resulting in a generalized edema [20]. Clonidine is associated with side effects of drowsiness, dry mouth, and if using a transdermal patch, pruritus as well as a skin rash. Clonidine can also cause constipation.

Herbs and Supplements Several herbal agents and dietary supplements have been studied for hot flash reduction. These include vitamin E, various soy products, black cohosh, and flaxseed. Vitamin E has been studied in two randomized clinical trials and has been shown to cause a reduction in hot flashes of about 35–40%, just slightly better than what is seen with a placebo [27, 28]. There have been numerous studies with various types of soy products with very mixed outcomes. However, the majority of studies looking at the effects of soy on hot flashes have revealed more negative than positive results, and therefore, there is not good evidence to support the use of soy for hot flash management at this time [29–32]. Similarly, black cohosh has been studied in several randomized clinical trials and a majority of those studies have also been clearly negative with respect to hot flash reduction [33, 34]. Finally, a pilot study looking at 40 g of flaxseed (400 mg of lignans) has provided preliminary data that flaxseed may be helpful with respect to hot flash reduction. The 28 women, phase II, open label study looked at the effects of 40 g of flaxseed over a 7-week period on hot flash reduction and found a 55% decrease in hot flashes [35]. The potential mechanism of action of flaxseed on hot flashes is not definitely known, but flaxseed is being evaluated for breast cancer prevention based on its estrogen agonist/antagonist properties as well its potential to inhibit aromatase. A large phase III randomized clinical trial is in progress to definitively address flaxseed’s efficacy. Other herbs such as red clover, licorice, chaste berry, hops, and dong quai have also been popularly touted in the complementary therapy literature to be effective for hot flashes. However, none of these have been studied in large, placebo-controlled trials, and some of these herbs may have the ability to bind with estrogen receptors and promote cell proliferation. Therefore, until more research is done to understand their biologic properties as well as effect on hot flashes, it is recommended that women who must avoid estrogen should not take these particular herbs.

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Nonpharmacologic Interventions Yoga is a popular intervention studied for menopausal symptoms based on the general health benefits it is believed to bestow. There are many types of yoga, but most involve a combination of breathing, focus of attention, postures, movement, and balance. A recent review article provided a systematic review of seven trials evaluating yoga for menopausal symptoms [36]. None of the randomized control trials resulted in a benefit of yoga in reducing hot flashes compared to the control. Uncontrolled trials did show favorable effects, however. The types of yoga studied were varied and included Iyengar yoga as well as restorative and Sahaja yoga and other forms that were not specified. Therefore, while the risk associated with yoga is low, there are little compelling data at this time to recommend yoga specifically for hot flash management; however, overall health benefits compared to risks would be favorable for this intervention. Yoga may be a helpful adjunct to other hot flash treatments. There are behaviors that can assist in keeping core body temperature low and, therefore, decrease the advent of hot flashes. These include wearing open weave, layered clothing, keeping air moving with a fan or open window, sipping on cool liquids or even ice or popsicles, and avoiding spicy foods and alcohol or other food/drink that can act as a hot flash trigger by resulting in increased body temperature [26]. There has been a Cochrane review as well as a more recent systematic review [37] about the use of exercise for menopausal symptoms, specifically hot flashes. Although some association studies provide data to hypothesize that decreased physical activity is associated with more menopause symptoms, at least one association study in over 500 perimenopausal and postmenopausal women found that women classified as highly active were more likely to have moderate to severe hot flashes than women classified as minimally active [38]. Randomized controlled trials evaluating walking and moderate aerobic activity have either found no benefit or small effect sizes (<0.20) [37]. It is scientifically plausible that exercise may improve hot flashes based on endorphin release; however, this benefit might be offset by an increase in core body temperature from exercise that can precipitate hot flashes. The role of lifelong exercise in preventing moderate or severe menopause symptoms versus managing existing symptoms needs to be studied and clarified. Acupuncture is another popular treatment for hot flashes and related menopausal symptoms that is getting much research attention. A systematic review of 11 randomized clinical trials remains inconclusive [39]. Trials have used various types of sham control arms consisting of shallow needling, the use of nonacupuncture points, and no needling. In most trials, the control arms were about as effective as the active arms. When nontreatment comparison groups were

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included in study designs, more often than not the active and sham acupuncture arms were significantly better in reducing hot flashes than the control arm [39]. Acupuncture research faces a couple of important methodologic challenges: namely, lack of an appropriate “placebo” control arm based on the knowledge of the mechanism of action of acupuncture as well as the individualized nature of the diagnosis and intervention. Current research methods do not readily allow for acupuncture to be evaluated in the way it is used clinically. Novel research in this area is truly needed. Stress is considered a precipitating factor for hot flashes and methods to reduce stress have been evaluated for hot flash management. Two of these, thought to impact serotonin much like an antidepressant, are paced breathing and relaxation therapy. Controlled trials have provided evidence that paced breathing/relaxation can reduce hot flashes by about 40% [40], which is equal to clonidine without any adverse effects. Slow, deep abdominal breaths, at about six per minute practiced twice a day may help prevent hot flashes [41] and utilizing a breath-relaxing strategy at the onset of hot flashes may decrease the intensity or ward off the hot flash all together. These types of interventions are being studied further. A second mind body intervention that is currently being studied in large, controlled, randomized trials is hypnosis. Hypnosis involves a deep relaxed state involving mental imagery. Imagery including cooling thoughts has been found in a pilot study to decrease hot flashes by almost 70% [42]. A large study with an attention control arm is currently in progress to replicate this finding as well as other pilot trials to evaluate the additive and/or synergistic effect of hypnosis with low-dose pharmacologic therapy.

Assessment and Evidence-Based Practice It is critical to do a thorough assessment regarding the hot flash/ night sweat experience in order to develop the best clinical practice plan. It is, of course, important to get an idea of the number and severity of hot flashes the woman is experiencing on an average day. In addition, though, it is important to evaluate to what degree the hot flashes are causing night awakenings as well as interference with activities of daily living such as job or care-taking demands. It is helpful to evaluate the degree of distress or bother associated with the hot flash experience. A thorough history of behaviors and pharmacologic agents that have been tried to alleviate hot flashes should be taken, along with as much detail as possible regarding dosing, length of time used, and degree of response. The clinical plan for hot flash management should reflect the degree of interference the hot flashes are causing in one’s life (Fig. 16.1). Nonpharmacologic interventions may take ­longer to see an effect than pharmacologic ones; therefore, if a woman has been without sleep for months, starting her on a pharmacologic treatment to get some

D.L. Barton and S.L. Wolf

relief and then incorporating a nonpharmacologic intervention would be an optimal strategy. If using an antidepressant, it is important to titrate patients on and off these medications slowly. Additionally, if mood disturbances are part of a woman’s experience of symptoms, antidepressants may be an optimal choice based on the ability to modulate mood as well as impact hot flashes. Small studies have shown that if one agent is not effective in reducing hot flashes, a woman can try another agent, even in the same class such as an SSRI, and may, indeed, obtain needed relief. Randomized trials have clearly shown that within 2 weeks, nice reductions in hot flashes are realized and there is generally a plateau of effect in 4–6 weeks [43]. Research has also demonstrated that gabapentin and an antidepressant are not synergistic or additive with respect to hot flash reduction; therefore, there is no benefit to using both pharmacologic interventions together. Finally, one last very important consideration is drug interactions. If women are taking tamoxifen, pharmacologic agents that inhibit CYP2D6 metabolism are not to be used as they will inhibit the conversion of tamoxifen into its active metabolite, thus reducing efficacy with regard to breast cancer management [44]. Agents that are known to inhibit CYP2D6 metabolism that are effective for hot flashes include paroxetine, sertraline, and fluoxetine [45]. There are some additional clinical considerations to think about when choosing a pharmacologic intervention for hot flashes. Side effects such as dizziness and drowsiness can be more of problem in an older population with gabapentin. Titrating this agent beginning with 300  mg at bedtime, increasing to 300 mg three times daily over a week, may not always be possible and women may require a longer titration beginning with 100  mg daily. Gabapentin requires dosing three times a day due to its short half-life, and some people may find it difficult to take the mid-day dose [46]. Pregabalin has the advantage of being able to be dosed twice a day but is associated with a few more side effects such as trouble concentrating [22]. If night sweats are the main issue, there are a couple slightly different strategies to consider. The first is the use of gabapentin 300 mg at bedtime alone. Gabapentin can cause some drowsiness which can help with sleep and has already been shown to help with hot flashes. The relatively short half-life makes it a good candidate to use right before bed to help with hot flashes/night sweats during the first several hours of sleep. Additionally, the antidepressant, mirtazapine, has been used as a sleep aid. In an open label phase II trial, mirtazapine was studied for its effect on hot flashes as well as its effect on sleep [47]. Hot flashes were reduced by about 53% on 15  mg of mirtazapine per night. Sleep was also improved. Some women did feel that they had residual drowsiness in the morning; however, if sleep disorders and night sweats are the primary bothersome symptoms, this may be a reasonable option to try.

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16  Menopause Symptoms Assess hot flashes

Moderate to severe

Mild to moderate

Assess interference with activity, night time flashes

Open weave clothing, air movement, watch trigger foods, breathingrelaxation exercises

Primarily at night, few during day Yes

No

Hot flashes that interfere all day and night

Mirtazapine 15 mg at hs or gabapentin 300 mg at hs

On tamoxifen?

No

Venlafaxine, paroxetine, citalopram, gabapentin Add behavioral interventions: clothes, air breathing/relaxation

Yes

Venlafaxine, gabapentin, citalopram Add behavioral interventions: clothes, air breathing/relaxation

Assess relief 50% decrease in 3-4 weeks Yes

Maintain current treatment

No

Switch to another option in original list and reassess in 3 weeks

Fig. 16.1  Hot flash assessment and treatment algorithm

Osteoporosis Definition and Incidence Osteoporosis is a skeletal disorder characterized by low bone mineral density (BMD) and poor bone quality, resulting in  reduced bone strength and increased risk of fractures [48, 49]. The World Health Organization defines osteoporosis as a bone density that is 2.5 standard deviations (expressed as a t-score) below peak bone mass or the mean bone density for young white adult women. Osteopenia, or low bone mass, is

defined as a t-score of –1 to –2.5 [49]. Bone density peaks in women in the third decade of life and thereafter begins to decline. Risk factors for osteoporosis include smoking, body mass index (BMI) <20  kg/m2, oral corticosteroid use >6 months, and advanced age [50]. In premenopausal women being treated for hormone sensitive cancers, estrogen depletion may occur as a result of chemotherapy or direct ovarian suppression via surgical (oophorectomy) or medical (goserelin) intervention. In postmenopausal women with breast cancer, AIs are often initiated to further reduce estrogen levels [51]. Several studies have shown that both steroidal (exemestane) and nonsteroidal

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(anastrozole and letrozole) AIs increase bone loss and ­fracture risk [25, 52, 53]. Tamoxifen protects against bone loss in postmenopausal women but has been linked to decreased bone density in premenopausal women due to its agonist/ antagonist properties at different tissue receptors in various hormonal milieus. Overall, breast cancer survivors are at an increased risk as a result of having undergone chemotherapy, surgical or medically induced ovarian suppression, and the use of AIs, all of which result in a more rapid decline in bone density. In the Women’s Health Initiative (WHI) study, breast cancer survivors had a 31% increased risk of fragility fractures compared with the general population [54].

Physiology Healthy bones are in a continuous state of turnover. Osteoporosis occurs when there is an increase in bone destruction (via osteoclast activity) relative to bone formation (via osteoblast activity) [55]. Estrogen regulates key cytokines involved in the development of osteoporosis including interleukin-1 (IL-1), tumor necrosis factor (TNF), transforming growth factor b (TNF-b), and osteoprotegerin [56]. All these play a role in the inhibition of NFkB receptor (RANK), and its ligand (RANKL), which represents an important signaling pathway for osteoclast differentiation, maturation, and functional activity [56]. During menopause, estrogen levels decrease and bone resorption increases. After menopause, residual estrogen aids in maintaining bone density, and cancer treatments that further deplete estrogen can have a negative effect on bone [50, 56].

D.L. Barton and S.L. Wolf

For exercise, most of the research points to the maintenance of bone in natural menopause and slowing effects on bone loss for women with an increased risk of bone loss as in breast cancer survivors. The summary in a recent Cochrane review [59] states that there are data to support that weightbearing exercise increases bone density but there has not been enough research to determine whether this translates to decreased risk of fracture. It would be reasonable to conclude that the role of calcium, vitamin D, and exercise is most appropriate as lifelong behaviors to decrease risk factors and maintain bone health [61]. Phytoestrogens, known as plant estrogens, have also been a popular topic of study for bone health. Isoflavones are one of the categories of phytoestrogens and soy is a major source of these dietary substances [62]. Isoflavones are structurally and functionally related to 17B-estradiol and may act like natural selective estrogen receptor modulators (SERMs), having both estrogen agonist and antagonist properties depending on what tissue/receptor they associate with. Much of the evidence about soy and bone health comes from association studies. Intervention trials in women have demonstrated some favorable results on BMD and bone turnover markers in postmenopausal women but the data are somewhat conflicted. The isoflavones, genistein, daidzein, and glycitein, need to be metabolized in the gastrointestinal system and some of these are dependent on the microflora. Phenotypical differences with respect to metabolism of isoflavones have not been routinely included in studies to date, and therefore, the precise type, dose, and role of isoflavones in bone health are not yet definitively known. In addition, longer term outcomes such as effects on bone fracture and safety have not been addressed [62, 63].

Bisphosphonates

Evidence-Based Prevention and Treatment Behavior and Dietary Supplements Several studies have looked at the contribution of calcium, vitamin D, and exercise in maintaining bone health [57–59]. Although the evidence clearly suggests a role for all these behaviors, they are not seen as primary treatment, particularly with respect to the high risk of bone loss related to treatments for breast cancer. Very large studies and metaanalyses have found fairly consistent benefits for calcium and vitamin D when used together, in reducing fracture risk, with higher doses of vitamin D providing more benefit [58]. One large study that did not show a decrease in fracture risk used only 400  IU of vitamin D3 [60] as opposed to other positive studies using 700–800 IU of vitamin D3 [58] along with calcium.

Bisphosphonates reduce bone resorption by inhibiting osteoclast activity [55]. This group of agents is the broadest with respect to options and research in osteoporosis management. While a variety of oral and IV bisphosphonates have been FDA approved for the treatment and/or prevention of osteoporosis in postmenopausal women (Table 16.1), research is relatively sparse and more recent with respect to the efficacy of these agents in women getting cancer treatment. There have been four large randomized controlled trials evaluating intravenous zoledronic acid, 4 mg every 3–6 months, in premenopausal women undergoing chemotherapy or receiving adjuvant endocrine therapy with tamoxifen, goserelin, or anastrozole. All four studies provided data to support the prevention of bone loss in all populations [64–67]. Two studies looking at oral risedronate, 35  mg weekly, have been mixed, one showing less bone turnover in women receiving and not receiving AI therapy [68, 69].

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16  Menopause Symptoms Table 16.1  Current bisphosphonates available for osteoporosis Generic

Trade name/company

Dose

Administered

FDA approval related to osteoporosis

Alendronate sodium (generic available) Alendronate sodium (generic available) Ibandronate sodium

Fosamax® (Merck)

5 mg daily 35 mg/weekly

Prevention of postmenopausal osteoporosis

Fosamax® (Merck)

10 mg daily 70 mg weekly

Boniva® (Roche)

2.5 mg daily 150 mg monthly 3 mg every 3 months

Oral on empty stomach; 30 min before eating; follow with 6–8 oz plain water Oral on empty stomach; 30 min before eating; follow with 6–8 oz plain water Oral Oral All oral, 60 min before eating, follow with water, no mineral water IV Oral; 30 min before eating; follow with 6–8 oz plain water

Risedronate sodium

Zoledronic acid

5 mg daily Actonel® also comes with calcium (Procter 35 mg weekly and Gamble) 75 mg for two consecutive days monthly 150 mg monthly Reclast® (Novartis) 5 mg once yearly 5 mg every 2 years

Treatment of postmenopausal osteoporosis; also corticosteroid induced Treatment of postmenopausal osteoporosis; oral is approved for prevention

Prevention and treatment ­postmenopausal osteoporosis; corticosteroid induced as well

Treatment of osteoporosis in postmenopausal women also corticosteroid induced Prevention of postmenopausal osteoporosis also corticosteroid induced every 12 months Bisphosphonates not FDA approved for osteoporosis are etidronate disodium (Didronel – Proctor and Gamble), pamidronate disodium ­(Aredia-Novartis), and tiludronate disodium (Skelid-Sanofi-Aventis)

While bisphosphonates are generally well tolerated, 10–30% of patients will experience fever and myalgias with their first dose. Osteonecrosis of the jaw has been linked to IV bisphosphonate use, and clinicians should be aware of the risk and avoid administering bisphosphonates to those undergoing dental surgery [55]. The more common side effects of oral bisphosphonates are mostly gastrointestinal such as abdominal pain, diarrhea, indigestion, nausea and vomiting, backache, headache, influenza-like symptoms, fatigue, and constipation. Rare but serious side effects include hypersensitivity reactions, esophagitis, and gastric ulcers [70].

IV IV

Bazedoxifene acetate (20 and 40 mg daily) is one of these, called a mixed-function estrogen having estrogenic activity in bone without similar effects in breast or uterine tissue. There are a few studies published on its positive effects on BMD and fractures, but this is not yet FDA approved in the USA [72–74]. Lasofoxifene is another agent that has shown significant decreases in bone turnover markers and increases in BMD compared to placebo [75] and even compared to raloxifiene [76]. In general, side effects of SERMs include hot flashes, night sweats, trouble sleeping, vision changes, leg cramps, blood clots, and dizziness.

Selective Estrogen Receptor Modulators Novel Agents Raloxifene is the first oral SERM, approved for osteoporosis prevention and therapy in postmenopausal women. It subsequently won FDA approval as a preventive agent for breast cancer in high-risk women based on results from a few different studies [71]. SERMs are an attractive class of agents for bone and breast health based on their ability to differentially impact various tissues in the body, inhibiting proliferation in some areas (such as the breast) and promoting activity in others (such as bone and lipids). Hence, newer SERMs are in the process of development and research.

Denosumab is a novel agent for osteoporosis that has not yet been approved by the FDA but will likely be in the near future. It is a fully humanized monoclonal antibody that inhibits the interaction of RANKL and RANK. Studies evaluating 60  mg administered subcutaneously every 6  months over 3  years have showed increases in BMD and reductions in fracture risk over placebo in postmenopausal women [77, 78] without increasing the risk of cancer or hypocalcemia. There were no cases of osteonecrosis of the jaw.

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Parathyroid Hormone The use of parathyroid hormone to prevent the adverse effects of estrogen depletion on bone has been known for some time with a randomized trial of proof of principle published as early as 1994 [79]. There are two forms of parathyroid hormone that have been studied for bone health. One is approved by the FDA in the USA, teriparatide (I-34) (20 mg subcutaneously daily) [80], and the other is a synthetic form, I-84 (100 mg subcutaneous daily) [81]. Teriparatide is approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture as well as for glucocorticoidinduced osteoporosis in both men and women. Studies have shown that these parathyroid-related agents can decrease new vertebral fracture risk by over 60% after 18 months [80, 81]. Side effects from these agents include hypercalcemia, nausea, joint aches and pain, dizziness, and depression, and teriparatide includes a black box warning for osteosarcoma, which was seen in rat studies.

Assessment and Evidence-Based Practice Early identification and management are critical in reducing the risk of fractures in this population. Osteoporosis will likely continue to be a problem for breast cancer survivors as tamoxifen therapy is replaced with AIs as long-term adjuvant therapy. Monitoring of BMD, via dual X-ray absorptiometry (DXA), is recommended annually for patients at risk of osteoporosis [82]. Currently, BMD tests are reimbursed by many insurance companies only every 2 years making other markers of bone health important. Biochemical markers for bone resorption may be measured at 3 months and annually thereafter to monitor compliance with oral bisphosphonate therapy [55]. BMD measurement alone is not sufficient to detect women at risk for fracture. A National Osteoporosis Risk Assessment (NORA) study revealed that women with osteopenia were more likely to suffer a fracture than women with osteoporosis. These results suggest that women with BMD in the osteopenic range (t-score −1.0 and −2.5) are at increased risk of fracture and treatment may be necessary before women become osteoporotic (t-score less than −2.5) [55]. The American Society of Clinical Oncology (ASCO) ­recommends all women beginning AI therapy receive calcium and vitamin D supplementation. General lifelong recommendations to maximize bone health include adequate calcium (1,000–1,500 mg/day) and vitamin D intake (800–1,000 U/day), weight-bearing exercise, and avoidance of smoking [50, 82]. Guidelines for the administration of bisphosphonate therapy are based upon expert advice in healthy women.

D.L. Barton and S.L. Wolf

Clinicians should consider individual risk factors in determining the optimal treatment approach. Adequate calcium and vitamin D concentrations should be evaluated and ensured before beginning and while on bisphosphonate therapy. Several algorithms are available to evaluate fracture risk [77, 82] and numerous guidelines exist to assist in determining when to start therapy. Guidelines differ a bit with respect to when interventions should begin, with the UK guidelines being a bit more aggressive [82, 83]. In general, women with BMD £ −2.5 should receive bisphosphonate therapy. The use of bisphosphonates in women with osteopenia and known risk factors is somewhat more controversial. However, it is generally accepted that any patient initiating or receiving AI therapy with a t-score less than −2.0 or with multiple risk factors should receive bisphosphonate therapy. The UK recommends intervening at a t-score of −1 for women who are estrogen deprived and on an AI or in a woman older than 75 years of age who has one or more risk factors for fracture regardless of BMD values [83]. While oral bisphosphonates are currently the most common treatment related to osteopenia or osteoporosis, poor bioavailability and patient compliance may limit their efficacy. A large study (n = 35,537) of women receiving oral bisphosphonate therapy for postmenopausal osteoporosis found that 57% of patients were noncompliant with therapy during the 2-year study period [50]. Therefore, an important aspect of managing osteoporosis includes the assessment of adherence and barriers to taking oral medications (such as unwanted side effects, intolerance, or lifestyle) as well as barriers to incorporating exercise into one’s life. Providers should facilitate problem solving against the challenges of maintaining healthy behaviors. Based on the black box warning of osteosarcoma, the use of teriparatide in women with a history of breast cancer is not generally recommended. People who are at higher risk for bone cancers including those with previous radiotherapy to the bone, Paget’s disease, and other metabolic disorders of the bone (besides osteoporosis) should also avoid the use of teriparatide [82, 84].

Vaginal Atrophy, Dryness, and Resulting Dyspareunia Definition and Incidence Vaginal atrophy is often one of the later symptoms to emerge during the transition to menopause, but it is one (similar to bone loss) that is not subject to spontaneous or adaptational improvement [85, 86]. The longer a woman is estrogen depleted, the worse this symptom is likely to get. Vaginal

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16  Menopause Symptoms

atrophy contributes to feelings of discomfort related to dryness, itching, burning, and irritation, and it also promotes negative sexual health due to dyspareunia and decreased arousal that can contribute to lack of libido or decreased sexual interest. Vaginal atrophy can also increase one’s susceptibility to urinary tract infections by increasing vaginal pH [85, 87]. The most common symptoms reported by women with vaginal atrophy include dryness, itching/irritation, and dyspareunia. In a recent study published in 2004 by Pastore et al. [88], the incidence of vaginal or genital dryness was 27% and vaginal or genital irritation/itching was 19% among postmenopausal women. Dennerstien [89] reported the incidence of postmenopausal vaginal dryness to be around 25–47%. There are unequivocal data that the menopause transition is responsible for urogenital atrophy accompanied by decreased lubrication, increased pain with intercourse, and decreased libido [90]. Cancer survivors, particularly breast and gynecologic, can experience the hypoestrogenic state much earlier than natural menopause, setting the stage for more prevalent and severe atrophic effects due to the duration of hypoestrogenism. In two studies that looked at menopausal symptoms in breast cancer survivors, the reported prevalence of vaginal dryness was high (36–71%) [91, 92] compared to other menopausal symptoms other than hot flashes. A more recent study describing symptoms in 558 women at the end of primary treatment for breast cancer found that 21% had difficulty with arousal or lubrication [93]. Similarly, in ovarian cancer survivors, a report of descriptive data of a heterogeneous group of 329 epithelial ovarian cancer patients at a single-institution cites among women who were sexually active, 80% had trouble with vaginal dryness (40% “very much”), 62% had dyspareunia (20% “very much”), and 75% had trouble reaching orgasm with 50% of those expressing this occurred 90% of the time [94]. In breast cancer patients, the causes of hypoestrogenism can be multifactorial. Chemotherapy is well known to cause ovarian failure in women with permanent ovarian failure seen in approximately 63–85% of women treated with cyclophosphamide-based regimens and in 50% or greater of women treated with anthracycline containing regimens [8]. Tamoxifen has agonist properties with respect to the estrogen receptor in the vagina, perhaps increasing vaginal moisture and/or discharge [95, 96]. However, it is not clear whether tamoxifen’s influence is enough to adequately compensate for the negative effects of estrogen depletion on the vagina. Based on their mechanism of action, it would be expected that the use of AIs would result in profound symptoms ­associated with vaginal atrophy. Documentation of this, however, is somewhat lacking. Early reports of the longterm side effects in the ATAC trial, for example, report the

prevalence of symptoms of dyspareunia as only 1% on ­anastrozole with a median follow-up of 68  months [97]. Another study looking at the completion of 5 years of ­therapy reports rates of vaginal dryness at 18.5% and ­dyspareunia at 17.3% [98]. One cross-sectional study of 251  women on endocrine therapy for breast cancer noted that 48% reported vaginal dryness, and of those, 46% reported that it was severe or very severe. This was the most common urogenital complaint [99]. Still other reviews cite rates of decreased vaginal lubrication at about 50% on letrozole [100]. This symptom was seen as early as during the first 3 months of treatment.

Physiology Estrogen and estrogen receptors play a major role in vaginal architecture [87]. The vaginal wall contains squamous epithelium, a lamina propria, a smooth muscle layer, and a covering membrane, all of which are very much influenced by estrogen [85]. Estrogen maintains the fluid film that separates the vaginal walls. Estrogen also keeps the epithelium dense, resulting in more superficial cells than basal or parabasal layer cells. Estrogen keeps vaginal smooth muscle functional and contributes to tissue elasticity through the regulation of fibroblasts that make collagen. Additionally, estrogen is responsible for vasodilatation in the lamina propria and promotes the expression of various neurotransmitters that ultimately result in increased blood flow [101]. Without estrogen, the vagina decreases in both size and function and changes occur in the vaginal epithelium. The epithelial cells decrease and parabasal cells become the major cytology. Collagen, blood flow, and lubrication decrease resulting in an inflexible network of dry cells with a higher pH, increased susceptibility to infection, and itchy, uncomfortable sensations. The smooth muscle becomes less functional, challenging orgasm, and intercourse becomes painful with fragile tissues that are subject to bleeding and trauma.

Evidence-Based Treatment Vaginal Versus Systemic Treatment Experts recognize that if the primary symptom is vaginal atrophy (not accompanied by hot flashes, for example), the most efficient way to impact that symptom is to focus on local, vaginal interventions as opposed to a systemic pharmacologic approach [96, 102].

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D.L. Barton and S.L. Wolf

Vaginal Estrogen

Dehydroepiandrosterone

Vaginal estrogen is clearly the recommended effective treatment for vaginal atrophy and several forms are available: rings, tablets, and creams [102]. The product with the lowest dose of estrogen that has been proven effective for the treatment of vaginal estrogen is the ring, with 7.5 mg of estrogen [103–106]. There is believed to be a dose response related to efficacy and related to systemic absorption. Higher doses of vaginal estrogen have been shown in studies to be systemically absorbed sufficiently to alleviate nonlocal symptoms such as hot flashes [104, 107]. However, it should be noted that, to date, there has not been a product that has been shown to be effective for vaginal atrophy that has had no systemic absorption. Data have shown that even with 7.5 mg of vaginal estrogen, there is an increase in systemic concentrations initially, followed by a decrease, but not in all women [108, 109]. In addition, the literature is limited by the fact that in most laboratories, serum estradiol assays do not reliably measure very low concentrations and may therefore miss small increases. Increases in systemic absorption may be insignificant statistically and remain in the postmenopausal range but may have biologic activity at distant target receptors (such as lipids, bones, or breast), some of which may be unwanted and even result in increasing a woman’s risk of cancer or its recurrence [108]. More research is needed regarding the clinical significance of short-term increases in systemic estrogen as well as the impact on distant target tissues with various doses of vaginal estrogen.

Dehydroepiandrosterone (DHEA) is a prohormone, an endogenous hormone produced by the adrenal glands [114]. It has a sulfate ester form (DHEA-S), which is interconvertible with DHEA. Both DHEA and DHEA-S are inactive forms of androgen and must be converted or synthesized to active metabolites [114]. Much of the conversion of DHEA is done in peripheral tissues at target sites [115] and is not diffused into the general circulation. There are target sites for DHEA in the vaginal epithelium [115]. The use of DHEA directly applied to the vagina is an approach that has been studied in detail by one of the foremost experts in female androgen physiology, Ferdinand Labrie, MD, PhD. Vaginal delivery of low-dose DHEA has the potential to improve vaginal health without unwanted systemic effects. A recent phase III, randomized controlled study in 216 women evaluating three doses of vaginal DHEA was recently published in the journal, Menopause [116]. Postmenopausal women were randomized to receive one of three doses of vaginal DHEA by ovule (0.25% – 3.25 mg, 0.5% – 6.5 mg, 1.0% – 13 mg) or placebo for 12 weeks. The primary outcome was the improvement in atrophy symptoms consisting of a decrease in parabasal cells and vaginal pH, increase in superficial cells, and improvement by self-report of the most bothersome symptoms: dryness, itching/irritation, or dyspareunia. All the primary outcome measures were significantly improved, some beginning at 2 weeks into the study [116]. Parabasal cells decreased by 29% in the 0.25% DHEA dose and about 36% with the two higher doses compared to a small increase in parabasal cells in the placebo by the second week. At 12  weeks, the decrease was even more pronounced in all doses of DHEA, while there was no change in the placebo group. Vaginal pH was also improved, showing significant decreases with each dose of DHEA at each data point compared to placebo. Women also reported significant improvements in their most bothersome symptom, be it dyspareunia, vaginal dryness, or itching/irritation and in general, sexual function measures with DHEA [117]. Sex steroid hormone concentrations were not significantly increased and were similar among the placebo arm and the two lower doses of DHEA [118]. This treatment has not been studied in cancer survivors and it is not known how this treatment would impact the vagina if a woman were on AIs. Furthermore, DHEA ovules are not widely available in the USA.

Vaginal Lubricants and Moisturizers Nonhormonal local treatment options include vaginal lubricants and moisturizers. Both of these products can ­provide temporary, symptomatic relief. Randomized trials involving a polycarbophil-based lubricant, Replens, have evaluated its effects comparing it to both dienoestrol cream as well as a placebo water-based lubricant [110–112]. All lubricants were effective in decreasing symptoms of dryness, dyspareunia, itching, and irritation as measured in each study.

Complementary Therapies and Dietary Supplements A phase II trial evaluating a vitamin E product for vaginal dryness was completed. The vaginal gel (containing hyaluronic acid, liposomes, phytoestrogens from Humulus lupulus extract, and vitamin E) was used in 100 menopausal women who reported a reduction in vaginal dryness over the course of a 12-week study [113]. This has not been studied in a controlled randomized trial, however.

Assessment and Evidence-Based Practice In summary, other than vaginal estrogen, there are no proven treatments for vaginal atrophy, but nonhormonal moisturizers

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16  Menopause Symptoms

and lubricants can temporarily relieve dyspareunia or ­discomfort due to dryness. Assessment of vaginal changes and discomfort with accompanying unwanted sexual symptoms should be part of good health care for cancer survivors. statements such as “A decrease in estrogen, as in menopause, can cause changes in the cells in the vagina. Some women report dryness, itching, burning, or pain, particularly with sexual activity. Have you experienced any of those symptoms which have impacted your life in a negative way?” may be helpful in allowing women to vocalize their concerns in this area. Information related to vaginal infections such as  whether the woman has experienced malodorous secretions, burning, and pain on urination should be solicited. Physical inspection of the vagina should be done. An atrophic vagina will have a thin, pale, parched epithelium and it will appear shorter, with a loss of rugae, elasticity, and decreased secretions [87]. Treatment options based on the evidence cited above should be reviewed. Education regarding the regular use of moisturizers or lubricants, increased foreplay to improve blood flow, and the degree to which vaginal symptoms are distressful and/or impact one’s quality of life are part of a comprehensive evaluation. Adequate blood flow is an important factor in enhancing vaginal health. Dyspareunia leading to decreased sexual activity further complicates vaginal health due to lack of blood flow to the vagina. Maintaining at least a modicum of sexual activity is one of the best ways to optimize blood flow and help maintain vaginal health. For women who are deeply bothered by vaginal symptoms or who experience multiple infections, dialog regarding the risks and benefits of very low-dose vaginal estrogen can be initiated. Alternatively, a trial of vaginal DHEA may be warranted.

Conclusions There are very clear sequelae experienced by women related to estrogen depletion. Due to the important role of sex steroid hormones on various tissue receptors throughout the body, a clear understanding of the extent to which estrogen ablation treatment impacts symptoms and broader aspects of quality of life is needed. A fair amount of research is available in the areas of hot flashes and osteoporosis, providing a menu of options in treating and, in the case of bone loss, even preventing these unwanted menopausal symptoms. More research is needed, however, in the area of vaginal atrophy to find effective and safe strategies to prevent and treat the signs and symptoms of this important problem for cancer survivors.

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Part VII

Hematological and Cardiac

Chapter 17

Preserving Cardiac Health in the Breast Cancer Patient Treated with Anthracyclines Neville Davidson

Introduction Globally, the number of women with breast cancer is increasing. It has been reported that each year over 1.2  million women worldwide are diagnosed with breast cancer and 4,45,000 die from the disease [1]. In the UK, the rate of breast cancer diagnoses has more than doubled in the last 25 years [2]. Despite the rising incidence, improvements in detection and the use of increasingly more effective treatments have resulted in breast cancer mortality decreasing by almost 20% in the last 10 years [2]. However, as treatments have become more clinically effective, they have also become more toxic, resulting in short- and long-term complications affecting the quality of life and, potentially, life expectancy of breast cancer survivors. One of the most significant complications is treatment-related cardiotoxicity, such as that associated with anthracyclines, which can manifest as mild, transient changes in cardiac function to potentially lifethreatening congestive heart failure (CHF) [3]. As more and more women are surviving and living with breast cancer, the impact of these complications on patients’ quality of life and their wider health is becoming an increasingly important issue and consideration for oncologists when deciding management. This is especially true for younger breast cancer survivors, who have the potential for significant long-term morbidity related to their cancer therapy [4]. Cardiovascular health has assumed a much greater clinical importance in the management of breast cancer patients, as cardiotoxicity can be a considerable complication both during and after cancer therapy. Both chemotherapy and radiotherapy are known to be cardiotoxic [5]. Anthracyclines, one of the most active and widely used antineoplastic agents, have well-recognised cardiac effects. In addition, several other established and emerging chemotherapies for breast cancer are also known to have potentially important adverse

N. Davidson (*) Department of Oncology Research, Broomfield Hospital, Ground Floor, West Wing 2, Court Road, Chelmsford CM1 7ET, Essex, UK e-mail: [email protected]

effects on the cardiovascular system [5]. These include ­taxanes, alkylating agents (e.g. cisplatin), antimetabolites (e.g. capecitabine), and mitoxantrone, as well as some of the more targeted agents, such as trastuzumab, bevacizumab, and sunitinib [5, 6]. The sequential and concomitant use of these agents, combined with other risk factors, such as age and obesity, may increase cardiovascular vulnerability and ultimately, the risk of premature cardiovascular-associated mortality in patients with breast cancer – a phenomenon labelled the “multiple-hit” hypothesis (Fig.  17.1) [5]. Moreover, the increasing use of combination therapy of two or three different agents has led to the general concern that any therapeutic effect of the combination regimen may be counterbalanced by additive toxicity [7]. In short, cardiotoxicity of cancer therapy has become a pivotal issue. In this chapter, the major aspects of cardiotoxicity arising from anthracycline therapy will be summarised, including discussion of the strategies for preserving cardiac function in patients undergoing treatment for breast cancer.

Breast Cancer Treatment and the Heart The heart is particularly vulnerable to the effects of cancer treatment because normal function and adaptation of the myocardium are tightly controlled by some of the same pathways and receptors targeted by cancer therapies (Fig. 17.2) [8]. If a number of these pathways are disrupted at the same time, there is a potential for myocardial dysfunction. The use of chemotherapeutic agents can cause injury to the cardiovascular system, both at a central level by deteriorating the heart function and in the periphery by enhancing haemodynamic flow alterations and thrombotic events, often latently present in cancer patients [9]. Cardiotoxicity can develop in a subacute, acute, or chronic manner. Acute and subacute cardiotoxicity are characterised either by the occurrence of abnormalities in ventricular repolarisation and electrocardiographic changes, by arrhythmia, or by acute coronary syndromes and pericarditis and/or myocarditis-like syndromes, observed at any time from the initiation

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_17, © Multinational Association for Supportive Care in Cancer Society 2011

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Fig. 17.1  The multiple-hit hypothesis (adapted from ref. [5], copyright 2007, with permission from Elsevier)

Adjuvant Therapy Direct Effects

Baseline cardiovascular risk factors

Breast cancer diagnosis

e.g. chemotherapy, radiotherapy, hormone therapy, HER2-directed therapies, angiogenesis inhibitors

Decreased cardiovascular reserve

Preclinical and clinical CVD

e.g. age, overweight or obese, physical inactivity, diabetes

Indirect effects

Modifiable Lifestyle Risk Factors e.g. reduced physical activity, weight gain

Fig. 17.2  Cardiac adaptation pathway components – many cancer therapies target the same pathways in cancer cells (adapted from ref. [8] with permission from MacMillan Publishers, Ltd, copyright 2006)

of therapy to up to 2 weeks after cessation of treatment [10]. Chronic cardiotoxicity can be differentiated into two subtypes based on the onset of clinical symptoms. The first subtype occurs earlier, usually within 1 year after termination of chemotherapy, and the second occurs more than 1 year after chemotherapy. The most typical manifestation of chronic cardiotoxicity is asymptomatic systolic and/or diastolic left ventricular dysfunction, which can lead to severe congestive cardiomyopathy and may ultimately lead to death [9].

Anthracyclines and Cardiotoxicity Since their introduction in the 1960s, the anthracyclines, doxorubicin and epirubicin, have been considered to be among the most active agents for the treatment of breast cancer and are a mainstay in the management of both early and metastatic disease. Their clinical utility is, however, limited by cumulative, dose-related cardiotoxicity. The cardiotoxicity appears to be distinct from their therapeutic mechanism and has been

17  Preserving Cardiac Health in the Breast Cancer Patient Treated with Anthracyclines

attributed to multiple effects on cardiac myocytes, including apoptosis, alterations in iron homeostasis, deregulation of calcium homeostasis, and mitochondrial dysfunction [11]. The most comprehensively evaluated cardiotoxicity of doxorubicin is cumulative and dose-related progressive myocardial damage leading to clinical events, ranging from an asymptomatic reduction in left ventricular ejection fraction (LVEF) to irreversible life-threatening CHF [3]. Epirubicin is also associated with cardiotoxicity, although on a mg/mg basis is less cardiotoxic than doxorubicin and can therefore, be administered at higher cumulative doses (up to a total of 800–900 mg/m2 vs. a total of 450–550 mg/m2 for doxorubicin before cardiotoxicity limits further therapy). However, to achieve the same clinical benefit as doxorubicin, epirubicin tends to be given at 25–50% higher doses, which potentially negates the advantage of any higher cumulative dose threshold [12]. The cardiac effects of anthracyclines differ fundamentally from those of trastuzumab. Anthracycline-associated abnormalities and their related cardiac insult represent an irreversible form of chemotherapy-related cardiac dysfunction (CRCD), referred to as type I CRCD [13]. By comparison, type II CRCD characterised by trastuzumab toxicity is not dose-related, does not appear to occur in all patients, and is not associated with any significant ultrastructural abnormalities. Furthermore, type II CRCD appears to be reversible, with a high likelihood of recovery, whereas, type I is not [13].

Risk Factors for Anthracycline Cardiotoxicity

Treatment-Related Risk Factors There is a direct relationship between the cumulative anthracycline dose and the occurrence of heart failure (Fig.  17.3) [14–16]. Generally, cumulative doses of doxorubicin greater than 450 mg/m2 are associated with a greater risk of cardiac injury [15]. The incidence of doxorubicin-induced heart failure is approximately 3% at a cumulative dose of 400 mg/m,2 7% at 550 mg/m2, and 18% at 700 mg/m2 [14, 15]. The recommended maximum lifetime cumulative dose of doxorubicin is 450–550 mg/m2, a limit set to reduce the risk of early heart failure. For epirubicin, the probability of developing heart failure increases substantially after a cumulative dose of 800– 900 mg/m2 [16]. Each dose of anthracycline appears to result in the death of cardiac myocytes. Although the heart has welldeveloped compensatory mechanisms, when these are overwhelmed, chronic-dilated cardiomyopathy develops [17]. In addition to total cumulative dose, the incidence of acute and chronic cardiotoxicity may depend on the rate of anthracycline administration during each session and on the schedule of delivery. There is evidence to suggest that continuous infusions of doxorubicin between 48 and 96 h duration can reduce cardiotoxicity, without compromising therapeutic efficacy [18]. Furthermore, a significantly lower rate of CHF has been reported with an anthracycline infusion duration of 6  h or longer as compared with a shorter infusion time (P = 0.001) [19]. Weekly doses of anthracyclines also appear to be associated with significantly less cardiotoxicity than

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dysfunction, long-term hypertension, concurrent cardiotoxic therapies, and prior radiation therapy all confer an increased risk of cardiotoxicity. Hence, a greater understanding of these factors and the implementation of strategies aimed at ameliorating any potential insults and/or improving cardiac health and vigour may help to reduce the occurrence and severity of the cardiovascular effects of anthracycline therapy.

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Several risk factors for anthracycline-induced cardiotoxicity appear to be involved in the development of clinical and subclinical cardiotoxic effects. Patients should be screened for risk factors before, during, and after treatment, and an attempt to modify them should be made. The best and most significant predictor of cardiotoxicity is the total cumulative dose of anthracycline [14, 15]. Advancing age, preexisting cardiac

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Fig. 17.4  Cumulative probability of developing doxorubicin-induced CHF stratified by age (data from ref. [14])

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when the drug is administered in the conventional three weekly schedule (P = 0.002) [20]. Additional risk factors include the combination of cardiotoxic agents given and the sequence of their administration, as both can exacerbate anthracycline-associated cardiac damage. Radiation therapy to the thorax may induce both early and late effects, if parts of the heart have been included in the irradiation field [21]. However, although it has been shown that anthracycline-associated cardiac damage may become clinically more evident in patients who have already received injury from radiotherapy [22], the development of new radiotherapy techniques has resulted in reduced radiation exposure to the heart in most patients. Despite showing very promising efficacy, the synergistic effects of anthracyclines and trastuzumab on cardiac dysfunction have restricted the use of this combination and are very well documented. In one of the early, pivotal studies, New York Heart Association (NYHA) III/IV heart failure was observed in 16% of patients treated with combined anthracycline/trastuzumab, compared with only 3% in those treated with anthracycline and cyclophosphamide [23]. The combination of anthracyclines with taxanes has also been associated with increased cardiotoxicity, although this finding is less clear-cut [24, 25]. Anthracyclines are typically given before paclitaxel, since the opposite sequence results in higher plasma levels of anthracycline [26].

15, 27]. Retrospective analyses [14, 15] have shown that the risk of developing doxorubicin-induced CHF is significantly associated with increasing age (Fig.  17.4). Similarly, in a prospective study of 120 patients with advanced breast cancer treated with epirubicin (cumulative dose 1,000 mg/m2), those aged >50 years had a 68% actuarial risk of developing a severe (>25% decline in LVEF from baseline) reduction in cardiac function compared with 36% for those <50 years of age (P < 0.001) [27]. Other major cardiac risk factors, such as hypertension, diabetes, smoking, and obesity, have also been associated with an increased probability of developing an anthracyclineinduced cardiac event [12, 15, 28, 29]. Early work by Von Hoff et al. [15] suggested that the risk of developing doxorubicin-induced CHF was elevated in patients with previous cardiac disease or hypertension or both. The evidence for obesity increasing cardiotoxic susceptibility is even more compelling. Weight ³70 kg has been identified as a significant predictive factor for doxorubicin cardiotoxicity in patients with metastatic breast cancer [28]. Furthermore, an elevated body mass index (BMI) >27 kg/m2 has been found to significantly correlate with declines in LVEF in patients with early breast cancer treated with epirubicin-based chemotherapy [29]. Overweight or obese patients will also receive proportionally larger doses of anthracyclines compared with average weight patients (on an mg/m2 basis), which may compound their overall risk of acute and long-term cardiac complications [12].

Patient-Related Risk Factors Many women with breast cancer may have preexisting cardiovascular disease and cardiac risk factors, which can increase the chances of experiencing a treatment-related cardiac event. Advancing age, in particular, appears a strong risk factor for anthracycline-induced cardiomyopathy [14,

Strategies for Preserving Cardiac Function There are various management strategies that can be employed to reduce and minimise the risk of anthracyclineassociated cardiotoxicity, many of which have recently been

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17  Preserving Cardiac Health in the Breast Cancer Patient Treated with Anthracyclines

reviewed and critically apprised by Barrett-Lee et  al. [12]. Strategies can be as simple as screening patients for cardiac risk factors and encouraging simple lifestyle changes, such as increased activity and exercise, to instituting detailed cardiac monitoring and therapy modifications; for example, the use of ACE inhibitors to treat preexisting cardiac dysfunction and/or using a less cardiotoxic form of anthracycline, such as liposomal doxorubicin. These management decisions should form part of the individualised treatment plan, with the costbenefit balance of maximising breast cancer outcome and survival while minimising any short- and long-term treatmentassociated complications discussed and agreed with the patient. It is important that all patients are screened for preexisting cardiovascular disease and cardiac risk factors so that the necessary remedial steps can be taken.

Lifestyle Modifications All women with breast cancer, regardless of their risk of treatment-related cardiovascular complications, should be encouraged and supported to make lifestyle modifications aimed at improving and maintaining their overall health. Exercising, weight loss, and other simple measures, such as an improved diet and stopping smoking, should always be recommended. Many women put on weight following their

diagnosis with breast cancer, often linked to adopting a more sedentary lifestyle [30], which can potentially exacerbate any preexisting cardiovascular conditions and risk factors and the adverse cardiac impact of antineoplastic treatment.

Cardiac Monitoring Routine monitoring of patients’ cardiac function before, during, and after chemotherapy may help to optimise management and allow early intervention if a clinically significant decline or abnormality is detected. There are a number of techniques available for monitoring cardiac function (Table  17.1) [12], with the evaluation of LVEF being the most widely used option for assessing anthracycline cardiotoxicity [31]. Echocardiography and radionuclide ventriculography [multiple uptake gated acquisition (MUGA) scan] are both well-established and validated methods of measuring LVEF. Echocardiography has the advantage over radionuclide ventriculography of not involving ionising radiation and providing a wider spectrum of information on cardiac morphology and function [32]. However, one potential issue with measuring LVEF is that there is currently no clear consensus on what degree of fall in LVEF represents a clinically significant decline in cardiac function. As a guideline, several studies have used a drop in LVEF of >10 points or a fall below

Table 17.1  Methods of monitoring anthracycline-associated cardiotoxicity Method Benefits Endomyocardial biopsy

Provides histological evidence of cardiotoxicity

Radionuclide ventriculography

Well-established and well-validated method to determine ejection fraction Can also assess regional wall motion and diastolic function Provides a wide spectrum of information on cardiac morphology and function Does not expose patients to ionising radiation Reliably diagnoses left ventricular systolic and diastolic dysfunction More reliable than conventional Doppler Cardiac abnormalities that remain occult at rest can be detected

Echocardiography

Tissue Doppler imaging Stress testing

Biomarkers

MRI

Troponin is a highly specific and sensitive biomarker for the detection of myocardial damage Potentially useful screening tool Valuable tool to assess myocardial function and damage

CT

Image quality better than MRI

Scintigraphy

Sensitive method to detect myocyte damage in patients after doxorubicin therapy MRI magnetic resonance imaging, CT computed tomography Adapted from [12] with permission from Oxford University Press

Limitations Invasive Requires specialist input for performing the procedure and interpreting the findings Invasive – exposes patients to radiation which limits its repeatability Observer dependence LVEF measurements are not sensitive for the early detection of preclinical cardiac disease Both FS and LVEF depend on preload and afterload Data analysis can be time consuming

Not routinely performed Mixed reports on ability to enhance diagnostic sensitivity Data regarding clinical value are limited

High costs of repeated examinations Limited availability High radiation dose Limited availability Larger prospective trials required to ascertain potential role

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the institutional lower limit of normal (60%) as indicative of anthracycline-associated cardiotoxicity [33–35]. The use of biomarkers, such as troponins and natriuretic peptides, might provide more detailed and useful information, particularly on early cardiac damage caused by anthracyclines [36, 37]; however, the use of such methods is still in its infancy.

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Liposomal Anthracyclines

An important step forward in reducing anthracycline-induced cardiotoxicity was accomplished by encapsulating the drug within a liposome. This significantly reduces its distribution volume, diminishing its diffusion in the body and consequently the toxicity for healthy tissues such as the heart, while increasing the accumulation of active drug at tumour sites [43]. There are two formulations of liposomal doxoruTherapeutic Modifications and Interventions bicin: non-pegylated and pegylated. Several clinical studies have shown them to have similar efficacy but less cardiac toxicity when compared with conventional doxorubicin as ACE Inhibitors and Beta-Blockers first-line treatment for metastatic breast cancer (Table 17.2) For patients at a heightened risk of cardiovascular dysfunc- [33–35, 44, 45]. In a phase III trial of 509 women with metastatic breast tion, it may be appropriate to treat them with ACE inhibitors and/or beta-blockers in order to prevent adverse cardiovascu- cancer, pegylated liposomal doxorubicin had comparable lar events associated with anthracycline treatment [12]. efficacy [median progression-free survival (PFS) 6.9 vs. 7.8 Preliminary evidence suggests that pretreatment with such months; hazard ratio (HR) 1.00] but significantly reduced agents can reduce or even prevent the fall in LVEF seen with cardiotoxicity compared with conventional doxorubicin (4% high-dose chemotherapy [38, 39]. Heart rate or rhythm-­ vs. 19%; P < 0.001) [34]. Furthermore, there was less risk of modifying drugs, antithrombotic agents and ACE inhibitors developing cardiotoxicity with pegylated liposomal doxorushould also be used to treat acute and long-term cardiac com- bicin than with doxorubicin in all subgroups analysed, plications of treatment, such as atrial fibrillation, pericarditis, including those subgroups at increased cardiac risk (>65 and CHF [11, 12]. However, it is important to remember that years of age, prior adjuvant anthracycline, cardiac risk facACE inhibitors and beta-blockers do not prevent anthracy- tors) [34]. However, pegylated liposomal doxorubicin was cline-induced myocyte apoptosis, but simply improve the associated with a higher incidence of palmar-plantar erythrodysesthesia (PPE; hand-foot syndrome) than conventional heart’s compensatory mechanisms [40]. doxorubicin (48% vs. 2%, respectively) [34]. Non-pegylated liposomal doxorubicin has also been demonstrated to have similar efficacy and be significantly less Dose Limitation and Schedule Modification cardiotoxic than conventional doxorubicin, in both anthracyTo minimise the risk of cardiotoxicity and CHF, the recom- cline-naïve patients and those who have received prior adjumended cumulative dose thresholds for doxorubicin and epi- vant anthracycline therapy [33, 35, 44]. In two prospective, rubicin are set at <550 mg/m2 and <900 mg/mg2, respectively. phase III trials involving a combined 521 patients, the effiThere is also evidence that reducing exposure to peak levels of cacy of non-pegylated liposomal doxorubicin was found to be anthracyclines may help to reduce cardiotoxicity [19, 41]. equivalent to conventional doxorubicin (response rate: 26% Using prolonged infusions over several hours rather than bolus both groups [33]; 43% both groups [35]), while the incidence injections of anthracyclines has been shown to be less cardio- of cardiac events was significantly reduced (13% vs. 29%, toxic [19], although is not widely recommended due to the P = 0.0001 [33]; 6% vs. 21%, P = 0.0002 [35]). Non-pegylated increased risk of extravasation/tissue necrosis and infections liposomal doxorubicin was also administered at a significantly greater cumulative dose than conventional doxorubicin and greater level of nursing time involved [12]. before signs of cardiotoxicity were observed (median 785 vs. 570 mg/m2 [33]; >2,220 vs. 480 mg/m2 [35]). In a subanalysis of the two studies, a significantly higher overall response rate Iron-Chelating Agents (31 vs. 11%, P = 0.04) and significantly longer time to treatUse of the iron-chelating agent dexrazoxane with doxorubi- ment failure (median 5.7 vs. 4.4 months, P = 0.007) was seen cin can prevent acute cardiotoxicity and heart damage (rela- for non-pegylated liposomal doxorubicin over conventional tive risk for CHF = 0.29, 95% confidence interval [CI] doxorubicin in those patients who had previously received 0.20–0.14, P < 0.00001, in favour of dexrazoxane over con- anthracyclines for early breast cancer [44]. Findings from a trol) [42]. However, it may also result in reduced efficacy meta-analysis that compared non-pegylated liposomal doxo(relative risk for response rate 0.89, 95% CI 0.78–1.02, rubicin with conventional doxorubicin also showed a statistiP = 0.08, in favour of control) [42] and increase the overall cally significant lower rate of clinical (relative risk 0.20, 95% CI 0.05–0.75; P = 0.02) and clinical and subclinical (relative cost of treatment, so is not commonly used.

Multicentre, phase III trial

O’Brien et al. [34]

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n PLD 50 mg/m2 (every 4 weeks) or doxorubicin 60 mg/m2 (every 3 weeks)

Regimen

Efficacy (PLD/NPLD vs. A)

Cardiotoxicitya (PLD/NPLD vs. A)

PFS: 6.9 months vs. 7.8 months; HR = 1.00 (95% CI 4% vs. 19%; HR = 3.16; 0.82–1.22) P < 0.001 RR: 33% vs. 38% OS: 21 months vs. 22 months; HR = 0.94 (95% CI 0.74–1.19) 13% vs. 29%; P = 0.0001 Harris et al. [33] Multicentre, phase III trial 224 NPLD 75 mg/m2 or doxorubicin 75 mg/m2 RR: 26% vs. 26% (both every 3 weeks) TTP: 3.8 months vs. 4.3 months; HR = 0.92 (95% CI 0.66–1.26); P = 0.59 TTF: 3.7 months vs. 3.4 months; HR = 1.21 (95% CI 0.90–1.63); P = 0.21 OS: 16 months vs. 20 months; HR = 0.76 (95% CI 0.56–1.04); P = 0.09 6% vs. 21%; P = 0.0002 Batist et al. [35] Multicentre, phase III trial 297 NPLD 60 mg/m2 or doxorubicin 60 mg/m2 RR: 43% vs. 43% both plus cyclophosphamide 600 mg/m2 TTP: 5.1 months vs. 5.5 months; HR = 1.03 (95% CI (every 3 weeks) 0.80–1.33); P = 0.82 TTF: 4.6 months vs. 4.4 months; HR = 1.14 (95% CI 0.89–1.47); P = 0.30 OS: 19 months vs. 16 months; HR = 1.04 (95% CI 0.77–1.42); P = 0.79 22% vs. 39%; HR = 5.42 68 As per Harris et al. and Batist et al. [33, 35] RR: 31% vs. 11%; OR = 4.0; P = 0.04 Batist et al. [44] Retrospective analysis of (95% CI 1.84–16.0); phase III trials [33, 35] TTP: 4.5 months vs. 3.4 months; HR = 1.14 (95% CI P = 0.001 0.63–2.04); P = 0.66 TTF: 4.2 months vs. 2.1 months; HR = 2.06 (95% CI 1.18–3.61); P = 0.01 OS: 16 months vs. 15 months; HR = 1.12 (95% CI 0.63–1.98); P = 0.71 Chan et al. [45] Multicentre, phase III trial 160 NPLD 75 mg/m2 or epirubicin 75 mg/m2 12% vs. 10% RR: 46% vs. 39%; P = 0.42 both plus cyclophosphamide 600 mg/m2 TTP: 7.7 months vs. 5.6 months; HR = 1.52 (95% CI (every 3 weeks) 1.06–2.20); P = 0.022 TTF: 5.7 months vs. 4.4 months; HR = 1.64 (95% CI 1.14–2.35); P = 0.007 OS: 18.3 months vs. 16.0 months; HR = 1.15 (95% CI 0.77–1.72); P = 0.504 PLD pegylated liposomal doxorubicin, NPLD non-pegylated liposomal doxorubicin, A doxorubicin/epirubicin, PFS progression-free survival, RR response rate, OS overall survival, TTP time to progression, TTF time to treatment failure, HR hazard ratio, CI confidence interval a Defined by LVEF

Design

Study

Table 17.2  Summary of key trials involving liposomal anthracyclines in metastatic breast cancer

17  Preserving Cardiac Health in the Breast Cancer Patient Treated with Anthracyclines 167

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risk 0.38, 95% CI 0.24–0.59; P = 0.00001) heart failure with non-pegylated liposomal doxorubicin [46]. In addition, nonpegylated liposomal doxorubicin was associated with significantly less grade 3 or 4 diarrhoea and nausea/vomiting and less grade 4 neutropenia than conventional doxorubicin [46]. PPE occurred in <0.5% of patients in the two phase III trials [33, 35]. Non-pegylated liposomal doxorubicin has also been compared with epirubicin in a phase III study involving 160 patients with metastatic breast cancer [45]. Non-pegylated liposomal doxorubicin and epirubicin were found to have a similar low level of cardiotoxicity (12 vs. 10%, respectively), but, interestingly, non-pegylated liposomal doxorubicin appeared to have advantages for some efficacy endpoints, including time to progression (7.7 vs. 5.6 months, P = 0.022) and time to treatment failure (5.7 vs. 4.4 months, P = 0.007) [45]. The improved cardiotoxicity profile and equivalent efficacy of liposomal doxorubicins over conventional doxorubicin suggests that they are an important option for patients with metastatic breast cancer being considered for anthracycline treatment, particularly for those patients at increased cardiac risk. There is also exciting evidence emerging that combining liposomal doxorubicin with trastuzumab in patients with metastatic breast cancer results in good efficacy and a low incidence of cardiotoxicity [47, 48]. The benefits of liposomal doxorubicin would be particularly manifest in patients with early breast cancer who have longer life expectancy, by reducing the potential for short- and long-term cardiac events and also by extending therapeutic options by preserving cardiac function; however, there are currently limited data on the use of these agents as primary or adjuvant therapy. In a phase II trial by Schmid et al. [49] of 44 patients with early breast cancer, the combined regimen of non-pegylated liposomal doxorubicin (60 mg/m2), docetaxel (75 mg/m2), and gemcitabine (350 mg/m2) as primary chemotherapy resulted in a clinical response rate of 80%, with complete remissions of the primary tumour occurring in 25% of patients49. Unpublished audit data from our hospital (Broomfield Hospital, Chelmsford, UK) indicate that there is no detectable change in cardiac function when patients are given non-pegylated liposomal doxorubicin as primary or adjuvant therapy. These preliminary data highlight the potential for using a liposomal preparation in early breast cancer, but larger prospective studies are required to confirm these promising findings.

Summary Cardiotoxicity is becoming an increasingly important consideration in the management of patients with breast cancer. Increased knowledge and understanding of the mechanisms of cardiotoxicity and the risk factors that make certain

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patients particularly vulnerable to cardiac dysfunction will allow for individualised treatment and monitoring both during and after therapy and improved outcomes. Specific recommendations for the prevention and management of anthracycline-induced cardiotoxicity include [12]: −− Vigilant screening for both patient- and treatment-related cardiovascular risk factors. −− Proactive treatment of modifiable risk factors (e.g. stopping smoking, use of ACE inhibitors for hypertension). −− Accurate monitoring of patient cardiac function, before, during, and after anthracycline treatment. −− Limiting lifetime cumulative anthracycline dose. −− Choosing an alternative to anthracycline treatment or using a liposomal preparation.

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17  Preserving Cardiac Health in the Breast Cancer Patient Treated with Anthracyclines 16. Ryberg M, Nielsen D, Skovsgaard T, et al. Epirubicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer. J Clin Oncol 1998;16:3502–3508. 17. Ewer MS, Martin FJ, Henderson IC, et al. Cardiac safety of liposomal anthracyclines. Semin Oncol 2004;31(Suppl 13):161–181. 18. Legha SS, Benjamin RS, Mackay B, et al. Reduction of doxorubicin cardiotoxicity by prolonged continuous infusion. Ann Intern Med 1982;96:133–139. 19. van Dalen EC, van der Pal HJ, Caron HN, et al. Different dosage schedules for reducing cardiotoxicity in cancer patients receiving anthracycline chemotherapy. Cochrane Database Syst Rev 2006;4: CD005008. 20. Torti FM, Bristow MR, Howes AE, et al. Reduced cardiotoxicity of doxorubicin delivered on a weekly schedule: assessment by endomyocardial biopsy. Ann Intern Med 1983;99:745–749. 21. Goethals I, De Winter O, De Bondt P, et  al. The clinical value of nuclear medicine in the assessment of irradiation-induced and anthracycline-associated cardiac damage. Ann Oncol 2002;13:1331–1339. 22. Hooning MJ, Botma A, Aleman BM, et al. Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst 2007;99:365–375. 23. Slamon DJ, Leylan-Jones B, Shak S, et  al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–792. 24. Biganzoli L, Cufer T, Bruning P, et  al. Doxorubicin-paclitaxel: a safe regimen in terms of cardiotoxicity in metastatic breast carcinoma patients. Results from a European Organization for Research and Treatment of Cancer multicentre trial. Cancer 2003;97:40–45. 25. Gianni L, Dombernowsky P, Sledge G, et al. Cardiac function following combination therapy with paclitaxel and doxorubicin: an analysis of 657 women with advanced breast cancer. Ann Oncol 2001;12:1067–1073. 26. Holmes FA, Madden T, Newman RA, et  al. Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer. J Clin Oncol 1996;14:2713–2721. 27. Jensen BV, Skovsgaard T, Nielsen SL. Functional monitoring of anthracycline cardiotoxicity: a prospective, blinded, long-term observational study of outcome in 120 patients. Ann Oncol 2002;13: 699–709. 28. Dranitsaris G, Rayson D, Vincent M, et al. The development of a predictive model to estimate cardiotoxic risk for patients with metastatic breast cancer receiving anthracyclines. Breast Cancer Res Treat 2008;107:443–450. 29. Fumoleau P, Roche H, Kerbrat P, et al. Long-term cardiac toxicity after adjuvant epirubicin-based chemotherapy in early breast cancer: French Adjuvant Study Group results. Ann Oncol 2006;17:85–92. 30. Goodwin PJ. Weight gain in early-stage breast cancer: where do we go from here? J Clin Oncol 2001;19:2367–2369. 31. Ng R, Better N, Green MD. Anticancer agents and cardiotoxicity. Semin Oncol 2006;33:2–14. 32. Jurcut R, Wildiers H, Ganame J, et al. Detection and monitoring of cardiotoxicity – what does modern cardiology offer? Support Care Cancer 2008;16:437–445. 33. Harris L, Batist G, Belt R, et al; for the TLC D-99 Study Group. Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer 2002;94:25–36. 34. O’Brien ME, Wigler N, Inbar M, et  al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal

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doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 2004;15:440–449. 35. Batist G, Ramakrishnan G, Rao CS, et al. Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J Clin Oncol 2001;19:1444–1454. 36. Dodos F, Halbsguth T, Erdmann E, et al. Usefulness of myocardial performance index and biochemical markers for early detection of anthracycline-induced cardiotoxicity in adults. Clin Res Cardiol 2008;97:318–326. 37. Ewer MS, Lenihan DJ. Left ventricular ejection fraction and cardiotoxicity: is our ear really to the ground? J Clin Oncol 2008;26:1–3. 38. Cardinale D, Colombo A, Sandri MT, et  al. Prevention of highdose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 2006;114: 2474–2481. 39. Silber JH, Cnaan A, Clark BJ, et  al. Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines. J Clin Oncol 2004;22:820–828. 40. López-Sendón J, Swedberg K, McMurray J, et al. Expert consensus document on angiotensin converting enzyme inhibitors in cardiovascular disease. The Task Force on ACE-inhibitors of the European Society of Cardiology. Eur Heart J 2004;25:1454–1470. 41. Chanan-Khan A, Srinivasan S, Czuczman MS. Prevention and management of cardiotoxicity from antineoplastic therapy. J Support Oncol 2004;2:251–266. 42. van Dalen EC, Caron HN, Dickinson HO, et al. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev 2008;2:CD003917. 43. Giotta F, Lorusso V, Maiello E, et al. Liposomal-encapsulated doxorubicin plus cyclophosphamide as first-line therapy in metastatic breast cancer: a phase II multicentric study. Ann Oncol 2007;18(Suppl 6):vi66–vi69. 44. Batist G, Harris L, Azarnia N, et al. Improved anti-tumour response rate with decreased cardiotoxicity of non-pegylated liposomal doxorubicin compared with conventional doxorubicin in first-line treatment of metastatic breast cancer in patients who had received prior adjuvant doxorubicin: results of a retrospective analysis. Anticancer Drugs 2006;17:587–595. 45. Chan S, Davidson N, Juozaityte E, et  al; on behalf of the Myocet Study Group. Phase III trial of liposomal doxorubicin and cyclophosphamide compared with epirubicin and cyclophosphamide as firstline therapy for metastatic breast cancer. Ann Oncol 2004;15: 1527–1534. 46. van Dalen EC, Michiels EM, Caron HN, Kremer LC. Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database Syst Rev 2006;4:CD005006. 47. Chia S, Clemons M, Martin LA, et al. Pegylated liposomal doxorubicin and trastuzumab in HER-2 overexpressing metastatic breast cancer: a multicenter phase II trial. J Clin Oncol 2006;24:2773–2778. 48. Cortes J, Di Cosimo S, Climent MA, et al. Nonpegylated liposomal doxorubicin (TLC-D99), paclitaxel, and trastuzumab in HER-2overexpressing breast cancer: a multicenter phase I/II study. Clin Cancer Res 2009;15:307–314. 49. Schmid P, Krocker J, Jehn C, et  al. Primary chemotherapy with gemcitabine as prolonged infusion, non-pegylated liposomal doxorubicin and docetaxel in patients with early breast cancer: final results of a phase II trial. Ann Oncol 2005;16:1624–1631.

Chapter 18

Thrombosis and Bleeding in Cancer Patients Wolfgang Korte

Introduction The writings of Virchow in 1856 opened the way to the understanding of the pathogenesis of thrombosis [1]. It is well known that hypercoagulability is a frequent phenomenon in cancer patients. Published knowledge dates back to Trousseau, who described a tendency to “spontaneous coagulation” in two patients with phlegmasia alba dolens and gastric cancer [2]. Since these observations, much progress has been made and it is now clear that activation of blood coagulation is not only a result of the presence of malignant cells but also a part of the malignant process [3]. In general, this leads to an overall procoagulant situation in cancer patients. However, cancer patients are also prone to a bleeding diathesis during interventions or when a DIC occurs. This chapter will review the important issues of thrombosis and bleeding in cancer patients.

Epidemiology of Hypercoagulability in Cancer Patients There is ample evidence that cancer patients frequently show increased biochemical markers of coagulation activation such as increased prothrombin activation (increased prothrombin fragment 1 + 2, increased thrombin–antithrombin complex); increased generation of soluble fibrin (increased fibrinopeptide A and B); as well as increased fibrinogen and fibrin degradation (fibrin degradation products, d-dimer) [4]. Markers of coagulation activation prove the increased procoagulant potential in cancer patients; some markers, such as fibrin monomer, have been shown to be associated with ­survival [5]. Other markers have also been found to be W. Korte (*) Institute for Clinical Chemistry and Hematology, Kantonsspital St. Gallen, St. Gallen and University of Bern, Bern, Switzerland e-mail: [email protected]

p­ rognostic for progression of disease and survival in solid tumors including lung and ovarian cancer [6]. Depending on the type of cancer and the state of the disease, increased surrogate markers of coagulation activation can be found in up to 90% of patients. However, one has to recognize that markers of coagulation activation make part of a dynamic phenomenon: even largely increased markers of coagulation activation are not necessarily associated with the occurrence of a thromboembolic event, although the risk increases with increasing activation marker concentrations [7]. On the other hand, cancer patients have a high prevalence of clinically silent thrombi, as can be deducted from the fact that cancer patients have a high prevalence of thrombi that are detected at autopsy only [8]. Venous thromboembolism (VTE) that is cancer associated can precede a cancer diagnosis. The highest risks for VTE before a cancer diagnosis is made are found in acute myelogenous leukemia (AML), non-Hodgkin-lymphoma (NHL), renal, ovarian, and pancreatic cancer (approximately threeto fourfold increased risk); the overall risk to develop a VTE as a sign of (the still undetected) cancer is approximately 1.3 [9]. In the first year after a cancer diagnosis is made, the greatest risks for being diagnosed with cancer are found for lymphoma (approximately fivefold) and ovarian cancer (approximately sevenfold) [10]. Prospective studies have confirmed the association between overt malignancy and VTE. A prospective case control study of 3,220 patients with VTE revealed an overall sevenfold increased risk in patients with cancers. Hematologic malignancies had the highest risk (OR 28), whereas solid tumors had ORs from 2 to >20 [11]. This increased risk for VTE in patients with lymphoma, leukemia, and plasma cell dyscrasias was also established in other studies [12]. Beside the fact that the tumor itself is able to induce (mainly) procoagulant changes, such changes are also found in relationship to cancer treatment. In a US study, 8% of 66,000 (neutropenic) cancer patients hospitalized were found to develop thromboembolic events [13]. The highest incidence for VTE was found in leukemias and lymphomas, pancreas, brain, endometrial, or cervical cancer; on the other hand, arterial thrombosis was most commonly seen in hematological

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malignancies, prostate, lung, and bladder cancer [14]. These observations are well in line with those in other patient cohorts with an incidence of VTE of 7% within 3 months after chemotherapy and an annual incidence of 11% [15]. VTE is a significant predictor of 2-year mortality in breast cancer patients with the greatest effect in patients with local or regional stage (hazard ratio 3.5–5) breast cancer [16]. These and similar observations [9] suggest that survival is worse the closer VTE and cancer diagnosis come together. This might be due to a more advanced cancer stage in such situations.

Pathogenesis of Thromboembolism in Cancer Patients According to Virchow, the main influences leading to the occurrence of a thrombosis are believed to be blood flow, vessel integrity, and composition of the blood [1]. Aberrant blood flow is frequently observed in situations associated with hyperviscosity, which can derive from both fluid and cellular blood components. As perfusion problems due to hyperviscosity frequently occur in small vessels first, it is easy to understand from a mechanistic point of view that the brain, the heart, the lungs, and the kidneys are frequently affected, with the resulting clinical manifestations. Laboratory tests for hyperviscosity are infrequently performed. Therefore, the recognition of hyperviscosity is usually from other laboratory data in conjunction with the clinical suspicion for this picture: for example, increased monoclonal proteins in multiple myeloma. These can affect flow characteristics via several mechanisms [17]. As hyperviscosity is also a function of the size of the molecules involved, it is most common with IgM paraproteins. Other (rare) reasons for hyperviscosity can be light chain disease as well as cryofibrinogenemia and cryoglobulinemia. Fibrinogen can significantly influence blood viscosity, and cancer patients are well known to frequently show increased fibrinogen levels [18]. Further important reasons for hyperviscosity are massively increased cell counts [19]. A high hematocrit can convey hyperviscosity, as can be deduced from the thromboembolic risk that is well documented for Polycythemia vera (P. vera) patients; thromboembolism is the most frequent cause of death in P. vera [20]. But other factors might also play an important role. These seem to include platelet activation, as thromboxane formation is increased in P. vera [21]. The recently identified JAK-2 (V617F) mutation, found in both P. vera and essential thrombocythemia, seems to confer an increased risk [22]: the incidence of thromboembolism seems to be dependent on the number of alleles affected but the exact mechanism remains to be elucidated.

W. Korte

Leukostasis can occur within the microcirculation of the central nervous and respiratory system when hyperleukocytosis is present. Although it can occur in chronic leukemias, especially chronic myeloid leukemia, it is rather found in AML variants with increased blast adhesiveness [23]. Leukostasis is much less frequently seen in lymphoid leukemias: lymphocytes are smaller and seem to have a lower adherence to vasculature. Different from myeloid leukemias, leukostasis in lymphoid leukemia might need additional risk factors such as a concurrent infection to upregulate adhesive cell surface molecules in order to precipitate clinical symptoms. Thrombocytosis is associated with an increased risk for VTE in cancer patients as well: patients with a platelet count >350 G/l have a significantly increased risk [24]. As most solid tumors or affected lymph nodes grow expansively at some point in time, vessel compression is a further potential reason for the occurrence of VTE in cancer patients. However, the classical example for this situation, the superior vena cava syndrome (SVCS), is probably much rarer than perceived. In a large retrospective cohort of more than 34,000 patients, only six had SVC thrombosis and most had to be attributed to central lines [25]. Any vein might be subject to external compression thus causing VTE [26]. Cancer patients are often immobilized or have to undergo surgery; both situations result in the impairment of the regular circulation, thus inducing a “double risk” in various types of cancer. This risk is severe, as was seen in a prospective cohort where up to 50% of the deaths early after cancer surgery were due to VTE [27]. As already mentioned above, direct tumor-associated vessel impairment increases the risk for VTE. Beside outside vessel compression, direct tumor cell invasion of the vessel wall might result in increased risk for VTE, probably due to breach of the (primarily anticoagulant) endothelium and the production of prothrombotic factors by the tumor cells themselves. Besides, the tumor itself might present as an intravascular mass that induces additional adjacent accumulation of blood cells and fibrin. This phenomenon might explain the reduced survival in hepatocellular carcinoma with portal vein tumor thrombi (3-year survival 20% with vs. 56% without [28]), with the extent of the portal vein thrombus likely also being important [29]. Other tumor entities have been found to show similar phenomena. Emboli directly deriving from tumors are rare but do occur, most frequently in gastrointestinal cancers [30]. It is well known that the procoagulant phenotype in cancer is at least partially related to cytokine trafficking from cancer cells, endothelial cells, and peripheral blood cells [31]. This can lead to tissue factor (TF) (over) expression (e.g., on monocytes), upregulation of procoagulants, downregulation of anticoagulants, platelet activation or neovascularization through proangiogenic signaling. Neutrophils can activate platelets via cathepsins, can produce elastase to degrade the

18  Thrombosis and Bleeding in Cancer Patients

endothelium, can expose thrombogenic subendothelium [32], and can bind to platelets via various mechanisms [33]. Tumor cells produce several factors that induce the prothrombotic state in cancer. TF is increased in patients with DVT [34], especially in leukemia and lymphoma [35]. On the other hand, increased profibrinolytic activity might be encountered in leukemic patients [36]. PAI-1 levels are frequently increased in cancer patients, which is associated with an increased risk for VTE in both cancer and noncancer patients [37]. Apoptosis of (tumor) cells results in a prothrombotic state as observed with different malignant and benign cell lines; thrombin generation seems to parallel the degree of apoptosis [38], resulting in an increased prothrombotic risk. This offers a mechanistic explanation for the hypercoagulability observed in the tumor lysis syndrome as well as the increased risk of VTE during therapy. Very small membrane fragments are known as microparticles (MP); they derive from normal cells (platelets, blood cells, or endothelial cells) but can also be derived from malignant cells. MP carry TF and may – through the provision of phospholipids – be involved in facilitation of complex formation and thus increased thrombin generation. Recent clinical studies have shown MP to be increased in cancer patients with different tumors [39]. Cancer patients can acquire a resistance against activated protein C (APC resistance) [40], but it remains to be elucidated whether this form of APC resistance is per se also associated with a higher incidence of thromboembolism. The antiphospholipid syndrome (APS) is characterized by thromboembolism and the presence of antiphospholipid antibodies (APA; by definition against cardiolipin or b-2 glycoprotein I or a lupus anticoagulant; to fulfill the diagnostic criteria for APS, the antibodies have to be found in two separate investigations at least 8 weeks apart). In a study of lymphoma patients, 27% showed APA [41]; with a follow up of more than 6 years, the annual rate of thrombosis was 5.1% in patients with APA and 0.75% in those without. This incidence of APA was in line with other findings [42]. The presence of antiphospholipid antibodies in cancer patients seems to be associated with an increased risk of VTE [43]; whether or not chemotherapy modulates this risk remains to be elucidated. Factor V Leiden is the most frequent inherited thrombophilia, also in cancer patients [44]. It confers an approximately sevenfold increased risk for DVT in heterozygotes and an 80-fold increase risk in individuals being homozygous. The prothrombin 20210A mutation causes increased prothrombin levels and is associated with a relative thrombotic risk of approximately three in heterozygotes. It is unclear to what extent these mutations add to the VTE risk in cancer patients, given partially conflicting results [44, 45]. Results on mutations of the methylene tetrahydrofolate reductase seem similarly unclear.

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Iatrogenic Factors Chemotherapies generally induce a hypercoagulable state [46]. Therefore, cancer patients undergoing chemotherapy have a high risk of developing a thromboembolic event [47]. A specific situation is the use of asparaginase with lymphoproliferative diseases; the initial phase with early reduction in protein synthesis is followed by a phase of hypercoagulability as procoagulants recover earlier than anticoagulants (mainly antithrombin); this is associated with an increased thrombin generation throughout therapy [48]. Corticosteroids, often used in conjunction, also might increase the prothrombotic risk [49]. Thalidomide and analogs such as lenalidomide are to be considered prothrombotic. When used for single agent therapy in myeloma, less than 2% of patients will develop thromboembolism [50]. In combination with steroids (dexamathasone) however, the rate increases; up to one-third (or even more if an anthracycline is added) of these patients will develop VTE [51]. The combination of thalidomide or its derivatives plus steroids seems to markedly increase the prothrombotic risk. Of 60 cancer patients who received thalidomide plus dexamethasone, 15% developed VTE complications, while among 326 cancer patients receiving thalidomide alone, only 5% developed thromboembolism [52]. Central venous catheters (CVC) are frequently used in order to provide a secure and reliable way for repeated access to the venous system during iv-based therapies. CVCs are believed to be thrombogenic due to the vessel injury to begin with, but also changes in blood flow as well as provision of an artificial surface in the setting of hypercoagulability from the underlying cancer [53]. Data on the frequency of CVCrelated venous thrombosis are not homogeneous [54]. In a registry of 2,945 cancer patients, DVT in the upper extremities overall occurred in 6.7%; association with a CVC occurred in 3.5% [55]. Other trials suggested ovarian cancer to induce a specific risk for CVC-related DVT [56], and thrombocytopenia to be somewhat protective in this setting.

Management of Hypercoagulable States As mentioned above, VTE is frequent in cancer patients (4–20% of the cancer patients) and is the second greatest cause of mortality in cancer. In the last 10 years, randomized clinical trials have clearly demonstrated that the long-term use of daily subcutaneous low molecular weight heparin (LMWH) is more efficient than Vitamin K antagonists to treat VTE in cancer patients [57]. Italian [58], American [59], and French (www.sor-cancer.fr) national guidelines recommend the use of LMWH for 3–6 months for the treatment of VTE in cancer patients with a high level of evidence.

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Despite convincing data, many physicians have not yet modified their clinical practice. This problem is of significance. In a recent cohort study, only 60% of cancer patients who were at risk for TE and later developed TE had received some form of thromboprophylaxis in the time preceding the TE; thus, 40% of these at risk patients had not received thromboprophylaxis [47]. And this is despite the fact that LMWH long-term use appears well tolerated and may also increase cancer patient survival [60]. Palliative care patients might be preferring LMWH injections over warfarin or compression stockings [61]. The exact rate of VTE with the use of thalidomide and its analogs remains a matter of debate [62], but the frequency of VTE is high enough to suggest that pharmacological thromboprophylaxis, probably preferably with LMWH, should be used [63]. Pneumatic compression stockings seem to work well for thromboprophylaxis in cancer patients but randomized controlled studies on their use are not frequent [64]. At present, there is no evidence that antithrombotic prophylaxis will prevent catheter-associated thrombosis in cancer patients [65]. Despite being frequently used, aspirin is not an adequate prophylaxis for primary or secondary prophylaxis of VTE in cancer patients [66]. In hypercoagulable states due to acquired anticoagulant deficiency such as antithrombin deficiency with asparaginase therapy, replacement therapy should be considered although randomized controlled trials are needed to clarify this question [67]. In patients with hyperviscosity due to paraproteins, plasma exchange, or plasmapheresis might be the most appropriate way to treat, at least for a short-term benefit. However, it has to be recognized that high protein concentrations – once they have been cleared from the circulation – tend to “rebound” due to the high protein concentrations present in the extravascular space (especially with IgG) [68]. Vena cava filters might be an option for the prevention of thromboembolism in patients with manifest thrombosis, very high risk for thromboembolism and bleeding risk with antithrombotic therapy (such as chemotherapy-induced thrombocytopenia) or contraindications to anticoagulation. CVC filters may be associated with device-related thromboembolic complications in nearly 10% of patients [69]; however, in the absence of randomized trials, results from different reports are difficult to compare as survival times of the patients might greatly differ [70].

Thrombocytopenia

Pathogenesis of Bleeding

Tumor Infiltration

Besides thromboembolic events, cancer patients – not infrequently – show also evidence of a bleeding tendency. This can be related to various, seemingly separate pathologies; however, recent research suggests that bleeding might occur as a result of interplay of various different pathologies.

Bleeding in cancer patients might be due to direct infiltration of the respective vessel, as it can be encountered for example in gastric lymphoma; here, therapy has shifted away from primary surgery. However, if bleeding occurs, early surgical intervention needs to be considered [82]. Radiation therapy

Drug-induced thrombocytopenia is a frequent finding in cancer patients undergoing chemotherapy [71]. It is common knowledge that thrombocytopenia increases the risk of bleeding, both in cancer and noncancer patients [72]. In acute leukemia, the degree of thrombocytopenia correlates well with the risk and degree of bleeding. Fever and infection further increase the bleeding risk and reduce the response to platelet transfusion [73]. There is some evidence that platelet substitution, for example, in AML induction chemotherapy can be lowered to trigger levels of 10 or 20 G/l [74]; the same group is performing a randomized trial to evaluate platelet substitution upon bleeding complications only and these data might have influence on clinical practice in the future. Although bleeding does occur during treatment for solid cancers such as lung cancer, it seems that thrombocytopenic bleeding in solid cancer patients is rather rare [75]. Defining the exact need for platelet transfusion seems relevant as treating patients in this setting consumes considerable resources, with approximately half of the therapy courses inducing the additional financial burden [76]. It is important to preemptively consider the need for platelet support in advanced cancer patients on a case-by-case basis; this should allow provision of the therapy necessary but also consideration of limitations associated with its use [77].

Platelet Dysfunction The potential reasons for platelet dysfunction are manifold; most frequently, platelet dysfunction in hospitalized patients is drug induced [78]. Frequently, nonsteroidal antiinflammatory drugs (NSAIDs) are inhibiting platelet function but platelet dysfunction can also be induced by other drugs; on the other hand, however, NSAIDs also impair mucosal healing or directly induce mucosal toxicity, both properties that will increase the risk for bleeding, for example, in the gastrointestinal tract [79]. In that respect, COX-2 inhibition could be an attractive target in cancer patients with pain [80]; however, as COX-2 inhibitors may be associated with increased cardiovascular risk [81], the decision to use them should be carefully evaluated and be taken on a case-by-case basis.

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might be an appropriate approach to control bleeding that comes from direct tumor infiltration; rarely, however, radiotherapy can aggravate or induce bleeding, especially when applied in combination with chemotherapy [83].

Fibrinolysis Many (especially hematological) malignancies might be associated with an increased fibrinolytic activity. Along with elevated levels of plasminogen activators in many hematological malignancies, excessive fibrinolysis can increase the risk of bleeding [84]. In DIC (with increased fibrinolysis), the extent of bleeding is correlated with fibrinolytic activity [85]. Bleeding can occur from a combination of DIC and fibrinolysis, as is probably the case in acute promyelocytic leukemia [36]. The increased fibrinolytic response in APL might have to do with the increased expression of uPA [86] and Annexin II [87], a receptor for tPA and plasminogen. Also, Annexin II has been found to be highly expressed in cerebral endothelial cells [88]. This may explain why intracranial hemorrhage in APL seems frequent and it provides a rationale to use antifibrinolytics for prevention. Annexin II is also increased in other acute leukemias and might therefore contribute to bleeding in these settings [87]. Rarely, coagulation factor inhibitors are found in cancer patients; in this situation, bleeding complications can be severe [89] (see also Sect. “Paraproteins” below). Despite recent advances in the understanding of (perioperative) bleeding problems in cancer patients unexplained intraoperative coagulopathies continue to be a diagnostic and therapeutic dilemma, especially in cancer patients. The pathophysiology behind unexplained intraoperative coagulopathies is of great variety and complexity as all the aforementioned mechanisms can occur. We have shown in prospective studies that patients with “unexplained” intraoperative coagulopathy have significantly less F. XIII per unit thrombin available at any point in time [90], resulting in the loss of clot firmness associated with an increase in intraoperative blood loss. Thus, these patients have less cross-linking capacity to begin with, which explains their preoperatively increased fibrin monomer concentration that seems therefore usable for preoperative risk stratification [91]. It is important to note that the acquired or (compared to the amount of thrombin generated) relative F. XIII deficiency in situations with surgical stress shows early clinical relevance (even if only mild-to-moderate changes are present), which differs from the experiences in patients with inborn F. XIII deficiency. There is proof of principle that this pathophysiology is relevant and important in cancer patients and that the use of F. XIII in high-risk patients (high preoperative fibrin monomer) leads to maintenance (vs. loss) of clot firmness and a significant reduction in blood loss [92]. Thus, it seems that

replacing F. XIII in cancer patients with a high-risk profile (increased fibrin monomer) early during surgery is an efficacious new strategy.

Adverse Effects of Drugs Chemotherapeutic drugs frequently induce myelosuppression, which can cause thrombocytopenia and thus induce bleeding. In addition, other mechanisms might include direct or indirect influences on coagulation factors. l-Asparaginase, used for the treatment of acute lymphocytic leukemia (ALL), induces a depletion in l-asparagine, leading to an impaired protein synthesis that also extends to procoagulants, anticoagulants, and fibrinolytic proteins. The lowering of various procoagulants induces a transient hypocoagulable state that is at least partially balanced due to the parallel decrease of anticoagulants [48]; however, replacement of coagulation factors in high-risk situations might be appropriate and needs to be decided on a case-by-case basis.

Paraproteins High levels of paraproteins can interfere with hemostasis by various means: they can inhibit polymerization of fibrin monomers, interfere with platelet aggregation or inhibit clotting factor activity [93, 94]. As already described for hyperviscosity, bleeding problems in such patients might improve with plasmapheresis. Although this is a clinically important problem in the single patient, it is unlikely that prospective trials on treatment modalities will be performed due to the fact that this is a rather rare problem.

Conclusions A very important message is the fact that hypercoagulability in cancer patients is not only an attendant phenomenon but also in fact a part of the problem. Therefore, the stringent evaluation for the need for thromboprophylaxis or continued use of anticoagulant therapy in every cancer patient is a must, especially as recent data suggest that the use of LMWH might improve tumor response and survival. On the other hand, recent advances in our knowledge (e.g., platelet transfusion in leukemia patients) suggest that we might be able to focus on (and thus make better use of) the available resources, avoiding unnecessary burdens and risk to the patient and economic strain to the healthcare system. Studies in recent years have advanced our understanding of thrombotic and bleeding complications in cancer patients.

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But as many of the clinical problems occur in patient populations with very specific pathophysiologies, more prospective controlled trials are needed to generate evidence-based knowledge.

References 1. Virchow R. Phlogose und Thrombose in Geaszsystem. In: Virchow R, ed. Gesammelte abhandlungen zur Wissenschafilichem Medicin Frankfurt von Meidinger Soln. 1856:458–636. 2. Trousseau A. Phlegmasia alba dolens. Clinique medicale de l’HotelDien de Paris. 1865. Paris: The Sydenham Society. 3. Schaffner F, Ruf W. Tissue factor and PAR2 signaling in the tumor microenvironment. Arterioscler Thromb Vasc Biol. 2009;29(12): 1999–2004. 4. Korte W. Changes of the coagulation and fibrinolysis system in malignancy: their possible impact on future diagnostic and therapeutic procedures. Clin Chem Lab Med. 2000;38(8):679–92. 5. Beer JH, Haeberli A, Vogt A, Woodtli K, Henkel E, Furrer T, et al. Coagulation markers predict survival in cancer patients. Thromb Haemost. 2002;88(5):745–9. 6. Antoniou D, Pavlakou G, Stathopoulos GP, Karydis I, Chondrou E, Papageorgiou C, et al. Predictive value of D-dimer plasma levels in response and progressive disease in patients with lung cancer. Lung Cancer. 2006;53(2):205–10. 7. Wada H, Mori Y, Okabayashi K, Gabazza EC, Kushiya F, Watanabe M, et al. High plasma fibrinogen level is associated with poor clinical outcome in DIC patients. Am J Hematol. 2003;72(1):1–7. 8. Rickles FR, Levine MN. Epidemiology of thrombosis in cancer. Acta Haematol. 2001;106(1–2):6–12. 9. White RH, Chew HK, Zhou H, Parikh-Patel A, Harris D, Harvey D, et al. Incidence of venous thromboembolism in the year before the diagnosis of cancer in 528,693 adults. Arch Intern Med. 2005; 165(15):1782–7. 10. Murchison JT, Wylie L, Stockton DL. Excess risk of cancer in patients with primary venous thromboembolism: a national, population-based cohort study. Br J Cancer. 2004;91(1):92–5. 11. Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005;293(6):715–22. 12. Jimenez-Zepeda VH, Dominguez-Martinez VJ. Acquired activated protein C resistance and thrombosis in multiple myeloma patients. Thromb J. 2006;4:11. 13. Khorana AA, Francis CW, Culakova E, Fisher RI, Kuderer NM, Lyman GH. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol. 2006;24(3):484–90. 14. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer. 2007;110(10): 2339–46. 15. Otten HM, Mathijssen J, ten Cate H, Soesan M, Inghels M, Richel DJ, et al. Symptomatic venous thromboembolism in cancer patients treated with chemotherapy: an underestimated phenomenon. Arch Intern Med. 2004;164(2):190–4. 16. Chew HK, Wun T, Harvey DJ, Zhou H, White RH. Incidence of venous thromboembolism and the impact on survival in breast cancer patients. J Clin Oncol. 2007;25(1):70–6. 17. Linenberger ML, Wittkowsky AK. Thromboembolic complications of malignancy. Part 1: risks. Oncology (Williston Park, NY). 2005; 19(7):853–61. 18. von Tempelhoff GF, Heilmann L, Hommel G, Schneider D, Niemann F, Zoller H. Hyperviscosity syndrome in patients with ovarian carcinoma. Cancer. 1998;82(6):1104–11.

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18  Thrombosis and Bleeding in Cancer Patients 40. Nijziel MR, van Oerle R, Christella M, Thomassen LG, van Pampus EC, Hamulyak K, et al. Acquired resistance to activated protein C in breast cancer patients. Br J Haematol. 2003;120(1):117–22. 41. Pusterla S, Previtali S, Marziali S, Cortelazzo S, Rossi A, Barbui T, et  al. Antiphospholipid antibodies in lymphoma: prevalence and clinical significance. Hematol J. 2004;5(4):341–6. 42. Genvresse I, Luftner D, Spath-Schwalbe E, Buttgereit F. Prevalence and clinical significance of anticardiolipin and anti-beta2-glycoprotein-I antibodies in patients with non-Hodgkin’s lymphoma. Eur J Haematol. 2002;68(2):84–90. 43. Horowitz N, Brenner B. Thrombophilia and cancer. Pathophysiol Haemost Thromb. 2008;36(3–4):131–6. 44. Decousus H, Moulin N, Quenet S, Bost V, Rivron-Guillot K, Laporte S, et al. Thrombophilia and risk of venous thrombosis in patients with cancer. Thromb Res. 2007;120(Suppl 2):S51–61. 45. Abramson N, Costantino JP, Garber JE, Berliner N, Wickerham DL, Wolmark N. Effect of Factor V Leiden and prothrombin G20210–>A mutations on thromboembolic risk in the national surgical adjuvant breast and bowel project breast cancer prevention trial. J Natl Cancer Inst. 2006;98(13):904–10. 46. Lechner D, Weltermann A. Chemotherapy-induced thrombosis: a role for microparticles and tissue factor? Semin Thromb Hemost. 2008;34(2):199–203. 47. Mandala M, Falanga A, Labianca R. Video meliora proboque sed deteriora sequor: The case of thromboprophylaxis in hospitalized cancer patients. Ann Oncol. 2010;21(5):911–3. 48. Mitchell LG, Sutor AH, Andrew M. Hemostasis in childhood acute lymphoblastic leukemia: coagulopathy induced by disease and treatment. Semin Thromb Hemost. 1995;21(4):390–401. 49. Jorgensen KA, Sorensen P, Freund L. Effect of glucocorticosteroids on some coagulation tests. Acta Haematol. 1982;68(1):39–42. 50. Singhal S, Mehta J. Thalidomide in cancer. Biomed Pharmacother. 2002;56(1):4–12. 51. Zangari M, Siegel E, Barlogie B, Anaissie E, Saghafifar F, Fassas A, et al. Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy. Blood. 2002;100(4): 1168–71. 52. Bennett CL, Schumock GT, Desai AA, Kwaan HC, Raisch DW, Newlin R, et al. Thalidomide-associated deep vein thrombosis and pulmonary embolism. Am J Med. 2002;113(7):603–6. 53. Agnelli G, Verso M. Therapy Insight: venous-catheter-related thrombosis in cancer patients. Nat Clin Pract Oncol. 2006;3(4):214–22. 54. Verso M, Agnelli G. Venous thromboembolism associated with long-term use of central venous catheters in cancer patients. J Clin Oncol. 2003;21(19):3665–75. 55. Monreal M, Munoz FJ, Rosa V, Romero C, Roman P, Di Micco P, et al. Upper extremity DVT in oncological patients: analysis of risk factors. Data from the RIETE registry. Exp Oncol. 2006;28(3):245–7. 56. Lee AY, Levine MN, Butler G, Webb C, Costantini L, Gu C, et al. Incidence, risk factors, and outcomes of catheter-related thrombosis in adult patients with cancer. J Clin Oncol. 2006;24(9):1404–8. 57. Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. New Engl J Med. 2003;349(2):146–53. 58. Mandala M, Falanga A, Piccioli A, Prandoni P, Pogliani EM, Labianca R, et al. Venous thromboembolism and cancer: guidelines of the Italian Association of Medical Oncology (AIOM). Cri Rev Oncol Hematol. 2006;59(3):194–204. 59. Lyman GH, Khorana AA, Falanga A, Clarke-Pearson D, Flowers C, Jahanzeb M, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25(34): 5490–505. 60. Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, et al. Randomized comparison of low molecular weight heparin and

177 coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005;23(10):2123–9. 61. Noble SI, Nelson A, Turner C, Finlay IG. Acceptability of low molecular weight heparin thromboprophylaxis for inpatients receiving palliative care: qualitative study. BMJ. 2006;332(7541): 577–80. 62. Rajkumar SV, Blood E. Lenalidomide and venous thrombosis in multiple myeloma. New Engl J Med. 2006;354(19):2079–80. 63. Zangari M, Elice F, Fink L, Tricot G. Thrombosis in multiple myeloma. Expert Rev Anticancer Ther. 2007;7(3):307–15. 64. Maxwell GL, Synan I, Dodge R, Carroll B, Clarke-Pearson DL. Pneumatic compression versus low molecular weight heparin in gynecologic oncology surgery: a randomized trial. Obstet Gynecol. 2001;98(6):989–95. 65. Young AM, Billingham LJ, Begum G, Kerr DJ, Hughes AI, Rea DW, et  al. Warfarin thromboprophylaxis in cancer patients with central venous catheters (WARP): an open-label randomised trial. Lancet. 2009;373(9663):567–74. 66. Kakkar AK, Levine M, Pinedo HM, Wolff R, Wong J. Venous thrombosis in cancer patients: insights from the FRONTLINE survey. Oncologist. 2003;8(4):381–8. 67. Korte W, Greiner J. PARKAA paves the way. Thromb Haemost. 2003;90(2):163–4. 68. Nand S, Molokie R. Therapeutic plasmapheresis and protein A immunoadsorption in malignancy: a brief review. J Clin Apheresis. 1990;5(4):206–12. 69. Zerati AE, Wolosker N, Yazbek G, Langer M, Nishinari K. Vena cava filters in cancer patients: experience with 50 patients. Clinics (Sao Paulo). 2005;60(5):361–6. 70. Usoh F, Hingorani A, Ascher E, Shiferson A, Tran V, Marks N, et al. Long-term follow-up for superior vena cava filter placement. Ann Vasc Surg. 2009;23(3):350–4. 71. Bodensteiner DC, Doolittle GC. Adverse haematological complications of anticancer drugs. Clinical presentation, management and avoidance. Drug Saf. 1993;8(3):213–24. 72. Avvisati G, Tirindelli MC, Annibali O. Thrombocytopenia and hemorrhagic risk in cancer patients. Crit Rev Oncol Hematol. 2003;48(Suppl):S13–6. 73. Webert K, Cook RJ, Sigouin CS, Rebulla P, Heddle NM. The risk of bleeding in thrombocytopenic patients with acute myeloid leukemia. Haematologica. 2006;91(11):1530–7. 74. Wandt H, Frank M, Ehninger G, Schneider C, Brack N, Daoud A, et al. Safety and cost effectiveness of a 10 x 10(9)/L trigger for prophylactic platelet transfusions compared with the traditional 20 × 10(9)/L trigger: a prospective comparative trial in 105 patients with acute myeloid leukemia. Blood. 1998;91(10): 3601–6. 75. Le Maitre A, Ding K, Shepherd FA, Leighl N, Arnold A, Seymour L. Anticoagulation and bleeding: a pooled analysis of lung cancer trials of the NCIC Clinical Trials Group. J Thorac Oncol. 2009;4(5): 586–94. 76. Elting LS, Cantor SB, Martin CG, Hamblin L, Kurtin D, Rivera E, et  al. Cost of chemotherapy-induced thrombocytopenia among patients with lymphoma or solid tumors. Cancer. 2003;97(6): 1541–50. 77. Deichmann M, Helmke B, Bock M, Jackel A, Waldmann V, Flechtenmacher C, et  al. Massive lethal cerebral bleeding in a patient with melanoma without intracranial metastasis. Clin Oncol (R Coll Radiol). 1998;10(4):272–3. 78. Koscielny J, von Tempelhoff GF, Ziemer S, Radtke H, Schmutzler M, Sinha P, et al. A practical concept for preoperative management of patients with impaired primary hemostasis. Clin Appl Thromb Hemost. 2004;10(2):155–66. 79. Lehmann FS, Beglinger C. Impact of COX-2 inhibitors in common clinical practice a gastroenterologist’s perspective. Curr Top Med Chem. 2005;5(5):449–64.

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Chapter 19

Lymphedema Care Andrea M. Steely and Patricia O’Brien

Introduction Lymphology is an important aspect of supportive oncology care. The lymphatic system is often underappreciated as an integral part of the circulatory and immune system until it is disrupted. Lymphedema has been referred to as an “orphan disease” because, until recently, it has been often ignored. In  the past, oncology appreciated the lymph nodes predominantly for their use in staging the spread of the cancer. As the field of Supportive Oncology has expanded, appreciation for chronic lymphedema in our cancer patients has grown. Lymphedema ranks highly among the serious concerns within the cancer survivor community [1]. Long-term survivors want more information about ways to prevent the onset of disease and the efficacy of current treatment options. In pursuit of this information, many patients will search the Internet and may find confusing and contradictory information about lymphedema as well as frightening pictures of disfiguration. The research on lymphedema prevention is limited, and as a result, many patients are left with lists of things they can and cannot do that they may find frustrating and limiting to their quality of life. Thus, there is an obvious demand for lymphedema research and information. Cancer survivor advocacy groups such as the American Cancer Society, the Susan G Komen Foundation, International Lymphedema Association, and the National Lymphedema Network have worked to improve the quality of information available to patients and their access to care throughout the world. Lymphedema care and services remain highly variable around the world. In this section, we provide the most current information about the prevalence of lymphedema as it relates to specific types of cancer. There is a review of the pathophysiology and

A.M. Steely (*) Department of Hematology and Oncology, University of Vermont College of Medicine, 89 Beaumont Ave., Burlington, VT 05405, USA e-mail: [email protected]

molecular biology of this chronic condition. The treatmentrelated risk factors and lifestyle-related risk factors remain controversial but have been outlined. The diagnostic techniques available around the world are also highly variable; those most commonly used are reviewed. Treatment modalities have been divided up into sections with case examples to demonstrate that the treatments need to match the patient and the stage of disease. The associated quality of life and psycho­social issues as related to the cancer patient are reviewed. While more research needs to be conducted, this text will hopefully serve as a basic guide for the treatment and care of patients with lymphedema and will help to raise awareness of the increasing prevalence of this debilitating condition among oncology care providers and researchers. Current sources indicate that between three and five ­million patients in the US alone currently suffer from ­lymphedema, with the majority of these individuals developing this condition as a result of cancer treatment [2]. The statistics on prevalence remain controversial, as the diag­ nostic criteria used in different research studies, and parts of the world vary widely. The lymphatic system is particularly important to the supportive oncologist, as the lymphatic system is often disrupted during cancer care. In the patient with advanced disease, the lymphatic system may be congested by tumor within the lymphatic system, or the congestion may result from physical compression of the tumor outside the lymphatic system. Either mechanism can leave the patient with extensive edema and pain. The patients with advanced endstage oncologic disease may need lymphatic care as a part of their palliative care program to address the pain associated with this swelling. Cancer survivors often identify lymphedema as a major complication of their cancer care. As the community of longterm cancer survivors grows, more awareness of the long-term costs of living with this chronic debilitation is being published in case reports and long-term follow-up studies. One elderly breast cancer survivor noted that “going through treatment for breast cancer (41 years ago) was nothing compared to all the (39) years with lymphedema.” This is a reminder that “cures”

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_19, © Multinational Association for Supportive Care in Cancer Society 2011

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often come at long-term chronic costs to the patient. We need to fully educate our patients about this possible long-term complication and monitor them as we build long term ­survivor care plans. As more research is conducted on mechanisms of metastasis, the complexity of the lymphatic system is being further elucidated. This increased basic science knowledge has allowed development of targeted cancer therapies, which are now being directed toward the lymphatics and the vascular endothelial pathways associated with lymphatic growth. As new cancer therapies develop, their effect on the lymphatic system may change, and we as clinicians must be ­vigilant to monitor this potential side effect.

Anatomy and Physiology The lymphatic system is an integral component of human anatomy. This network of unidirectional vessels functions as a drainage system that parallels the venous system; lympha­ tics help remove waste and debris from tissues and return them to the cardiovascular system in an effort to maintain interstitial fluid composition and volume. Lymphedema is the specific term used to describe the pooling of high-protein lymphatic fluid, or lymph – tissue fluid from the interstitium – in the tissue spaces, which results in swelling, or edema, of

the involved area. More specifically, the stasis of protein-rich lymph fluid within the interstitium increases tissue colloid pressure, which further promotes fluid accumulation and regional ischemia, thereby stimulating reactive inflammatory changes that result in chronic lymphatic vascular insufficiency. The processes that follow lead to tissue expansion, fibrotic changes, matrix degeneration, neurologic changes [2], and fatty deposition [3]. Additionally, collagen, adipose, and inflammatory cell deposition may lead to a chronic inflammatory state, further compromising the lymphatics [4]. Lymphedema is primarily characterized by numerous dilated lymphatics in the dermis and the subdermis, which can lead to incompetent vessels and backflow [4]. This condition can be primary, being of a congenital nature, or secondary, meaning that the condition is of an acquired nature, with the latter being most common. Our cancer patients that present with primary lymphedema may require special attention to their lymphatics during their cancer treatments. Secondary lymphedema can result from a variety of treatments and conditions and can occur in virtually any part of the body, though breast cancer treatment-related ­secondary lymphedema is most common in the developed world [3]. Structural and functional disruption of the lymphatic system may occur as a result of trauma, infection, ­surgical disruption, irradiation, or direct malignant invasion [4]. This high-protein edema may be caused by decreased lymphatic transport or increased ­lymphatic load [5] (Fig. 19.1).

Lymphatic Protein Pathway protein

blood capillary extracellular protein

tissue cells

prelymphatic titissue channel initial lymphatic collecting lymphatic

FACTORS THAT INFLUENCE LYMPHATIC COMPRESSION •Skeletal muscle contraction lymph node •Smooth muscle contraction

lymph node lymph duct

•Respiration •Intra abdominal and intrathoracic pressure lymph duct •Air pressure gradient •Compressive clothing •Scar tissue, fibrosis

vein

Fig. 19.1  Lymphatic protein pathway (Courtesy of Dr. Patricia O’Brien, Department of Physical Therapy, University of Vermont, Burlington, VT, USA)

19  Lymphedema Care

The Molecular Biology of Lymphedema While tumors may arise in any tissue of the body, epithelialderived tumors are capable of spreading to other sites of the body via the lymphatic system. As scientific research findings continue to provide clues about the science behind cancer development, growth, and dissemination, treatments are becoming increasingly specialized. The research discussed in the following paragraphs has improved the effectiveness of our cancer therapies. Our increased understanding of the neoplastic process is enabling our treatments to specifically target the biologic components, like the lymphatics, that allow cancer to grow and spread. Lymphangiogenesis, that is, lymphatic vessel formation after embryonic development of the lymphatic system, usually occurs in parallel with angiogenesis in the nonneoplastic setting in the context of transient inflammation and wound healing [3]. There is increasing evidence that tumors stimulate lymphangiogenesis – the development of new lymphatic vessels from preexisting lymphatic structures [6]. Stimulation of lymphangiogenesis is a primary method via which micrometastatic disease spreads from the primary tumor site to other areas of the body and is thus an active area of research. Some patients may first be diagnosed with a malignant neoplasm based on the detection of lymphatic metastases at a time when the primary tumor is not detectable [7]. It is widely believed that tumor cells trigger lymphangiogenesis via the production of growth factors and cytokines. Vascular endothelial growth factor, or VEGF, is a key regulator of endothelial cell function that is required for vasculogenesis and physiological and pathological angiogenesis. The VEGF family of chemokines includes five different signaling molecules that can bind to one of three distinct receptors. VEGF-C and VEGF-D, which bind the receptor VEGFR-3, are the best-studied and most lymphatic-specific signaling molecules [3], yet, interestingly, also stimulate angiogenesis. VEGF-C and VEGF-D have been characterized as being prolymphangiogenic factors with respect to therapeutic potential and cancer metastasis [3]. Thus, secretion of these growth factors increases blood flow to the primary tumor site and surrounding areas, thereby facilitating tumor growth. As most tumor cells grow at a faster rate than their blood supply, the tumor environment quickly becomes hypoxic. This hypoxia serves as a catalyst for additional ­vessel growth via stimulation of the production of specific factors that upregulate the production of cytokines like VEGF. As previously stated, these chemical stimuli not only upregulate vessel growth, but emerging research also suggests that these chemokines also have cross-reactive stimulatory effects on the lymphatic system [8]. Tumors may also increase lymphatic vessel production via a process named

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l­ymphvasculogenesis, which involves the recruitment of precursor lymphatic endothelial cells onto the angiogenic lymphatics [6]. In the past, lymph treatments were based on physical modalities. As these biochemical pathways are better understood, targets for intervention in lymphedema may also be identified. The basic science understanding of lymphatics and lymphangiogenic pathways is changing rapidly. Despite the fact that tumor cells produce the same types of chemical signals that nonneoplastic cells produce to stimulate lymphangiogenesis, intratumoral and peritumoral lymphatics are often characterized by a disorganized network that may lack the drainage function of nonneoplastic cellderived lymphatics [6]. Tumor-infiltrated inflammatory cells and stromal cells can be activated in the tumor environment to secrete interleukins and chemokines, which further contribute to lymphangiogenesis. There is also a great deal of evidence-based literature ­supporting the involvement of integrins in the angiogenic process, as particular integrins are prominent components of proliferating vascular endothelial cells. Some integrins appear to be specific to lymphangiogenesis and angiogenesis, rendering these molecules possible targets in the specific treatment of cancer growth and metastasis. Many integrins are more highly expressed in proliferating tumor blood and lymphatic vessels than they are in nonneoplastic vessels. Pharmaceutical companies have recently patented a variety of humanized antibodies and peptide inhibitors of particular integrins involved in tumor growth. These agents appear to be relatively nontoxic, as their molecular targets are only highly expressed or activated in remodeling tissues such as tumors [8]. Thus, lymphangiogenesis and angiogenesis ­represent clinically important areas of tumor biology that can serve as molecular targets of modern chemotherapy, since these processes are often hyperactivated in areas of neoplastic growth. How this new basic science research will be used in the treatment of lymphedema remains unknown. It is clearly a hot topic in cancer treatment research. The lymphologist of the future and oncologists will need to integrate these new data into the future treatment plans for patients with cancer and lymphedema. Eventually, we may have therapeutic pharmacologic agents that are able to treat lymphatic dysfunction or congestion.

Lymphedema Risk Factors and Prevention Lymphedema is an overwhelmingly common complication of cancer treatment. Recently, Norman et  al. [9] reported a 42% 5-year cumulative incidence of lymphedema in a

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p­ opulation-based prospective study of randomly selected female breast cancer patients. Of the affected women, 80% developed clinically significant lymphedema within the first 2 years of breast cancer diagnosis, with almost 90% having clinically diagnosed lymphedema by 3 years following their initial breast cancer diagnosis. Despite these high incidence rates, there have been limited randomized clinical trials devoted to identification of risk factors for lymphedema. As a result, clinicians lack evidence-based resources with which to approach the care, management, and treatment of lymphedema in the growing population of cancer survivors [10]. Thus, all breast cancer patients, including those whose staging is restricted to sentinel lymph node biopsy (SLNB), assume some risk of lymphedema [2]. Surgical intervention and radiation therapy pose the greatest risk for development of treatment-related lymphedema, since disruption, removal, and ablation of lymph nodes and lymphatic vessels is common with these treatment modalities. Given these facts, it is important to take note of the advancements that have been made in these areas, as previous treatments were associated with much higher rates of disfigurement, handicap, and morbidity.

Surgical Procedures As a Risk Factor Surgical intervention is classically associated with the development of secondary lymphedema. According to Deutsch et  al. [11], up to 58.1% of women with breast cancer who underwent a radical mastectomy (surgical removal of breast, underlying chest muscle (including pectoralis major and pectoralis minor), and lymph nodes of the axilla) experienced arm edema at some point. This group also reported that even patients who elected to have surgical intervention that did not include axillary dissection or those who did not undergo radiation therapy suffer from lymphedema of the upper extremity. Though radical mastectomy data is now outdated since it is an uncommonly performed procedure, these data remain important, as they illustrate the significantly increased rates of upper extremity lymphedema that plagued most women following this procedure and highlight the progress we have made in reducing such complications. The degree of surgical intervention in the axilla also influences breast edema. Ronke et al. found a 23% prevalence of breast edema after SLNB without further axillary treatment. A lumpectomy alone carries only a 6% risk of lymphedema. Breast edema frequency ranges from about 6–48% if both surgery and radiation therapy are performed. In the case of SLNB plus radiation therapy, the risk of lymphedema increases up to 23%. If both an ALND and radiation therapy are performed, the risk of lymphedema ranges from 35 to 48%, depending on the lymph node status – there’s a higher

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likelihood of lymphedema in lymph node positive patients [2]. Moreover, Nesvold et al. found that arm/shoulder problems, including lymphedema, were more common after mastectomy compared with breast conserving surgery [12]. The known fact that breast cancer and melanoma often spread to lymph nodes necessitates surgical interventions that disrupt lymphatic flow. In particular, patients who undergo axillary lymph node dissection (ALND) often develop some form of lymphedema, which usually presents as visible or palpable tissue swelling [8]. It was for this reason that the novel idea of the potentially lymph node sparing technique called SLNB was so well received. SLNB is a technique that capitalizes on the anatomy of the lymphatic system to identify the lymph node(s) that drain(s) the primary tumor. Removal of only the sentinel lymph nodes dramatically reduces the risk for lymphedema when compared to the risk associated with removal of all the lymph nodes, as occurs with an axillary node dissection [13, 14], since not all lymphatic tissue, and thus drainage capability, is removed. Furthermore, disruption of axillary nerves and lymphatics is believed to occur less often with SLNB than with ALND [15]. Randomized trials comparing the SLNB and axillary dissections techniques have illustrated that the risk of lymphedema from axillary sampling is about one-third less than that observed with axillary dissection [11, 16]. In a cohort of patients treated with breast conservation, Hayes et al. reported that the strongest predictor of lymphedema is the number of lymph nodes dissected, with the risk increasing by 8% for each additional lymph node dissected for patients with N1 or N2 disease [17]. Primary melanoma can metastasize to any part of the body, though the most common sites involve the cervical, axillary, or inguinal node regions. Emerging evidence suggests that resection of the inguinal nodes carries the greatest risk of morbidity, including complications such as infection, wound dehiscence, lymphedema, seroma/hematoma, and venous thromboembolism. The Gynecologic Oncology Group reported rates of lymphedema of 19% and wound infection and or separation rates up to 29% for patients with superficial groin node dissections [18]. SLNB has improved the postoperative outcome of patients being treated for melanoma with micrometastasis, when identified before palpable macrometastatic disease is clinically apparent. Despite the widespread usage of the SLNB technique, postsurgical lymphedema remains a common casualty of surgical intervention, since 25–45% of women who have node-positive disease will require an ALND [19]. As such, a variety of new preoperative, postoperative, and surgical approaches are being piloted to improve the outcomes of surgical intervention for neoplastic treatment. Recently, a group in Arkansas postulated that the higher than expected rate of lymphedema observed in patients who undergo SLNB may be a secondary consequence of disruption

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of arm lymphatics during the procedure. In this study, after the injection of radioactive material for the SLNB was completed, dermal blue dye was injected into the upper inner arm to localize lymphatics draining the arm in a process they have named axillary reverse mapping or ARM for short. Multiple studies have illustrated that the SLNB technique has minimized the risk of lymphedema. However, this group, led by Boneti et al. [16], reported that 42.7% of axilla had blue ARM lymphatics close or juxtaposed (5.5%) to the sentinel lymph node, which might partly explain the high incidence of lymphedema observed following SLNB. Interestingly, only 3.9% of the cohort had common lymphatic channels that drained both the arm and the breast; however, none of these common nodes had detectable metastatic disease. Thus, 38.9% of the cohort could have avoided arm lymphedema if the ARM procedure were used in conjunction with the SLNB technique. The only possible limiting factor to implementation of the ARM technique is the fact that about one-third of the SLNB procedures currently being performed are conducted using blue dye instead of radioactive material. Thus, with the standardization of use of radioactivity for all SLNB procedures, the ARM technique is likely to prove to be a highly valuable tool to successfully limit or even prevent the destruction of lymphatics that lead to lymphedema in the first place. Though still observed, the incidence of lymphedema in the treatment of melanoma is significantly lower than that observed in the treatment of breast cancer. Implementation of the SLNB has dramatically improved the risks of lymphedema; however, treatment of cutaneous melanoma still holds a lymphedema risk that is as high as 53% following additional axillary radiation therapy; a study of upper extremity lymphedema resulting from ALND for melanoma concluded a 10% risk for upper extremity lymphedema following a complete level I to level III ALND [2]. Thus, it is clearly the axillary radiation therapy, in combination with an ALND, which is primarily responsible for this dramatic increase in the risk for development of lymphedema. Another study found that patients treated for melanoma or other cancers of the pelvis by inguinal dissection have a 7–46% risk of lymphedema [20], illustrating the importance of factors other than surgical intervention in the development of this chronic condition.

Radiation Therapy As a Risk Factor Radiation therapy has a dramatic effect on the lymphatic ­system; radiation directed at the axilla greatly increases the incidence of lymphedema [2], as noted above with respect to the treatment of cutaneous melanoma. Falk et  al. [4] have shown that radiation therapy leads to constriction of lymphatic vessels, which decreases the filtering capacity of lymph nodes and thus decreases their immune surveillance

capabilities. Hayes et al. [17] claim that a posterior axillary boost (PAB) of radiation did not increase the risk for development of lymphedema in their cohort when combined with supraclavicular radiation but administration of a PAB and when combined with supraclavicular and whole breast radiation did significantly increase the risk of lymphedema. Thus, location of radiation therapy also plays a role in determining its effects on the lymphatic system. Breast edema is also significantly affected by radiation treatment. A recent study observed a 21% incidence of breast edema following breast resection and radiation therapy compared to the 5% incidence of breast edema among nonirradiated patients [21]. Multiple studies have confirmed that it is the extent of axillary dissection and the addition of radiation that are the most important treatment-related predictors of lymphedema [2, 11, 22]. In women with four to nine positive nodes, PAB led to a 4.5-fold increase in the risk for lymphedema, indicating that one should consider avoiding PAB unless there are absolute indications for its use. It is important for clinicians to try to inform every patient of their individualized risk of developing lymphedema. After an extensive review of the literature, Lawenda et al. [2] compiled the frequency of developing upper extremity lymphedema after specific surgical and radiation treatment interventions in the axilla. A very limited summary of their findings follows. The incidence reports are highly variable, and the range is given. The main conclusion we can draw from this is that the effect of multiple interventions are additive and that the more invasively a patient is treated, the higher the risk of lymphedema (Table 19.1).

Other Medical Precautions and Risks Although Surgery and radiation are traditionally thought of as the major risk factors for lymphedema, medical interventions have also been considered risk factors. The “advice” to not use the arm on the side that has a mastectomy for blood

Table 19.1  Overview of treatment-related complications Procedure Complications (%) LP 0–3 LP + BR 2.6–3.0 LP + SLNB 9.9–9.9 LP + ALND 2–14 LP + SLNB + BR 9–27.5 MRM + ALNR 7–28.2 MRM + ALND + AR 17–44 LP lumpectomy; BR breast radiation; SLNB sentinel lymph-node biopsy; ALND axillary lymph-node dissection; MRM modified radical mastectomy; ALNR axillary lymph-node radiation; AR axillary radiation

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pressures and blood draws goes back many years and is found on many of the “do not” lists that patients are given. These simple overgeneralized rules have caused great confusion on the part of patients and care providers, as it is now not uncommon for patients to have had bilateral breast procedures. Some patients insist on absolute and direct interpretation of these rules and therefore demand blood pressures and blood draws from their legs. At the opposite extreme are interventionists who refuse to acknowledge that prolonged compression of limited lymphatic pathways might cause lymphatic congestion. Patients who have had prolonged blood pressure cuffs kept on the affected extremity for monitoring surgery have presented with acute lymphedema. These old rules about avoiding all blood draws on the affect side need to be updated. Venipunctures on a mildly immunocompromised limb should be minimized or avoided when possible, but blood draws in the leg come with their own potential risks for DVT and infection. In light of these rules and the current literature, a common sense approach is encouraged. The physiology should be acknowledged and risks/benefits should be discussed with each patient. Providers should help each patient sort out what makes the most sense for that individual patient based on their own unique risks. Each person will have unique anatomy and physiology to take into consideration.

Lifestyle Risk Factors Apart from neoplastic specific treatment interventions, there is a growing list of lifestyle-related risk factors associated with the development of lymphedema. Increasing evidence is emerging that implicates a BMI of greater than 30 as a major risk factor for lymphedema [23]. In fact, Deutsch et  al. [11] report that increasing BMI was the only factor identified by multivariate analysis that was significantly associated with development of arm lymphedema, regardless of treatment. Other studies have shown that there is an increased incidence of arm lymphedema among heavier women [11, 22, 24]. Poor glycemic control will put the patient at increased risk for lymphedema by several physiologic mechanisms. The fluid balance will shift toward retention peripherally, thereby increasing congestion. The risk for infection, a major complication of lymphedema, will also be increased as a result of poorly controlled blood sugars. A recent study published by Taylor et al. [25] reported that obesity, hypertension, and diabetes also increase the risk of arm lymphedema. Weight loss has been shown to improve the management and severity of lymphedema [23], further implicating weight as a major factor contributing to the risk of developing lymphedema. Recent evidence also suggests that exercise and movement contribute to the overall health and well-being of lymphedema

A.M. Steely and P. O’Brien

patients by stimulating the lymphatic system and increasing muscle mass, which increases lymphatic flow. Historically, women who had undergone surgical or radiation therapy for the treatment of breast cancer were told to avoid upper extremity exercise to prevent exacerbation of lymphedema. However, two recent randomized and prospective trials found that supervised exercise did not increase the risk of or exacerbate preexisting lymphedma [23]. Moreover, exercise has been found to increase flexibility, aerobic capacity, strength, mood, and well-being in patients suffering from lymphedema. In fact, a recent study indicates that exercise and weight lifting with the affected arm is actually beneficial to the overall health of lymphedema patients; this study concluded that there was a decreased incidence of exacerbations of lymphedema, a reduction in symptoms, and an increase in muscle and overall strength [26]. As an added benefit, exercise helps decrease the likelihood of developing obesity, which is a major risk factor for lymphedema in and of itself. Petrek et al. [22] report that they found the most important events associated with the development of lymphedema in the years subsequent to initial diagnosis of breast carcinoma to be infection and weight gain, which are both under the patient’s control to some extent. A statistically significant association was observed between a history of arm infections requiring antibiotics or arm injuries and the presence of lymphedema at 20 years postsurgical follow-up. Additionally, late-onset lymphedema was associated with a history of infection and injury [22]. Since lymphedema is a chronic condition that can easily flare up, extra care must be taken to prevent its exacerbation. This is where patient education becomes a key factor in the overall health and well-being of patients with lymphedema. While historically, most recommendations regarding the lifestyle of patients suffering from lymphedema focused on the limitation of activities and procedures that could be performed with/on the lymphedema-afflicted arm, modern research suggests that education and a “common sense” approach makes the most sense. Patients that understand their own post cancer treatment physiology and risk factors for the lymphedema can take better “ownership” of their own care. The Lance Armstrong Foundation has encouraged all cancer survivors to receive “Cancer Treatment Summaries” so that they can understand what treatments they have had, and to understand their longterm risk factors for complications from that treatment. The Survivorship Movement within the cancer community will help encourage this patient ownership and education.

Diagnostic Testing Despite the overwhelmingly common nature of this chronic condition, no unanimously accepted criteria for the diagnosis of lymphedema exist. The high degree of variability in

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measure­ment methodology, extent of surgical or radiationbased intervention, duration of follow-up, availability of lymphedema specialists, and reporting biases are likely contributing factors. Lymphedema assessment is based primarily on visual inspection. The physical measures include circumferential and volumetric measurements and some clinics use skin/soft tissue tonometry. It can also be diagnosed through radiology by ultrasound examination, magnetic resonance imaging (MRI), computer tomography scanning (CT scan), lymphangiography, and lymphoscintigraphy [4]. Bioelectric impedance analysis is another type of noninvasive measurement that can be used in the clinic. This looks at water content, and multiple companies now manufacture these tools. A major problem with current diagnostic criteria is the fact that circumference measurements do not quantify the volume of extra lymph fluid, which can accumulate in a nonuniform manner. Additionally, multiple measurement sites are important, as extra lymphatic fluid can accumulate preferentially in specific areas [22]. Moreover, low-grade lymphedema is difficult to measure but may be experienced as the sensation of heaviness and/or as a slight difference in appearance. Furthermore, a 2.5  cm difference is the most common definition for lymphedema, but this could be very disfiguring on a thin arm and hardly noticeable on an obese arm. Thus, the definition of lymphedema needs to be adapted to body size, as every patient and thus every case of lymphedema is unique. Water displacement has been regarded as the sensitive and accurate gold standard for volume measurement in the lab, but this methodology is rarely used in the clinical setting because it is cumbersome and messy [24] and has significant margins of error. Measuring circumferences at various points of the body is the most frequently used technique to quantify lymphedema, but again, several problems exist: not all body parts have a perfectly circular circumference, especially in the face of skin damage and again, and lymph fluid does not always accumulate in a uniform fashion. Additionally, though it is inexpensive and easy to perform, circumferential measurements for the diagnosis and management of lymphedema are highly nonspecific. The Perometer 400T/350S is an optoelectronic volumetry (OEV) device that was developed to quickly, hygienically, and accurately measure limb volume. It works like a CT scan but uses infrared light instead of X-rays [24]. Despite its ability to accurately assess lymphedema, there are a number of factors that limit its use. Due to the expense, it is commonly used only at larger research centers. Armer et al. [24], who compared four distinct diagnostic criteria for assessing lymphedema, found a great deal of variation in each methodology. Though it is not possible to claim with certainty which technique is most accurate, it is important to note that this study proves that there exist multiple distinct techniques that each has differing criteria for the diagnosis of lymphedema. One very important finding is that

baseline measurements are essential, since without them, there is no basis for assessment and therefore management. Ultrasonography is a good tool for use in the assessment of skin thickness, thereby rendering it an important tool for the diagnosis and management of lymphedema. It also has the included benefits of being portable, user-friendly, radiation-free, specific, fast, and painless. Ultrasound technology is typically used in many cancer centers as it also allows evaluation of lymph nodes. It is important to detect breast edema and intervene early in its course, as its progression to the arm is likely, given that the breast and the ipsilateral upper extremity share the axillary lymph nodes as the major lymphatic drainage route [27].

Treatment of Lymphedema Lymphedema is generally regarded as an incurable and chronic condition since it often results from disruption of the lymphatic structures that prevent its development [2]. Thus, subclinical lymphedema likely exists whenever disease or treatment intervention disrupts lymphatic flow or its elements. When thinking about the supportive care of the cancer patient, it may be helpful to identify the patient’s lymphedema stage. One might modestly consider all cancer patients to be at lymphedema stage 0 or to have latent lymphedema if they have had some disruption to their lymphatic system due to disease or treatment. Stage 0 disease is followed by 3 increasingly progressive stages of lymphedema that are clinically characterized by their distinguishing features. Given that it is possible to assign a lymphedema stage to each cancer patient, education regarding appropriate precautions to prevent lymphedema progression may be helpful. When designing a supportive care program for the patient with lymphedema, it is important to identify the stage of the lymphedema and the mechanisms that precipitated progression to that more advanced stage of the disease. The treatment modalities required will depend on both the stage of the disease and the unique factors challenging that patient’s lymphatic system. As a result of the progressive nature of this condition, it is imperative that treatment matches the stage of lymphedema so that evolution from one stage to the next can be slowed and/or prevented (Fig. 19.2). It is important to note that while many initial presentations of clinically detectable arm lymphedema are mild, as many as 48% of those mild cases of lymphedema will progress to more severe cases, thereby bringing with them additional complications and frustration [10]. Early detection of infection and quick treatment can limit the progression of lymphedema. Treatment of lymphedema will vary with each patient but the same principals exist. Excellent skin care to prevent infection must be taught to the patient. Efforts should be made to mobilize the excess fluid through manual massage,

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A.M. Steely and P. O’Brien Treatment- or tumor-related injury to lymphatics

Pathways

Acute localized lymphedema

Resolves as watershed collaterals pick up overflow

Collateral lymphatics overload Early mild lymphedema

Inflammation, fibrosis Infection

Grade 0 lymphedema • Normal sensation • Normal appearance • Patient at risk to develop lymphedema, latent phase

Grade I lymphedema • Abnormal sensation • Normal or nearly normal on physical exam, pitting • Early intervention needed • Reversible with elevation

Grade II lymphedema • Low-grade chronic pain • Abnormal tissue texture • Irreversible with elevation due to fibrosis

Grade III lymphedema • Elephantitis • Persistent pain • Grossly abnormal • Irreversibly damaged tissue • Treatment will help decrease severity of symptoms

Fig. 19.2  Variable presentations of lymphedema (Courtesy of Dr. Patricia O’Brien, Department of Physical Therapy, University of Vermont, Burlington, VT, USA)

deep breathing to move deep lymphatics, or mechanical pumps. Various types of daytime and nighttime compression can be used to keep the fluid from recollecting. Patients should be taught to become independent with a home program to maintain their self-care. Lymphedema care must be individualized to meet the needs of the individual patient. Factors to take into consideration will be the stage of the lymphedema, the stage of the cancer, the cancer treatments that are planned, risk factors for infection or progression of the lymphedema, and the treatments that are accessible to the patient. Access to treatment is highly variable, for a variety of reasons: Therapists who understand cancer care and lymphedema are limited, insurance coverage of lymphedema treatment tools is highly variable, and patients may have personal preferences based on their lifestyle, fatigue, and many other factors. The cases below are examples of two complex cases of patients with metastatic disease. The team was able to develop comprehensive lymphedema care as part of their supportive care that worked for each patient’s unique needs.

Case 1:  Metastatic Breast Cancer The first case is a woman that presented with advanced metastatic breast cancer. She was treated with palliative radiation

therapy, which helped close the open draining wound she presented with at the time of initial diagnosis. She has done well clinically on hormonal therapy. She had significant chest wall and arm lymphedema on presentation. She continues to work and must use her arms at her employment on a regular basis. She is very motivated to be independent with her self-care program. She presented to physical therapy with a problem list that included impaired lymphatic flow, limited knowledge of lymphedema precautions and management, decreased range of motion and flexibility of the right shoulder, pain in the shoulder, and loss of function with many overhead activities. For her initial treatment, she was seen 1–2 times a week, receiving Complete Decongestive Therapy. This treatment included manual lymphatic drainage massage, compression strategies, patient education related to skin care and risk reduction management, and compression strategies (Figs. 19.3–19.5). The massage technique utilized the standard lymph node clearance, deep breathing, trunk clearance, and arm sequence. She was instructed in a self-massage program. The compression strategies utilized included Kinesio tape to assist in decongestion of her arm. In addition, she received an off the shelf Solaris nighttime garment, which this patient initially wore on/off throughout the day until she was able to tolerate it at night. Once the volume of her lymphedema stabilized, this patient had a custom daytime compression sleeve and glove,

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Fig.  19.3  Breast cancer-associated lymphedema with noncustom glove

Fig. 19.5  Breast cancer lymphedema with nighttime compression sleeve

As this patient progressed with her lymphedema, her p­ rogram was modified. To increase the support of the night garment, she was instructed to wrap over the forearm with short stretch bandage and later an outer jacket was fabricated to achieve this. She was issued commercial chip pads to assist with decongestion of the trunk. She underwent a series of treatments with multilayered short stretch wraps when her edema exacerbated. Lastly, she trialed and then purchased a pump to further assist in maintaining her volume. With her pump, she continues to utilize her daytime compression sleeve, her nighttime compression sleeve, daily self-massage, and her exercises. She continued to be active throughout her treatment working out of the house as a bartender. This demonstrates that a variety of tools can be used, and selection of these tools must be based on the unique needs of that patient, their stage of lymphedema, their stage of cancer, and their lifestyle choices.

Fig. 19.4  Breast cancer lymphedema with custom glove and sleeve

as well as a custom nighttime garment, fitted. The daytime sleeves are designed to hold the volume whereas the nighttime garment is designed to soften fibrosis and reduce ­volume. The nighttime garment is bulky; therefore, wearing it during the day is restricted to home as activities allow. Pads of foam of varying size and densities were fabricated to soften specific fibrotic areas and assist in moving fluid.

Case 2:  Metastatic Prostate Cancer This second case is a gentleman with lower extremity lymphedema secondary to advanced hormone-resistant prostate cancer. His prostate cancer has been treated with multimodality therapy, which has included surgery, radiation therapy, and chemotherapy. Multiple chemoagents have been used for an extended time, but he has progressive bulky pelvic disease that contributes to his risk for lymphedema. He is extremely active and has continued to hike around the world throughout

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his cancer treatments. He has taken his portable pump and lymphedema supplies with him on these adventures that have been an integral part of his life and an important part of his quality of life. Physical Therapy has worked with him to develop a chronic self-care program that fits his choices and needs (Figs. 19.6–19.8). The patient presented initially to physical therapy with chief complaint of lymphedema in the right lower extremity. This was noted following cross-country skiing and had not responded to use of TED hose. He was evaluated by physical therapy and then initially treated with traditional complete

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decongestive therapy consisting of manual lymphatic drainage. He initially was fit to a Class 1 (20–30 mmHg) thighhigh stocking for daytime use and a custom nighttime leg unit. He had a lot of fibrotic tissue initially in the buttocks and upper leg, as well as fluctuating volumes of edema in his genitals, buttocks, and leg. All these responded well to compression wrapping and massage techniques, and the patient stabilized despite evolving cancer status and was eventually discharged to self-management. Later on, the patient developed metastatic disease, and lymphedema progressed to involve his genitals as well as the right leg. He developed fibrosis in his buttock and upper leg as well as in the genitals. Additional therapy tools were needed to manage this worsening condition. The patient was fitted to chip pads, which were custom-made by his therapist with foam of various densities, chipped into small pieces of less than 1 cm diameter, and layered within adhesive gauze in a shape determined by the therapist. The pad was then placed in the patient’s garments or wrapped directly against fibrotic tissue. In addition, the patient used compression bandages applied by the therapist until a stable limb volume could be obtained at which point he was transitioned to garments for various activities. These included compression bike shorts from an athletic store, an extra bike short pad worn within the shorts to increase pressure on the genitals, a custom Solaris garment for the lower torso, custom stockings of 30–40 mmHg or 20–30 mmHg (often layered one over the other), and a custom Solaris leg unit with outer compression jacket which could be adjusted for increased pressure on the limb at night.

Fig. 19.6  Prostate cancer with compression stocking

Fig. 19.7  Prostate cancer with lower extremity pump

Fig. 19.8  Prostate cancer with nighttime compression garment

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To promote lymphatic drainage between self-massage ­sessions, the patient wore compression tape along lymphatic drainage pathways on his trunk and leg. These various garments and tools worked well for the patient for several years, until additional metastases formed, which presumably created additional lymphatic blockage. At this point, his treatment was modified to include use of a pneumatic pump. His pump is attached to custom “Lympha Pants,” which are a multichamber garment worn from the metatarsals to the lower rib cage, which inflates in sequence to promote lymphatic drainage similar to a manual lymphatic drainage massage done by a therapist. The patient continues to be actively treated in oncology and at this point is independent with management of his chronic lymphedema with use of the many treatment options and tools he has been provided with over the past 6 years. These cases were chosen to reflect that even with advanced metastatic cancer, there are options to get good symptomatic control of lymphedema. Patients may need to use a variety of tools in a chronic self-care program. Patient education and motivation are key to long-term lymphedema control. Early intervention is important in any problem. In lymphedema, the tools for early intervention may be totally different from those needed for more advanced disease. The tools and the intervention need to be matched to problem.

Other Treatment Modalities 1. Laser Therapy. Low-Level Laser therapy has been found to be a useful adjunctive therapy in limited small studies. It has been reported to decrease the volume of the affected limb in breast cancer patients [2]. Further research is needed. 2. Gene Therapy. Gene therapy is an emerging area of medicine that may also have a role in the treatment of lymphedema. Jig et al. [4] recently reported that treatment of axillary lymph node dissected mice with an adenovirally delivered VEGF-C or VEGF-D recombinant protein stimulated the growth of the initial lymphatic system, which matured into a functional lymphatic system, even in the absence of lymph nodes. Additional studies must be performed to determine if this same effect could be achieved in a human subject and whether a single recombinant adeno-associated virus administration is sufficient to induce lifelong transgene expression [4]. However, the potential promise of such an agent provides an immense amount of hope for patients whose lives are significantly impacted by chronic lymphedema. Currently, the best treatment of all is prevention and early diagnosis to prevent further complications of this chronic condition [4]. 3. Lymph Node Transplantation. Lymph node transplantation is not a new concept. This type of surgery has been

attempted via various surgical methods for over 20 years. Microsurgical attempts have typically worked only for short periods, due to fibrosis of the anastomosis. Newer attempts to transplant lymph-node beds from the inguinal area to the axilla have given mixed results. Referring physicians and patients should be advised to research the long-term outcome results of the center offering this procedure before considering this invasive treatment.

Quality of Life and Psychosocial Issues Cellulitis Lymphedema, while a problem on its own, can also lead to associated complications, such as cellulitis, lymphangitis, and capsulitis, since the immune system cannot respond as well to foreign bacteria and debris in these swollen areas, thereby predisposing these patients to systemic infections. These inflammatory conditions can lead to sepsis and permanent damage if not corrected in a timely fashion with oral and intravenous antibiotics, though swelling may persist following treatment. Lymphangitis and cellulitis are unfortunately very common in lymphedema patients, since the swollen tissues of stagnant protein provide a fertile environment for growth of microscopic organisms. Repeated infections leads to irreversible changes in the tissue that may include fibrosis, hyperkeratosis, and extensive tissue remodeling referred to as elephantiasis [1].

Pain Lymphedema may or may not be painful. Sudden changes in fluid volume that compresses nerves may be acutely painful. Many of these patients may have significant scar tissue from radiation and surgery so that swelling in these areas may be very sensitive. Tumor may be associated with lymphedema, and it may be difficult to sort out tumor-related pain and lymphedema-related pain. Pain of any kind needs to be evaluated, and lymphedema care may be an adjunct to help resolve or alter the pain syndromes in some challenging care patients.

Psychosocial Issues While the physiologic complications are numerous, there are also many psychological and emotional symptoms that

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accompany lymphedema. For example, patients may ­experience alterations in the sensation of the limb, decreased physical activity, loss of body confidence, psychological distress, including depression, anxiety and frustration, and fatigue, which all contribute to a reduction in the patient’s quality of life. Breast cancer patients with lymphedema may also experience social isolation and sexual problems [27]. Additionally, there is often a great deal of pain, discomfort, reduction in strength, and difficulties with arm movement associated with lymphedema in breast cancer patients, further contributing to a decreased quality of life. Prominent themes associated with lymphedema include its pervasive impact, grief, loss, associated uncertainty, isolation, and social impacts [28]; therefore, lymphedema clearly impacts all facets of an individual’s life. A recent study conducted by Mak et al. found that Chinese women who had undergone axillary node dissection for the treatment of breast cancer and who developed clinically detectable lymphedema reported a reduced quality of life and increased distress related to their upper extremity lymphedema symptoms [29]. Thus, quality of life seems to be an underserved area in the care and treatment of cancer patients. This very fact was one of the major driving forces to explore treatment options outside of the traditional radical mastectomy like SLNB and selective ALND. These more modern techniques exploit our knowledge of cancer and human physiology and have the added benefit of carrying a reduced risk for the development of lymphedema. Velanovich et al. have documented the fact that postoperative lymphedema in breast cancer survivors truly does diminish quality of life and thus needs to be addressed in the whole care of these patients both preoperatively and postoperatively. This group found that body image was better maintained postoperatively with breast conservation. Moreover, intensive physical therapy and a self-management regimen dramatically improved the quality of life of patients suffering from lymphedema [30]. Thus, it is evident that the whole-body care of lymphedema patients is of critical importance to their well-being.

The Future of Lymphedema With such a high frequency of occurrence, one must wonder why the literature does not provide a plethora of research studies about lymphedema. While many factors contribute to the underresearched aspect of this condition that has not been a top priority in past years, some of the most prevalent factors contributing to the paucity of accessible information include the patient’s prolonged susceptibility to lymphedema throughout her/his survivorship [22]. The clinical oncologist is focused toward monitoring for cancer recurrence and not cancer treatment-related disabilities. There is growing interest in

A.M. Steely and P. O’Brien

the needs of long-term cancer survivors. These longitudinal outcome studies will assist in bringing to light the quality of life issues like lymphedema. The growing number of cancer survivors, many of whom suffer now or will suffer from lymphedema, requires that we, as health care providers, be well versed in the etiology and available treatment options to this chronic condition. Thus, it is our hope that as the number of cancer survivors continues to grow this chapter serves as a valuable resource and primer for the ever-evolving supportive care of newly diagnosed, recovering, and surviving cancer patients around the world with lymphedema. Acknowledgments  The department of physical therapy at Fletcher Allen Health Care assisted in the patient photographs and the lymphedema-care summaries.

References 1. Hayes SC, Janda M, Cornish B, Battistutta D, Newman B. Lymphedema after breast cancer: incidence, risk factors, and effect on upper body function. J Clin Oncol. 2008;26(21):3536–3542. 2. Lawenda BD, Mondry TE, Johnstone PA. Lymphedema: a primer on the identification and management of a chronic condition in oncologic treatment. CA Cancer J Clin. 2009;59(1):8–24. 3. Nakamura K, Rockson SG. Molecular targets for therapeutic lymphangiogenesis in lymphatic dysfunction and disease. Lymphat Res Biol. 2008;6(3–4):181–189. 4. Ji RC. Lymphatic endothelial cells, lymphedematous lymphangiogenesis, and molecular control of edema formation. Lymphat Res Biol. 2008;6(3–4):123–137. 5. O’Brien P. Lymphedema Research 2001. 6. Cao Y. Why and how do tumors stimulate lymphangiogenesis? Lymphat Res Biol. 2008;6(3–4):145–148. 7. Sarnaik AA, Puleo CA, Zager JS, Sondak VK. Limiting the ­morbidity of inguinal lymphadenectomy for metastatic melanoma. Cancer Control. 2009;16(3):240–247. 8. Garmy-Susini B, Varner JA. Roles of integrins in tumor angiogenesis and lymphangiogenesis. Lymphat Res Biol. 2008;6(3–4):155–163. 9. Norman SA, Localio AR, Potashnik SL, et  al. Lymphedema in breast cancer survivors: incidence, degree, time course, treatment, and symptoms. J Clin Oncol. 2009;27(3):390–397. 10. Bar Ad V, Cheville A, Solin LJ, Dutta P, Both S, Harris EE. Time course of mild arm lymphedema after breast conservation treatment for early-stage breast cancer. Int J Radiat Oncol Biol Phys. 2010; 76(1):85–90. 11. Deutsch M, Land S, Begovic M, Sharif S. The incidence of arm edema in women with breast cancer randomized on the National Surgical Adjuvant Breast and Bowel Project study B-04 to radical mastectomy versus total mastectomy and radiotherapy versus total mastectomy alone. Int J Radiat Oncol Biol Phys. 2008;70(4):1020–1024. 12. Nesvold IL, Dahl AA, Lokkevik E, Marit Mengshoel A, Fossa SD. Arm and shoulder morbidity in breast cancer patients after breastconserving therapy versus mastectomy. Acta Oncol. 2008;47(5): 835–842. 13. Golshan M, Martin WJ, Dowlatshahi K. Sentinel lymph node biopsy lowers the rate of lymphedema when compared with standard axillary lymph node dissection. Am Surg. 2003;69(3):209–211; discussion 212. 14. Schijven MP, Vingerhoets AJ, Rutten HJ, et al. Comparison of morbidity between axillary lymph node dissection and sentinel node biopsy. Eur J Surg Oncol. 2003;29(4):341–350.

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19  Lymphedema Care 15. Chen JJ, Huang XY, Liu ZB, et al. Sentinel node biopsy and quality of life measures in a Chinese population. Eur J Surg Oncol. 2009;35(9):921–927. 16. Boneti C, Korourian S, Bland K, et al. Axillary reverse mapping: mapping and preserving arm lymphatics may be important in preventing lymphedema during sentinel lymph node biopsy. J Am Coll Surg. 2008;206(5):1038–1042; discussion 1042–1044. 17. Hayes SB, Freedman GM, Li T, Anderson PR, Ross E. Does axillary boost increase lymphedema compared with supraclavicular radiation alone after breast conservation? Int J Radiat Oncol Biol Phys. 2008;72(5):1449–1455. 18. Moore RG, Robison K, Brown AK, et al. Isolated sentinel lymph node dissection with conservative management in patients with squamous cell carcinoma of the vulva: a prospective trial. Gynecol Oncol. 2008;109(1):65–70. 19. Bennett Britton TM, Wallace SM, Wilkinson IB, Mortimer PS, Peters AM, Purushotham AD. Sympathetic nerve damage as a potential cause of lymphoedema after axillary dissection for breast cancer. Br J Surg. 2009;96(8):865–869. 20. Pinell XA, Kirkpatrick SH, Hawkins K, Mondry TE, Johnstone PA. Manipulative therapy of secondary lymphedema in the presence of locoregional tumors. Cancer. 2008;112(4):950–954. 21. Ronka RH, Pamilo MS, von Smitten KA, Leidenius MH. Breast lymphedema after breast conserving treatment. Acta Oncol. 2004;43(6):551–557. 22. Petrek JA, Senie RT, Peters M, Rosen PP. Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis. Cancer. 2001;92(6):1368–1377. 23. Poage E, Singer M, Armer J, Poundall M, Shellabarger MJ. Demystifying lymphedema: development of the lymphedema ­putting evidence into practice card. Clin J Oncol Nurs. 2008;12(6): 951–964. 24. Armer JM, Stewart BR. A comparison of four diagnostic criteria for lymphedema in a post-breast cancer population. Lymphat Res Biol. 2005;3(4):208–217. 25. Taylor ME, Keleti D, Perez CA, et  al. The effect of medical comordbidities of diabetes, hypertension and obesity on the incidence

of arm edema after breast conservation therapy for stage I and II breast cancer patients. Int J Radiat Oncol Biol Phys 2000; 48(Supplement):144. 26. Schmitz KH, Ahmed RL, Troxel A, et al. Weight lifting in women with breast-cancer-related lymphedema. N Engl J Med. 2009;361(7): 664–673. 27. Chachaj A, Malyszczak K, Pyszel K, et  al. Physical and psychological impairments of women with upper limb lymphedema ­following breast cancer treatment. Psychooncology. 2009;19(3): 299–305. 28. Hayes SC, Reul-Hirche H, Turner J. Exercise and secondary lymphedema: safety, potential benefits, and research issues. Med Sci Sports Exerc. 2009;41(3):483–489. 29. Mak SS, Mo KF, Suen JJ, Chan SL, Ma WL, Yeo W. Lymphedema and quality of life in Chinese women after treatment for breast cancer. Eur J Oncol Nurs. 2009;13(2):110–115. 30. Velanovich V, Szymanski W. Quality of life of breast cancer patients with lymphedema. Am J Surg. 1999;177(3):184–187; ­discussion 188.

Helpful Resources 31. The American Cancer Society http://www.cancer.org/docroot/MIT/ content/MIT_7_2x_Understanding_Lymphedema.asp 32. Lymphedema Resources http://www.lymphedemaresources.org/ 33. The National Lymphedema Network http://www.lymphnet.org 34. The Lymphatic Research Foundation http://www.lymphaticresearch. org 35. Fashionable Lymphedema Garments http://lymphedivas.com/ 36. Lymphedema People http://www.lymphedemapeople.com/ 37. Susan G. Komen Breast Cancer Foundation http://ww5. komen.org/ 38. Solaris Supplies http://www.solarismed.com/index.php

Part VIII

Infections in Cancer

Chapter 20

Infections and Cancer Bernardo L. Rapoport and Ronald Feld

Introduction Infections are major causes of morbidity and mortality in cancer patients. The risk of infection is determined by the intensity and duration of immunosuppressive chemotherapy. It is essential to know the patient’s quantitative and qualitative immune defects and to stratify the risk for specific pathogens in the context of the history, physical examination, and radiological and laboratory data. This chapter will deal with infections associated with malignancy in general, the predisposing factors, and with the management of the patients with febrile neutropenia.

Factors Predisposing to Infection in Patients with Cancer Cancer patients comprise a very heterogeneous population, both in terms of the underlying malignancy as well as the level of immunosuppression. Multiple predisposing factors may exist in a single patient.

Infections in Patients with Hematological Malignancies In patients with hematological malignancies, the underlining malignancy itself may be associated with immune defects. Patients with hematological malignancies associated with defective immunoglobulin production have an increased susceptibility to encapsulated bacteria, mainly Streptococcus

B.L. Rapoport (*) Department of Medical Oncology, The Medical Oncology Centre of Rosebank, Johannesburg 2196, South Africa e-mail: [email protected]

pneumoniae, recurrent sinopulmonary infections, septicemia, and disseminated infection. • Chronic lymphocytic leukemia: This is frequently associated with hypogammaglobulinemia [1], and the low levels of immunoglobulin (IgG) increase the risk of severe infections in these patients [1]. • Multiple myeloma and other related plasma cell dyscrasias: These patients are often functionally hypogammaglobulinemic, despite the fact that the total level of immunoglobulin production is elevated as the antibodies produced are inadequate. Early reports by Savage et  al. [2] noted a biphasic ­pattern of infection among multiple myeloma patients. Infections by S. pneumoniae and Haemophilus influenzae occurred early in the disease, while patients responding to chemotherapy had a higher incidence of bacterial infections mainly by Staphylococcus aureus and gram-negative organisms. This occurred more commonly in advanced disease and during neutropenia. Therapy with bortezomib increases the risk for reactivation of the herpes simplex and herpes zoster viruses. Stem cell transplantation has broadened the spectrum of infection to include those caused by Clostridium difficile, cytomegalovirus (CMV), and opportunistic molds [3]. • Hairy-cell leukemia: Infections are a major cause of morbidity and mortality in patients with hairy-cell leukemia, presumably due to neutropenia and monocytopenia. The infections seen may be due to unusual pathogens, including Mycobacterium and Listeria [4]. • Hodgkin disease: Patients with untreated Hodgkin disease have significant immune abnormalities that persist in the majority of long-term survivors [5]. Such patients are at increased risk for toxoplasmosis, nocardiosis, pneumocystosis, cryptococcosis, mycobacterial infections, and herpes zoster. Most opportunistic infections occur with uncontrolled malignancy when patients are treated with corticosteroids, chemotherapy, or both [6]. • HIV-related non-Hodgkin lymphoma (NHL): This represents another subset of cancer patients at risk of opportunistic infection [7].

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_20, © Multinational Association for Supportive Care in Cancer Society 2011

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Infections in Patients with Solid Tumors In solid tumors, anatomical factors may predispose patients to infection. Tumors that overgrow their blood supply become necrotic and infected. • Head and neck tumors may cause erosion through the neck and floor of the mouth. • Esophageal cancer may increase the risk of aspiration pneumonia. • Endobronchial lung tumors are associated with recurrent postobstructive infections. • Abdominal tumors may obstruct the genitourinary or hepatobiliary tracts, predisposing to pyelonephritis and cholangitis, respectively. • Tumor invasion through the colonic mucosa is associated with local abscess formation by enteric flora. • Breast cancer patients have an increased risk of abscess formation, usually by S. aureus.

Effect of Radiation Therapy Local radiotherapy is associated with loss of epithelial integrity, necrosis, and loss of blood supply, resulting in poor wound repair. Visceral complications include radiation pneumonitis, esophagitis, and enteritis.

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less frequent at 100–500/mL and 500–1,000/mL. This relationship was sustained independent of the disease status (relapse or remission); however, the overall risk of infection was greater during relapse. Most disseminated fungal infections and septicemias occurred when the ANC was less than 500/mL. Neutropenia (of less than 100/mL) resulted in infections in all patients within 3 weeks and in severe infections within 6 weeks. The likelihood of survival from severe infections was related to both the initial granulocyte level and whether an increase in the neutrophil count occurred within the first week. The risk of invasive aspergillosis is also directly related to the duration of neutropenia. In patients with leukemia, Gerson et al. showed that aspergillosis was uncommon when neutropenia lasted for less than 2 weeks [10]. However, after day 14, the risk of aspergillosis increased in direct proportion to the length of neutropenia. Invasive aspergillosis is also a major mortality cause in patients with persistent neutropenia in the bone marrow transplant (BMT) setting [11]. The diagnosis of infection in granulocytopenic patients may be delayed by the lack of typical signs and symptoms. Fever was present in virtually all patients with an ANC less than 100/mL. However, in patients with similar infections, physical findings of infection were less frequent in neutropenic than in nonneutropenic patients.

Mucosal Immunity Intravenous Devices Implantable intravenous devices and A-ports used for administration of chemotherapy are potential sources of infection [8].

Effect of Neutropenia Neutropenia may develop independently of chemotherapy in patients with acute leukemia and myelodysplastic syndromes. In these conditions, the marrow may be replaced with malignant cells and patients develop neutropenia. Patients rendered neutropenic by myeloablative chemotherapy are likely to be at greater risk for life-threatening infections due to the concomitant disruption of epithelial mucosal barriers by such agents. The relationship between circulating leukocytes and risk of infection was established by Bodey et al. in patients with acute leukemia [9]. It has been established that the frequency of severe infections was the highest when the absolute neutrophil count (ANC) was less than 100/mL and proportionately

Treatment with chemotherapy and radiation therapy is associated with defects in mucosal immunity at several different levels. The mucosal linings in the gastrointestinal, sinopulmonary, and genitourinary tracts constitute the first line of host defense against a variety of pathogens. The physical protective barrier conferred by the epithelial lining is damaged, thus allowing access to colonizing microflora. In BMT patients, chronic graft-versus-host disease (GVHD) further affects mucosal immunity.

Immunosuppressive Agents Not Related to Neutropenia Corticosteroids Corticosteroids have profound effects on the distribution and function of neutrophils, monocytes, and lymphocytes. They induce a neutrophilic leukocytosis by accelerating the release of neutrophils from the bone marrow and by inhibiting the egress of neutrophils from the circulation. Corticosteroids

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reduce the adherence of neutrophils to the endothelium, thus inhibiting migration to inflammatory sites [12]. Corticosteroids elicit a peripheral blood monocytopenia. In addition, the following impaired monocyte functions have been documented: (1) chemotaxis, (2) bactericidal activity, (3) production of interleukin-1 (IL-1), and (4) tumor necrosis factor-alpha (TNF-alpha). Corticosteroids inhibit T-cell activation and peripheral lymphocytopenia. This redistribution predominantly involves T cells. At high doses, corticosteroids also inhibit immunoglobulin generation by B cells. In patients with cancer, corticosteroids are used in high doses and often in combination with other immunosuppressive agents. These patients are highly susceptible to a broad spectrum of bacterial, fungal, viral, and protozoal pathogens.

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Splenectomy The spleen is a reservoir in which rapid antigen presentation occurs, leading to the production of opsonizing antibodies by B cells. Splenic macrophages remove both opsonized and nonopsonized particles from the blood stream. The removal of nonopsonized bacteria is a particularly important function to protect against encapsulated bacteria to which the patient is not immune. Asplenic patients are primarily at risk for overwhelming sepsis by encapsulated bacteria. The most common pathogen is S. pneumoniae, but other pathogens include H. influenzae and Neisseria meningitidis [18]. Asplenic patients should be advised to seek medical attention when fever occurs.

Bone Marrow Transplantation Monoclonal Antibodies 1. Rituximab is an antiCD20 monoclonal antibody that has demonstrated efficacy in patients with various lymphoid malignancies, including indolent and aggressive forms of B-cell NHL, chronic lymphocytic leukemia, posttransplant lymphoproliferative disorder, Waldenström’s macroglobulinemia, and idiopathic thrombocytopenic purpura (ITP) [13]. The use of rituximab was associated with a significant increase in the incidence of hypogammaglobulinemia between 12 and 24  months post stem cell transplant (SCT) [14]. Other studies have reported the occurrence of unexplained peripheral blood cytopenia, particularly neutropenia following rituximab treatment [15]. A concern associated with the prolonged administration of rituximab maintenance is viral reactivation. Several cases of hepatitis B reactivation have now been reported with the use of this agent. Accelerated cases of hepatitis C and increased viral loads have also been reported. Other viral reactivations that have been reported with rituximab use include adenovirus, CMV, and varicella-zoster virus (VZV) [16]. 2. Alemtuzumab is a humanized monoclonal antibody against CD52, an antigen found on the surface of normal and malignant lymphocytes. It is approved for the treatment of B-cell chronic lymphocytic leukemia. The exact mechanism by which alemtuzumab mediates its biological effects in vivo is not clearly defined. The antibody not only targets malignant cells but also affects normal, healthy immune cells. The cumulative effects of successive courses of treatments and the effect of the underlining malignancy have an adverse effect on patients’ immune responses to certain bacterial, fungal, and viral infections [17].

The spectrum of pathogens to which BMT recipients are most susceptible follows a time line corresponding to the predominant immune defects observed at different periods. In the early stage of BMT, neutropenia is the principal host defense defect. These patients are at risk for the same spectrum of bacterial and fungal infections that affect nontransplant patients who have been treated with potent myeloablative therapy. Severe mucocutaneous herpes simplex virus infection is also commonly observed in the first month of transplantation in association with chemotherapy-induced mucositis. After myeloid engraftment, fever and mucositis typically resolve, and the risk of serious bacterial and fungal infections decreases. After myeloid engraftment, a qualitative dysfunction of phagocytes persists due to corticosteroid therapy and other immunosuppressive agents. The risk of infection by filamentous fungi during this period is strongly associated with the severity of GVHD and the requirement for potent immunosuppressive regimens [19].

Evaluation and Management of Febrile Neutropenia Patients with cancer and neutropenic fever often have an established or an occult infection, and bacteremia is documented in approximately a quarter of these patients. Patients with febrile neutropenia have an occult infection and they don’t have localized symptoms or signs. The clinical history may only be restricted fever following chemotherapy treatment. Due to the potential for rapid progression to severe sepsis, prompt initiation of empiric antibiotics is indicated. The risk of bacteremia is related to the intensity (with an ANC of less than 100/mL carrying the greatest risk) and the

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duration of neutropenia. A rapid decrease in the neutrophil count may also be a risk factor for infection, whereas evidence of bone marrow recovery even if the neutrophil count is still less than 500/mL, is a positive prognostic factor. Neutropenic fever is defined as: 1. A single oral temperature of greater than 38.3°C (101°F) or greater than or equal to 38.0°C (100.4°F) over at least 1 h. 2. ANC less than 500/mL or less than 1,000/mL with predicted rapid decline to less than 500/mL. The evaluation of a patient with febrile neutropenia begins with a careful history and physical examination. Prior invasive candidiasis or fungal infection may recur during subsequent neutropenic periods. Prolonged neutropenia is associated with invasive fungal infections (IFIs). The duration of neutropenia correlates with the risk of serious infectious complications. In these settings, patients with leukemia and BMT recipients are at higher risk. Certain clinical settings are important to identify in patients with febrile neutropenia. It is very important to recognize that the typical signs of infection may be blunted or even absent as a result of immunosuppression in the clinical setting of febrile neutropenia. • Recent colitis caused by C. difficile should raise a suspicion of recurrent infection in a patient presenting with neutropenic fever and diarrhea. • Patients undergoing corticosteroid treatment: This raises the possibility of opportunistic infection (such as Pneumocystis carinii). A physical examination is mandatory. • Mucositis may occur following chemotherapy treatment. Severe mucositis may be very difficult to distinguish from herpes infection. The presence of oral candidiasis is associated with impaired immunity. In patients with prolonged neutropenia, or those patients who are undergoing concomitant high-dose corticosteroid therapy, fungal infection of the palate (Zygomycete or Aspergillus species) may require urgent surgical management. A black necrotic region is the most common sign of such infections. Specific aspects of the clinical examination of a febrile neutropenic patient include: (1) ophthalmologic and anterior sinuses examinations, (2) detailed inspection of the skin and the nails, (3) inspection of catheter sites and surgical wounds and biopsies, and (4) inspection and palpation of the perineum and perianal regions. An ENT specialist consultation may be warranted in some cases. • Inspection of the skin and nails may reveal lesions suggestive of systemic infection (ecthyma gangrenosum caused by Pseudomonas aeruginosa or erythematous papules caused by disseminated candidiasis). The initial laboratory evaluation should include the following: complete blood cell and differential count and differential

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serum chemistry including liver function tests, two sets of blood cultures from different sites (including one from each lumen of the central venous catheter), a urine culture, and a chest radiograph. Details of potential sites of infection, such as skin lesions or sputum, should be obtained before starting antibiotic therapy. Febrile neutropenia should be considered a medical emergency, and prompt initiation of empiric antibiotics should not be delayed if culture material is not immediately available [20]. After the initial physical examination, it is critical to reevaluate the patient regularly to monitor the response to therapy and to identify evolving signs of infection that were not present during the initial evaluation.

Empiric Antibiotic Regimes Historical Perspective In the early 1970s, Schimpff and colleagues conducted a study of patients with cancer and febrile neutropenia who were treated empirically with carbenicillin and gentamycin. Treatment of patients with P. aeruginosa infection had dramatic survival improvement compared with historic controls. This study was the basis for empiric combination antibiotic therapy [21]. Empiric combination therapy increases the likelihood that at least one antibiotic will have activity against the isolate before the availability of susceptibility data. In addition, the beta-lactam plus an aminoglycoside gentamycin combination has synergistic bactericidal activity in vitro. Since this early study, typical combination regimens for neutropenic fever have included an antipseudomonal penicillin plus an aminoglycoside with or without a drug with antistaphylococcal activity, such as vancomycin. In the 1980s, there was a shift in the relative prevalence of specific pathogens afflicting patients with cancer. Whereas in the 1960s and 1970s, gram-negative bacterial pathogens (Enterobacteriaceae and P. aeruginosa) were the principal causes of bacteremia, in the 1990s and 1980s, gram-positive bacterial pathogens became predominant [22]. Recent data analysis has shown that the prompt empirical usage of a broad spectrum beta-lactam antibiotics with antipseudomonal activity is sufficient as an initial antibiotic therapy for febrile neutropenic patients. Meta-analyses have shown that the usage of a combination treatment with a broad spectrum of beta-lactam antibiotics with antipseudomonal activity and aminoglycoside antibiotic resulted in increased toxicity and similar survival [23–25]. The addition of aminoglycoside antibiotics (which used to be the standard of care) should be limited to patients who

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are hemodynamically unstable. Ciprofloxin is an important alternative to aminoglycoside antibiotics in this setting (as part of a combination regimen), particularly in those patients with impaired renal function [23–25]. The rationale for adding vancomycin to an empiric regimen for neutropenic fever stems from the increased proportion of infections by gram-positive bacteria. The change in the proportion of infections in neutropenic patients from predominantly gram-negative to gram-positive bacteria is associated with the widespread use of intravenous catheters in this patient population. Occasionally, one might need to use new gram-positive antibiotics for pathogens not sensitive to vancomycin. Some examples include tigecycline, daptomycin, and telavancin, but none of these has been used extensively in this setting [26]. Catheter-associated infection by coagulase-negative staphylococci has become the most common cause of bacteremia in patients with cancer. Among the common grampositive infections in neutropenic patients, the following are typically resistant to cephalosporins: MRSA, coagulase-negative Staphylococcus species, and Enterococcus species [22]. Numerous studies have evaluated single and multiple drug regimens with and without vancomycin. In the largest study, ceftazidime plus amikacin with and without vancomycin were compared in patients with febrile neutropenia in Europe and Canada [27]. The addition of vancomycin to the empiric regimen was not associated with any benefit with regard to duration of fever or morbidity or mortality related to gram-positive infections. The initial empiric antibiotic coverage with vancomycin or other anti gram-positive bacterial pathogens should be avoided in most patients as this approach is associated with higher toxicity and increased cost and no improvement in overall outcome. Today, with the availability of highly effective monotherapy regimens such as merepenem, cefipime, piperacillin, and tazobactam for neutropenic fever, initial empiric duo-therapy regimens may be most appropriate in unstable patients and in institutions in which multidrug-resistant pathogens are frequently encountered [28].

Persistent Fever in the Neutropenic Patient The patient should be very closely observed after selection of an initial empiric regimen for neutropenic fever. Physical examinations should be performed at least daily throughout the duration of neutropenic fever. Modifications of the initial antibiotic regimen should be made on the basis of new physical examination findings (pointing to a previously not apparent focus of infection), and radiographic and culture data.

Patients with persistent fever and a positive blood culture before or during the start of empirical antibiotic therapy for febrile neutropenia, or those with venous catheter sepsis should be considered candidates for anti gram-positive antibiotic treatment with vancomycin or linezolid, if resistant to vancomycin. Antibiotic therapy should be continued for the duration of neutropenic fever. New symptoms and signs of infection in neutropenic patients may be very subtle and should be aggressively investigated. Signs and symptoms should be systematically evaluated on a daily basis.

Common Scenarios in This Setting Include • Biopsy and culture may be necessary if a new erythematous papular lesion develops, as this may be indicative of cutaneous or disseminated bacterial or fungal infection. • Catheter sites, surgical wounds, and biopsy sites should be carefully examined for signs of infection. Fever and local tenderness may be the only signs of infection in the neutropenic patient. • A diffuse maculopapular rash may be suggestive of a drug etiology; cultures should be performed to exclude infection. • Blurred vision is an important clinical sign. It may also represent a central nervous system (CNS) process or could be indicative of keratitis or endophthalmitis caused by a bacterial, viral, or candidal infection. Careful ophthalmologic examination by a specialist may be needed to establish the diagnosis. A magnetic resonance imaging (MRI) scan of the brain with or without a lumbar puncture may be indicated. • In patients receiving high doses of corticosteroids, upper respiratory tract symptoms in a persistently neutropenic patient (longer than 10 days) may be indicative of a fungal infection. A computerized tomography (CT) scan is more sensitive and provides superior evidence of disease compared to a chest radiograph. Aspiration or biopsy of lesions should be performed where possible, especially in patients with persistent radiological evidence of pulmonary infiltration. The use of serial serum galactomannan in combination with chest CT might be useful to detect early aspergillosis [29–31]. False-negative results are common especially in patients already receiving antifungal agents. The b-d-glucan test also has false-positive and false-negative results [32]. • In cases of suspected bowel or perianal infection, the antibiotic regimen should have broad-spectrum activity against anaerobes, such as metronidazole.

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Superinfection During Neutropenia Should persistent fever be present, blood cultures from different sites should be obtained frequently to avoid a delay in adjusting the antibiotic regimen.

Empiric Antifungal Therapy Before standard implementation of empiric antifungal therapy, there was a high mortality in patients with cancer due to fungal infections (frequently found at autopsy). Randomized prospective studies demonstrated that empiric amphotericin B was associated with fewer fungal infections in antibiotictreated neutropenic patients with persistent fever [33]. Because fungal infections are uncommonly encountered in the first 7 days of neutropenic fever, empiric antifungal therapy is typically begun between days 4 and 7 of neutropenic fever and should be continued for the duration of neutropenia. Liposomal Amphotericin B’s (L-AmB) efficacy is similar to that of conventional amphotericin for empiric therapy, but with fewer adverse events. Because the overall success rate of voriconazole was lower than that of L-AmB in a study in febrile neutropenic cancer patients, and because noninferiority was not demonstrated, voriconazole did not receive FDA approval as empiric therapy [34]. In a randomized, comparative trial of caspofungin versus L-AmB in cancer patients (<10% HCT) with febrile neutropenia, the agents were comparable in overall response, breakthrough IFI, and resolution of fever during neutropenia, although caspofungin was superior for baseline infection resolution, survival through 7 days of follow-up, and discontinuations as a result of toxicity [35]. It should be considered that Zygomycetes can occur as a superinfection in patients treated with voriconazole, the standard therapy for documented or probable aspergillosis. Voriconazole should not be used to treat this infection, if present [36, 37].

Outpatient Antibiotic Therapy for Neutropenic Fever Historically febrile neutropenia was associated with a high morbidity and mortality, and urgent treatment with systemic antibacterial therapy and hospital admission were regarded as necessary. Inpatient observation was typically continued until resolution of neutropenia. More recent studies have shown that patients with febrile neutropenia can be stratified according to their risk of developing major or ­life-threatening infectious complications.

B.L. Rapoport and R. Feld Table 20.1  Medical complications considered serious   1. Hypotension: systolic blood pressure less than 90 mmHg or need for pressor support to maintain blood pressure   2. Respiratory failure: arterial oxygen pressure less than 60 mmHg while breathing room air or need for mechanical ventilation   3. Intensive care unit admission   4. Disseminated intravascular coagulation   5. Confusion or altered mental state   6. Congestive cardiac failure seen on chest X-ray and requiring treatment   7. Bleeding severe enough to require transfusion   8. Arrhythmia or ECG changes requiring treatment   9. Renal failure requiring investigation and/or treatment with IV fluids, dialysis, or any other intervention 10. Other complications judged serious and clinically significant by the investigatora a All reviewed by one investigator. Viral or fungal, microbiologically documented primary infection during the febrile episode, without any described complication and resolving under therapy, was considered a part of the infectious process and was not considered a serious complication From [38]. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved

Table 20.2  MASCC scoring system Characteristic

Weight

Burden of illness: no or mild symptoms 5 No hypotension 5 No chronic obstructive pulmonary disease 4 Solid tumor or no previous fungal infection 4 No dehydration 3 Burden of illness: moderate symptoms 3 Outpatient status 3 Age < 60 years 2 Points attributed to the variable “burden of illness” are not cumulative The maximum theoretical score is therefore, 26 From [38]. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved

In terms of risk assessment, the MSACC has pioneered work in this field and developed an index that predicts for high risk or low risk of medical complications (see Table 20.1) [38]. The index consists of seven independent prognostic factors with an assigned integer value. The index consists of the sum of these integers. Patients with a MASCC risk index equal to or greater than 21 are identified as low-risk patients with a positive predictive value of 91% (specificity 68% and sensitivity 71%) (see Table 20.2). The index is being validated by other institutions in their respective patient populations and clinical settings [39, 40]. Patients with a risk index greater than 21 may be candidates for outpatient antibiotic therapy for febrile neutropenia. Prospective randomized studies have suggested that patients in the lowest risk group are reasonable candidates for carefully monitored empiric outpatient antibiotic therapy.

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Patients with a duration of neutropenia of 7 days or less are considered to be at low risk for serious infectious complications and were also far less likely to require modifications in the initial antibiotic regimen compared with patients with neutropenia lasting longer than 14 days. The greatest concern about early hospital discharge or outpatient management of neutropenic fever relates to the possibility of life-threatening complications that may be reversible if detected early, and appropriate interventions are immediately implemented (e.g., intravenous fluid, vasopressors, broadening of antibiotic coverage). The results of most outpatient antibiotic therapy studies are encouraging about the safety of outpatient antibiotic therapy for low-risk patients with neutropenic fever [39–43]. However, important limitations exist in making broad conclusions. The prospective studies described previously individually each enrolled fewer than 200 patients, and therefore lacked sufficient power to detect small differences between treatment groups. Pooling data from different studies in the form of a meta-analysis is difficult due to the differences in eligibility criteria, choice of antibiotics, criteria for hospital admission and discharge, and criteria for a successful outcome. Although outpatient antibiotic therapy for febrile neutropenic patients is widely used, this approach cannot be considered routine standard care. Randomized clinical trials with sufficient statistical power are required to further define more precisely patients for whom outpatient management of neutropenic fever is safe and to further delineate optimal antibiotic regimens (oral vs. parenteral) for different patient subgroups. Key issues for outpatient management include the observation of low-risk patients by adequate staff who are experienced with this patient population and such approaches, the facility must be in a geographic location, in proximity to an emergency care facility as well as having adequate infrastructure for emergency management. These facilities should also include fluid resuscitation, intravenous antibiotics, and high care facility in the institution treating the patient. Patients with severe sepsis or septic shock should be treated aggressively with fluid resuscitation and prompt administration of broad spectrum intravenous antibiotics including vancomycin is reasonable. Antifungal therapy should be strongly considered early in the course of management. Modifications of the antibiotics should be made as soon as the culture results and sensitivity data are available. The use of prophylactic granulocyte-colony stimulating factors (G-CSFs) has shown benefits in terms of reducing the time to neutrophil recovery and the duration of fever and hospitalization in patients with acute leukemia. However, the prophylactic usage of G-CSF is costly and is not associated with a reduction in treatment-related mortality. The American Society of Clinical Oncology (ASCO) has established authoritative guidelines in the treatment related to the prophylactic and therapeutic use of G-CSF in clinical practice [44].

Febrile neutropenia in low-risk patients is associated with a favorable outcome. Future randomized studies should ­validate outpatient antibiotic therapy. New approaches are needed in patients at high risk, in addition to standard antibiotic therapy to improve the outcome in this subset.

References 1. Morrison VA. Infectious complications in patients with chronic lymphocytic leukemia: pathogenesis, spectrum of infection, and approaches to prophylaxis. Clin Lymphoma Myeloma. 2009; 9: 365–70. 2. Savage DG, Lindenbaum J, Garrett TJ. Biphasic pattern of bacterial infection in multiple myeloma. Ann Intern Med. 1982; 96: 47–50. 3. Nucci M, Anaissie E. Infections in patients with multiple myeloma. Semin Hematol. 2009; 46: 277–88. 4. Kraut EH. Clinical manifestations and infectious complications of hairy-cell leukaemia. Best Pract Res Clin Haematol. 2003; 16: 33–40. 5. Fisher RI, DeVita VT Jr, Bostick F, Vanhaelen C, Howser DM, Hubbard SM, Young RC. Persistent immunologic abnormalities in long-term survivors of advanced Hodgkin’s disease. Ann Intern Med. 1980; 92: 595–9. 6. Lavoie JC, Connors JM, Phillips GL, Reece DE, Barnett MJ, Forrest DL, Gascoyne RD, Hogge DE, Nantel SH, Shepherd JD, Smith CA, Song KW, Sutherland HJ, Toze CL, Voss NJ, Nevill TJ. High-dose chemotherapy and autologous stem cell transplantation for primary refractory or relapsed Hodgkin’s lymphoma: long-term outcome in the first 100 patients treated in Vancouver. Blood. 2005; 106: 1473–8. 7. Bower M, Palmieri C, Dhillon T. AIDS-related malignancies: changing epidemiology and the impact of highly active antiretroviral therapy. Curr Opin Infect Dis. 2006; 19: 14–9. 8. Vescia S, Baumgärtner AK, Jacobs VR, Kiechle-Bahat M, Rody A, Loibl S, Harbeck N. Management of venous port systems in oncology: a review of current evidence. Ann Oncol. 2008; 19: 9–15. 9. Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med. 1966; 64: 328–40. 10. Gerson SL, Talbot 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. 11. Bhatti Z, Shaukat A, Almyroudis NG, Segal BH. Review of epidemiology, diagnosis, and treatment of invasive mould infections in allogeneic hematopoietic stem cell transplant recipients. Myco­ pathologia. 2006; 162: 1–15. 12. Löwenberg M, Stahn C, Hommes DW, Buttgereit F. Novel insights into mechanisms of glucocorticoid action and the development of new glucocorticoid receptor ligands. Steroids. 2008; 73: 1025–9. 13. Cvetković RS, Perry CM. Rituximab: a review of its use in nonHodgkin’s lymphoma and chronic lymphocytic leukaemia. Drugs. 2006; 66: 791–820. 14. Shortt J, Spencer A. Adjuvant rituximab causes prolonged hypogammaglobulinaemia following autologous stem cell transplant for non-Hodgkin’s lymphoma. Bone Marrow Transplant. 2007; 40: 597–8. 15. Cattaneo C, Spedini P, Casari S, Re A, Tucci A, Borlenghi E, Ungari M, Ruggeri G, Rossi G. Delayed-onset peripheral blood cytopenia after rituximab: frequency and risk factor assessment in a consecutive series of 77 treatments. Leuk Lymphoma. 2006 Jun; 47: 965–6.

202 16. Aksoy S, Harputluoglu H, Kilickap S, Dede DS, Dizdar O, Altundag K, Barista I. Rituximab-related viral infections in lymphoma patients. Leuk Lymphoma. 2007; 48: 1257–8. 17. Elter T, Vehreschild JJ, Gribben J, Cornely OA, Engert A, Hallek M. Management of infections in patients with chronic lymphocytic ­leukemia treated with alemtuzumab. Ann Hematol. 2009; 88: 121–32. 18. Cadili A, de Gara C. Complications of splenectomy. Am J Med. 2008; 121: 371–5. 19. Parody R, Martino R, Rovira M, Vazquez L, Vázquez MJ, de la Cámara R, Blazquez C, Fernández-Avilés F, Carreras E, Salavert M, Jarque I, Martín C, Martínez F, López J, Torres A, Sierra J, Sanz GF; Infectious/Non-infectious Complications Subcommittee of the Grupo Español de Trasplante Hematopoyético (GETH). Severe infections after unrelated donor allogeneic hematopoietic stem cell transplantation in adults: comparison of cord blood transplantation with peripheral blood and bone marrow transplantation. Biol Blood Marrow Transplant. 2006; 12: 734–48. 20. Klastersky J. The changing face of febrile neutropenia-from monotherapy to moulds to mucositis. Why empirical therapy? J Antimicrob Chemother. 2009; 63: 14–5. 21. Schimpff S, Satterlee W, Young VM, Serpick A. Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia. N Engl J Med. 1971; 284: 1061–5. 22. Paul M, Borok S, Fraser A, Vidal L, Cohen M, Leibovici L. Additional anti-Gram-positive antibiotic treatment for febrile neutropenic cancer patients. Cochrane Database Syst Rev. 2005; 20: CD003914. 23. Paul M, Yahav D, Fraser A, Leibovici L. Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2006; 57: 176–89. 24. Paul M, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis. BMJ. 2003; 326: 1111–19. 25. Paul M, Soares-Weiser K, Grozinsky S, Leibovici L. Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropaenia. Cochrane Database Syst Rev. 2003; 3: CD003038. 26. Linden PK. Optimizing therapy for vancomycin-resistant enterococci (VRE). Semin Respir Crit Care Med. 2007; 28: 632–45. 27. European Organization for Research and Treatment of Cancer (EORTC) International Antimicrobial Therapy Cooperative Group and the National Cancer Institute of Canada-Clinical Trials Group. Vancomycin added to empirical combination antibiotic therapy for fever in granulocytopenic cancer patients. J Infect Dis. 1991; 63: 951–8. 28. Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, Feld R, Pizzo PA, Rolston KV, Shenep JL, Young LS. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002; 34: 730–51. 29. Hope WW, Walsh TJ, Denning DW. Laboratory diagnosis of invasive aspergillosis. Lancet Infect Dis. 2005; 5: 609–22. 30. Girmenia C, Micozzi A, Gentile G, Santilli S, Arleo E, Cardarelli L, Capria S, Minotti C, Cartoni C, Brocchieri S, Guerrisi V, Meloni G, Foà R, Martino P. Clinically driven diagnostic antifungal approach in neutropenic patients: a prospective feasibility study. JCO Early Release, published online ahead of print Oct 19 2009. Journal of Clinical Oncology, 10.1200/JCO.2009.21.8032. 31. Maertens J, Theunissen K, Verhoef G, Verschakelen J, Lagrou K, Verbeken E, Wilmer A, Verhaegen J, Boogaerts M, Van Eldere J. Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal

B.L. Rapoport and R. Feld infection: a prospective feasibility study. Clin Infect Dis. 2005; 41: 1242–50. 32. Mennink-Kersten MA, Warris A, Verweij PE. 1,3-b-d-Glucan in patients receiving intravenous amoxicillin-clavulanic acid. N Engl J Med. 2006; 354: 2834–5. 33. Pizzo PA, Robichaud KJ, Gill FA, Witebsky FG. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. Am J Med. 1982; 72: 101–11. 34. Walsh TJ, Pappas P, Winston DJ, Lazarus HM, Petersen F, Raffalli J, Yanovich S, Stiff P, Greenberg R, Donowitz G, Schuster M, Reboli A, Wingard J, Arndt C, Reinhardt J, Hadley S, Finberg R, Laverdière M, Perfect J, Garber G, Fioritoni G, Anaissie E, Lee J; National Institute of Allergy and Infectious Diseases Mycoses Study Group. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002; 346: 225–34. 35. Mora-Duarte J, Betts R, Rotstein C, Colombo AL, ThompsonMoya L, Smietana J, Lupinacci R, Sable C, Kartsonis N, Perfect J; Caspofungin Invasive Candidiasis Study Group. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 2002; 347: 2020–9. 36. Trifilio S, Singhal S, Williams S, Frankfurt O, Gordon L, Evens A, Winter J, Tallman M, Pi J, Mehta J. Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole. Bone Marrow Transplant. 2007; 40: 451–6. 37. Siwek GT, Dodgson KJ, de Magalhaes-Silverman M, Bartelt LA, Kilborn SB, Hoth PL, Diekema DJ, Pfaller MA. Invasive zygomycosis in hematopoietic stem cell transplant recipients receiving voriconazole prophylaxis. Clin Infect Dis. 2004; 39: 584–7. 38. Klastersky J, Paesmans M, Rubenstein EB, Boyer M, Elting L, Feld R, Gallagher J, Herrstedt J, Rapoport B, Rolston K, Talcott J.J. The multinational association for supportive care in cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. Clin Oncol. 2000; 18: 3038–51. 39. Uys A, Rapoport BL, Anderson R. Febrile neutropenia: a prospective study to validate the multinational association of supportive care of cancer (MASCC) risk-index score. Support Care Cancer. 2004; 12: 555–60. 40. Klastersky J, Paesmans M, Georgala A, Muanza F, Plehiers B, Dubreucq L, Lalami Y, Aoun M, Barette M. Outpatient oral antibiotics for febrile neutropenic cancer patients using a score predictive for complications. J Clin Oncol. 2006; 24: 4129–34. 41. Innes H, Lim SL, Hall A, Chan SY, Bhalla N, Marshall E. Management of febrile neutropenia in solid tumours and lymphomas using the multinational association for supportive care in cancer (MASCC) risk index: feasibility and safety in routine clinical practice. Support Care Cancer. 2008; 16: 485–91. 42. Rolston KV, Rubenstein EB, Freifeld A. Early empiric antibiotic therapy for febrile neutropenia patients at low risk. Infect Dis Clin North Am. 1996; 10: 223–37. 43. Rapoport BL, Sussmann O, Herrera MV, Schlaeffer F, Otero JC, Pavlovsky S, Iglesias L, Stein G, Charnas R, Heitlinger E, Handschin J. Ceftriaxone plus once daily aminoglycoside with filgrastim for treatment of febrile neutropenia: early hospital discharge vs. standard in-patient care. Chemotherapy. 1999; 45: 466–76. 44. Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, Bennett CL, Cantor SB, Crawford J, Cross SJ, Demetri G, Desch CE, Pizzo PA, Schiffer CA, Schwartzberg L, Somerfield MR, Somlo G, Wade JC, Wade JL, Winn RJ, Wozniak AJ, Wolff AC. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006; 24: 3187–205.

Part IX

Gastrointestinal

Chapter 21

Cancer Cachexia and Anorexia Neil MacDonald and Vickie Baracos

The beginning of wisdom is to call things by their right name Chinese Proverb

Clinicians and their patients benefit when the condition treated is clearly defined. Alas, this has not been the case for the cancer anorexia–cachexia syndrome. Reflecting the past lack of knowledge about causative factors, no generally agreed upon definition existed and reaching a consensus definition has been a significant focus of several recent efforts. A generic definition encompassing cachexia in all disorders in both adults and children was proposed recently by a group of experts who contributed to an international cachexia consensus conference [1]. This definition of cachexia notably makes a distinction between the behavior of skeletal muscle and of adipose tissue: “….cachexia, is a complex metabolic syndrome associated with underlying illness and character­ized by loss of muscle with or without loss of fat mass”… Importantly, this definition recognizes that skeletal muscle wasting can be hidden within the bulk of body weight and body weight change, and underscores the recent recognition of sarcopenia (severe muscle wasting) as a clinically important phenomenon [2]. Sarcopenia is a term denoting a reduced quantity of skeletal muscle, of which a generally accepted definition is an absolute muscularity below the fifth percentile for healthy adults. Related efforts to define and provide diagnostic criteria for cancer cachexia are ongoing among the community of experts in clinical cancer cachexia research. A few publications have appeared [3, 4]; however, these efforts are not consensus based and have not been validated prospectively. The results of this ­dialog on cancer cachexia are ongoing; however, several clear concepts are emerging from these discussions that we use as the foundation of our work. The defining features of cancer cachexia: • Is multifactorial in nature. • Is characterized by an ongoing loss of skeletal muscle mass (with or without loss of fat mass). N. MacDonald (*) Department of Oncology, McGill University, Montreal, QC, Canada H2W 1S6 e-mail: [email protected]

• It cannot be fully reversed by conventional nutritional support. • Has as a consequence progressive functional impairment. • Its pathophysiology is characterized by a variable combination of reduced food intake and abnormal metabolism including tumor metabolism and inflammation. Management of cancer cachexia depends upon identifying elements contributing to patient wasting. While somewhat arbitrary, in a clinical setting it is useful to consider contributing factors as “primary” or “secondary.” Primary Cachexia arises from an aberrant metabolic state generated by both the tumor and the host inflammatory response to the tumor. Cancer patients are, however, bedeviled by a plethora of problems that contribute to poor nutrition. A list of the most important factors such as mood disorders and pain are listed in Table 21.1, together with a brief listing of possible therapeutic options. These causes of Secondary Cachexia (secondary causes of impaired food intake or poor dietary habits) should be prioritized, as these factors may be readily reversed by appropriate treatments. The distinction between primary and secondary cachexia is not absolute, as some types of secondary cachexia are probably influenced by ­primary cachexia (e.g., pain, fatigue, and mood disorders), while some secondary cachexia causes (e.g., bowel obstruction) can cause severe wasting in the absence of primary cachexia features.

Clinical Workup In concordance with the criteria mentioned above, the clinical workup focuses on: • The degree and rate of depletion of body weight, muscle protein, and energy stores in adipose tissue. • Evaluation of muscle mass and degree of functional impairment. • Anorexia and reduced food intake (primary and secondary causes).

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_21, © Multinational Association for Supportive Care in Cancer Society 2011

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Table 21.1  An approach to identify potentially correctable cause of cancer cachexia Potentially correctable problems Possible approaches Psychological factors Anxiety Depression Family distress Spiritual distress

Anxiolytics Antidepressants Social assistance Counseling

Eating problems Appetite Disturbed taste or smell

Referral to a nutrition clinic or a dietician

Oral Dentures, mouth sores Thrush Dry mouth

Antifungal medication Oral moisteners Change medications

Swallowing difficulties Antifungal medication Esophageal dilation Stomach

Regurgitation therapy

Early satiety Nausea and vomiting

Gastric stimulants Related to cause

Bowel Obstruction Constipation Diarrhea

Related to cause Laxatives, especially if on opioids

Malabsorption Pancreas Fistulas Fatigue Sleep disturbances Physical limitation Motivation “Cognitive fatigue” Function Home setting Pain

Pancreatic enzymes Related to cause Anxiolytics Exercise protocol Sleep protocol Exercise protocol Methylphenidate Exercise protocol Cause related Appropriate analgesics

ing as well as further detailed assessment as indicated of all patients with advanced cancer, at diagnosis and at periodic intervals over the course of their illness. Elements of this protocol include the evaluation of weight and weight loss, level of dietary intake, biological criteria, and nutritional risk factors associated with the underlying pathologies and treatments. Patient-reported outcomes are of value in the assessment of various facets of cachexia. There is evidence to support the reliability of self-reported height, weight, and weight ­history [5]. Patient/family generated questionnaires are valuable for the screening process. We use the following battery; ­however, a variety of similar tools exist that may be used to ­capture the same information: • Edmonton System Assessment (ESAS) [6] helps to identify and measure the severity of common symptoms affecting people with advanced cancer, using a 0–10 scale. • Patient-Generated Subjective Global Assessment (PG-SGA) [7] is an adaptation for oncology patients of the earlier SGA thatwas originally validated as a screening tool for malnutrition in hospitalized patients. The PG-SGA is scored and incorporates questions relating intake, weight, and nutritional risk factors, and is a mixture of patient – report (weight history, food intake, functional status, and symptoms affecting food intake) and assessments made by health care professionals (comorbid conditions, corticosteroid use, and fever). • Distress Thermometer [8]. This screening tool is used to assess the level of patient distress (on a 0–10 scale) and the specific problems contributing to it by giving them a problem list to indicate their reason(s) for distress. It is an easy way for patients to differentiate between the normal distress and a more significant form of distress that requires help from a health care professional. Patients can fill these questionnaires in a few minutes. Initially, instruction from clinic personnel is desirable.

Nerve blocks: surgical, percutaneous Counseling Metabolic Diabetes Adrenal insufficiency Hypogonadism Thyroid insufficiency

As indicated

• Catabolic drivers including tumor burden, systemic inflammation, and altered endocrine status. • Psychosocial stress related to food, eating, and altered body image. Cachexia is not just a late stage phenomenon; patients with some tumors (e.g., pancreas, upper gastrointestinal, and lung cancer) commonly present with weight loss and other nutritional issues. Early identification of cachexia may lead to treatments that reverse or prevent, if only for a while, further deterioration. Therefore, oncology clinics must employ protocols for screen-

Assessment of Weight and Weight Loss Body weight should be determined and recorded in a consistent fashion, with caution taken to remove footwear, and the contents of pockets at all times patients are weighed. The same scale should be used consistently for follow-up weights, and all scales used in the unit should be regularly calibrated. A measurement of patients’ height, determined with a stadiometer, must be entered into the patient record, to facilitate computation of the common anthropometric descriptor, body mass index (BMI) (kg/m²). Percentage of weight lost is calculated, either relative to premorbid (habitual) weight, or over a defined period of time (e.g., 6 months). Weight loss and BMI cut points are treated heterogeneously in the nutritional screening tools, in the literature and in publications by various health authorities and expert

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groups. Variously, 3–20% weight loss (either in total or during a specified time frame) is attributed to a level of nutritional risk. BMI defining a clinically underweight population spans a large range (17–25 kg/m2). We regard the cut points in the Common Terminology Criteria for Adverse Events as clinically useful (Grade 1 >5%; Grade 2 >10%; and Grade 3 >20%); however, it should be taken into account that any degree of loss is of greater consequence in patients with a premorbid BMI <22  kg/m2 or who by cumulative prior weight loss have achieved a BMI <22 kg/m2. Edema, ascites, increased organ volume (e.g., hepatomegaly), constipation, and tumor burden including metastasis, contribute to shifts in body weight in advanced cancer patients [9–11] and should be taken into account in the assessment of weight and weight change over time.

Evaluation of Muscle Mass and Degree of Functional Impairment Wasting of lean tissues and especially skeletal muscle is an important component of cancer-associated weight loss. Muscle wasting can coexist with the depletion of adipose tissue but may also coexist with obesity, and this independent behavior of lean and adipose tissues makes body composition analyses essential. Cancer patients with significant erosion of the lean body mass and skeletal muscle (even if they have large body weights) have an elevated risk of being partially or entirely bedridden and a substantially reduced survival [12, 13]. Sarcopenic patients are also prone to severe toxicity during chemotherapy [14–16], necessitating reductions in the dose of drugs or treatment delays. Defined sex-specific reference values and standardized body composition measurements are essential to perform assessment of skeletal muscle depletion. While there remains a paucity of reference values related to cancer-specific outcomes [12, 13], a generally accepted rule is an absolute muscularity below the fifth percentile for normal healthy adults. Assessment of muscularity remains far from routine, although a variety of clinically expedient approaches are available. The following approaches may be used; sex-specific cut points consistent with sarcopenia are given for each measure: • Mid upper arm muscle area by anthropometry: men <32 cm2; women <18 cm2. • Appendicular skeletal muscle index determined by dual energy X-ray absorptiometry: men <7.26 kg/m2; women <5.45 kg/m2. • Lumbar skeletal muscle index [12] determined by CT imaging: men <55 cm2/m2; women <39 cm2/m2. • Whole body fat-free mass index without bone determined by bioelectrical impedance: men 14.6  kg/m2; women 11.4 kg/m2.

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Function Tests Simple tests, with minimal patient burden, can be employed. We use a six-minute walk, sit to stand time, gait speed, and the Community Health Activities Model Program for Seniors (CHAMPS) tests. Physician assessment of patient capacity to perform a six-minute walk is necessary prior to testing. Articles which outline their use and precautions include: • Jones and Eves – Cardiorespiratory exercise testing in clinical oncology research – LANCET Oncology 2008 9 (8): 757-65. • ATS Statement on six-minute walk test. • American Journal of Respiratory Critical Care Medicine (2002) 166:111-117. • Carli F et al - Analgesia and functional outcome after total knee arthroplasty - British Journal of Anaesthesiology 2010 106: 196-200.

Assessment of Dietary Intake Prospectively collected dietary records are the standard for evaluation of total energy and macronutrient intake. A 3-day collection period seems to be the compromise generally taken between the length of the assessment and the frailty or vulnerability of the studied patients; 24  h dietary recall and food frequency questionnaires are sometimes used as alternates. Dietary records require the specialized expertise of a registered dietitian and are generally very rare in clinical practice. Nutrition screening tools generally replace dietary records with questions pertaining to the type, number, and frequency of meals or verbal descriptors such as “very little of anything,” “only liquids,” or “little solid food” [7]. Questions related to the patient’s ability to purchase, shop for, prepare, and eat independently are often included, especially in nutrition assessment tools for the elderly. Dozens of symptoms have the potential to exert a negative impact on food intake (e.g., nausea, vomiting, constipation, early satiety, chemosensory dysfunction, pain, fatigue, difficulty swallowing, mouth sores, dental problems) and should be evaluated.

Biological Criteria Laboratory data may or may not be routinely collected in different cancer care settings. The most clinically useful laboratory measures relate to the acute phase response, a series of reactions initiated in response to infection, physical trauma, or malignancy. The acute phase response is characterized by leukocytosis, fever, alterations in the metabolism of many organs as well as changes in the plasma concentrations of acute-phase proteins [17]. The positive acute-phase proteins (fibrinogen, a1-acid glycoprotein serum amyloid A, and C-reactive protein)

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increase and negative acute-phase ­proteins (albumin and transferrin) decrease during an inflammatory disorder. The laboratory values vary according to different authors: albumin (cut points variously <30 to <35  g/L), transthyretin (prealbumin) (<110 or <180 mg/L), and C-reactive protein (>5 or >10 mg/L). The presence of an acute phase response is also prognostic of reduced survival [18], and these measures may have additional clinical utility for prognostication. While the production of proinflammatory cytokines is understood to be central to the host inflammatory response to malignant disease [19], serum cytokine levels have proven too inconsistent to be useful biological criteria. Thyroid function and the possible presence of hypogonadism (testosterone screen) may provide additional information on possible causes of weight and muscle loss.

Assessment of Nutritional Risk Factors Associated with the Underlying Pathology(ies) and Treatments This category is quite heterogeneous and includes any factors likely to drive weight loss or poor food intake. Some examples in this category include old age, poor cognition, limited mobility, advanced disease stage, extensive tumor burden and metastases, the presence of fever, and comorbid conditions associated with additional nutritional risk (i.e., compromised organ function, major stress, infection). Depression is a significant independent factor explaining nutritional risks. A variety of medications may contribute to poor food intake or altered metabolism (i.e., high-dose corticosteroid).

General Therapeutic Platform The management of cancer cachexia is a moving target; new approaches are expected in the near future. While awaiting clinical research advances, much can be done today. Elements include: 1. Initially decide whether elements of both primary and secondary cachexia are present; they usually are. You will be alerted to primary cachexia if the patient has a high C-reactive protein or unexplained high neutrophil/low lymphocyte count. A low albumin is usually a late feature. Address all identified secondary cachexia problems. Use a checklist for secondary cachexia, as a variety of treatment approaches will be required. 2. Team approach – Adoption of this concept is critical. In addition to the nurse/physician dyad, core members should include a dietitian and a physiotherapist; availability of an occupational therapist, social worker, and a clinical psychologist is also desirable.

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3. Our clinics have varying resources. Based on the initial workup, you may establish decision points for the involvement of the registered dietitians based on PG-SGA quantitative scores, or physiotherapists based on fatigue/ activity scores. 4. Exercise patients within their safe capacity. It is becoming increasingly clear that many categories of cancer patients can benefit from planned physical activity. A most striking example is patients undergoing cytotoxic therapy in the course of bone marrow transplantation, a group that many may view as being unlikely to be able or willing or capable of responding to exercise therapy [20]. Physio­ therapists and occupational therapists can evaluate and motivate your fatigued, inactive patients to exercise and carry out daily tasks. Fatigue, the most prevalent, devastating symptom encountered by cancer patients has no established drug therapy – methylphenidate in selected patients and modafinil are under review – but directed exercise can relieve fatigue. 5. Involve the patient and family as members of the therapy team. Almost all cancer therapies call for patients to be passive receptors of care – somebody is doing something to them. Diet and exercise are their therapies. We advise but they run the enterprise. An important concept enhancing psychosocial care and life quality. 6. Stress must be placed on early detection and management. Meticulous attention to the early onset of weight or muscle loss, inflammation, or other contributing causes can forestall the development of severe wasting. 7. Work from protocols. It is of importance to develop standard practices in the care unit with regard to cachexia and anorexia. • What is your screening platform? • What is your nutrition platform? • How do you identify and manage constipation? • What is your policy on appetite stimulants? • What is your exercise policy?

Specific Nutrient Supplement Therapy 1. No specific enhanced amino acid supplements are proven; however, there is current research interest in leucine, branch chain amino acids, and cystine–cysteine (glutathione antioxidant progenitors). Aim at a dietary protein intake in the range of 1.5 g/kg body weight/day. Herein, another reason to ensure a dietitian is part of the team; they know how to help patients achieve the desirable levels as part of a balanced diet. 2. Omega 3 fatty acids are lipids of proven benefit in maintaining cardiac health. In a wide range of animal studies, they demonstrate antitumor effects, maintain muscle mass in tumor-bearing mice, and protect against chemotherapy

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injury. A pedigree such as the above makes them attractive agents in oncology practice, particularly as they are safe components of human diets. Alas, as is often the case, there is a wide gap between mouse and man. While many Phase II studies on the management of cancer cachexia are encouraging, large Phase III trials are either negative or weakly positive [21, 22]. These trials, however, can be faulted for not studying muscle and function, short duration, or patient adherence to randomization class. 3. Many recent meta-analyses have been published with somewhat conflicting results. In the authors’ opinion, omega 3 fatty acids should be employed in weight-losing patients because they act as broadly based anti-inflammatory agents that reduce both inflammatory prostanoid and cytokine production; they may particularly benefit the high C-reactive protein group, but studies are lacking. The usual dose: eicosapentanoic acid (EPA) 2.0–2.5 g daily. Use with caution in those with low platelet counts or bleeding disorders. 4. Vitamins – vitamin deficiencies, notably C, D, and B’s, are common in patients following prolonged hospitalization. Although there is only modest research on this topic (aside from many confirmatory studies on Vitamin D deficiency, particularly in the Northern latitudes), one may assume that a number of malnourished outpatients may also develop deficiencies. A number of positive results are emerging on Vitamin D supplementation in elderly individuals [23]. It is our practice to prescribe multivitamin therapy in physiologic doses, plus Vitamin D, based on clinical assessment. While the multivitamin dose is low, some oncologists may prefer that they be withheld during chemo/radiotherapy because of antioxidant properties. 5. Complementary therapy supplements – None proven; take care as some may have unknown adverse effects and drug interactions.

purchased at the cost of increasing muscle catabolism. Consequently, aside from other long-term adverse effects, they are not suitable for continual therapy in mobile patients with reasonable muscle function, other than in short-term (1–2 week) bursts. They are useful in patients whose maintenance of physical function is no longer a high priority. Prednisone and its congeners are the corticosteroids of choice, as dexamethasone, a fluorinated corticoid, is particularly active in stimulating muscle breakdown.

Pharmaceutical Therapy

Cannabis has a well-defined orexigenic effect in many patients. In some part, this benefit stems from the unique ability of cannabinoids to relieve taste and smell aberrations. This may relate to the central action of cannabinoids on cerebral and hypothalamic centers mediating the sense of pleasure in eating [26]. Cannabinoid receptors are widespread, so they may also enhance appetite through unknown peripheral mechanisms. Their use is limited by real or feared adverse effects and by societal views on marijuana. A virgin user, particularly if elderly, may regard the psychoactive effects as fearful and unpleasant; a view perhaps not shared by younger, experienced patients. At usual doses, psychoactive properties are commonly not expressed while a side benefit, improved sleep, may be noticed. Cannabinoids are probably underutilized. They may be helpful in people with taste and smell problems who are not at risk for cognitive changes (e.g., people with dementia or at risk for becoming demented) or interactive adverse drug

To date, drug therapies are only proven to be effective in stimulating appetite. No agent demonstrates efficacy in maintaining muscle mass and function, although there is controversial supportive evidence for anabolic agents, omega 3 fatty acids, and NSAIDS.

Appetite Stimulation Corticosteroids These agents have powerful orexigenic action [24]. Their mode of action is not clear, but presumably it relates to their anti-inflammatory properties. Unfortunately, this benefit is

Megestrol Acetate Numerous randomized studies support the use of Megestrol and other progestational agents for appetite enhancement [25]. These molecules are structurally similar to corticosteroids, and probably increase appetite through their antiinflammatory actions. Although not to the same extent as corticosteroids, they also have catabolic effects on skeletal muscle. Moreover, they may increase the risk of thromboembolism, although this risk seems to be modest at usually employed dose levels in patients without a prior history of thrombotic disease and low risk factors. Weight gain during therapy with progestational agents is composed of fat, and this can be a welcome finding in patients with severe weight loss. Lean body mass is not enhanced – not a surprising finding in relatively inactive people. Concern for muscle function leads many clinicians to limit megestrol use to intermittent schedules, reserving longer term therapy for patients no longer fighting to maintain strength and mobility.

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effects. What is the best route of administration? A number of oral cannabinoids are available, albeit marketed as antinauseants for chemotherapy patients. It is not clear whether smoked marijuana or nasal tetrahydrocannabinoids (marketed to relieve muscle spasms in multiple sclerosis and patients with other neurologic symptoms) are superior.

Gastric Stimulants and Laxatives While not direct appetite stimulants, these agents may reduce gastric atony and constipation, thus making the gastrointestinal tract more receptive to nutrition. Both metoclopromide and domperidone are widely employed as gastric stimulants. Clinical wisdom is not yet backed up by convincing trials. We know little about the efficacy of gastric stimulants in cancer cachexia. Certainly patients may benefit, but which subsets of patients are helped, and which are not? We do not know. Without doubt, constipation, which can cause a wide range of symptoms including anorexia, is often overlooked, even in patients not on opioids. A history of a daily stool does not rule out constipation; how much stool is passed and what are its characteristics? A daily stool may be extruded from a column of feces backed up to the ileum. Increasingly, physicians are ordering abdominal films in patients at risk, to determine the presence and severity of constipation, which will guide the patient’s laxative protocol. This is the practice in our clinic.

Anabolic Steroids There may be a role for physiologic replacement doses of testosterone in elderly hypogonadal male patients [27]. Hypogonadism is very common in advanced cancer patients, who are generally elderly, and clinically practical approaches to treatment are available in the gerontology literature. Notably, many chemotherapy drugs and opioids can reduce testosterone production. Screening for this condition as part of the metabolic profile of the primary cachexia patient is recommended.

Enteral and Parenteral Feeding Patients with defined limitations to oral intake may benefit from artificial feeding [28, 29]. To the present, this nourishment is thought to be wasted in primary cachexia patients as unless the basic metabolic aberration is corrected, the

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s­ ituation is analogous to pouring water into a plugless basin; it will not refill. Muscle proteolysis, tissue wasting, anorexia, and other manifestations of primary cachexia continue apace even though a spurious increase in weight may occur, but changes in lean body mass are minimal. 2009 ASPEN Guidelines states “The palliative use of nutrition support therapy in terminally ill cancer patients is rarely indicated” and this view is espoused in other international clinical practice guidelines on parenteral nutrition. Clearly, this advice concerns patients with far- advanced ­illness. Guidelines are more positive for malnourished patients facing surgery, encountering severe chemotherapy/ radiation therapy, or undergoing bone marrow transplantation. The author’s antennae for detecting cachectic patients who may benefit from artificial feeding are sensitized when patients exhibit the following features: • Secondary cachexia features and normal C-reactive protein. • Muscle strength well maintained. • Life expectancy greater than 6 months. This situation is not uncommonly seen in patients with alimentary tract obstruction at any level or malabsorption syndrome. If doubt exists, a brief clinical trial is justified. Will this negative outlook on the efficacy of artificial nutrition in primary cachexia patients continue? First, one must acknowledge that, because of the lack of clear landmarks, it is a controversial subject today. Secondly, research on nutrient feeds that also substantively reduce inflammation is promising [30]. Such feeds are used in critical care, but not sufficiently studied in those with cancers exhibiting chronic inflammation.

Agents of Research Interest Although still cloudy and complex, recent research stressing the preeminence of a chronic inflammatory state as a causative factor for primary cachexia and information on the mechanics of muscle wasting is resulting in the introduction of more rational clinical trials than heretofore conducted. To advance treatment, we strongly hold that centers and clinics with research capacity for randomized clinical trials of cachexia/ anorexia therapy, should ensure that the opportunity to participate in these trials is available to patients in their setting. In the author’s opinion, agents of special interest include:

Anti-Inflammatory Agents • Cytokine inhibitors directed toward Il-6; Il-1b • further studies on NSAIDS in combination with other agents.

21  Cancer Cachexia and Anorexia

Muscle Synthesis • Selective androgen receptor modifiers (SARMS) , a class of specific ligands for the skeletal ­muscle androgen receptor, which enhance muscle synthesis without undue androgenic effects. • Antimyostatin compounds. Monoclonal antibodies or peptibodies neutralizing ­myostatic activity.

Autonomic Nerve Modulators • B2 antagonists and agonists. • A seeming paradox – the antagonists (beta blockers) can regulate wasteful increased resting energy expenditure (REE), while some agonists (e.g., clenbuterol, formaterol) have direct effects enhancing muscle synthesis. How can they both be potential helpful drugs? The answer is not clear and may depend upon the primacy of an increased REE in a given patient or on selective activity of certain second messenger ­systems in muscle.

Hypothalamic Neurotransmitters • Melanocortin receptor 4 (MCR4) inhibitors acting ­centrally may influence all elements of cachexia. While demonstrated in mice, human data are awaited. This is not an all inclusive list and may reflect author bias – others may include agents such as thalidomide, ­mirtazepine, or olanzepine.

References 1. Evans WJ, Morley JE, Argilés J et al. Cachexia: a new definition. Clin Nutr. 2008;27(6):793–9. 2. Rolland Y, Czerwinski S, Abellan Van Kan G et al. Sarcopenia: its assessment, etiology, pathogenesis, consequences and future perspectives.J Nutr Health Aging. 2008;12(7):433–50. 3. Fearon KCH, Voss AC, Hustead DS; on behalf of the Cancer Cachexia Study Group. Definition of cancer cachexia: effect of weight loss, reduced food intake and systemic inflammation on functional status and prognosis. Am J Clin Nutr. 2006;83: 1345–50. 4. Bozzetti F, Mariani L. Defining and classifying cancer cachexia: a proposal by the SCRINIO Working Group. JPEN J Parenter Enteral Nutr. 2009;33:361–7. 5. Perry GS, Byers TE, Mokdad AH et al. The validity of self-reports of past body weights by U.S. adults. Epidemiology. 1995;6:61–6.

211 6. Nekolaichuk C, Watanabe S, Beaumont C. The Edmonton Symptom Assessment System: a 15-year retrospective review of validation studies (1991–2006). Palliat Med. 2008;22(2):111–22. 7. Ottery FD. Definition of standardized nutritional assessment and interventional pathways in oncology. Nutrition. 1996;12(1 Suppl):S15–9. 8. Tuinman MA, Gazendam-Donofrio SM, Hoekstra-Weebers JE. Screening and referral for psychosocial distress in oncologic ­practice: use of the Distress Thermometer. Cancer. 2008;113(4): 870–8. 9. Doyle D, Hanks G, Nathan IC, Calman K (eds). Oxford Textbook of Palliative Medicine. Oxford University Press, Oxford; 2005. 10. Honnor A. Classification, aetiology and nursing management of lymphoedema. Br J Nurs. 2008;17(9):576–86. 11. Lieffers JR, Mourtzakis M, Hall KD et  al. A viscerally driven cachexia syndrome in patients with advanced colorectal cancer: contributions of organ and tumor mass to whole-body energy demands. Am J Clin Nutr. 2009;89(4):1173–9. 12. Prado CM, Lieffers JR, McCargar LJ et al. Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Lancet Oncol. 2008;9(7):629–35. 13. Tan BHL, Birdsell LA, Martin L et al. Sarcopenia combined with overweight/obesity is an adverse prognostic factor in pancreatic cancer. Clin Cancer Res. 2009;15(22):6973–9. 14. Prado CM, Baracos VE, McCargar LJ et al. Body composition as an independent determinant of 5-fluorouracil-based chemotherapy toxicity. Clin Cancer Res. 2007;13(11):3264–8. 15. Prado CMM, Baracos VE, McCargar LJ et  al. Sarcopenia as a determinant of chemotherapy toxicity and time to tumor progression in metastatic breast cancer patients receiving capecitabine treatment. Clin Cancer Res. 2009;15(8):2920–6. 16. Antoun S, Birdsell L, Sawyer MB et al. Low body mass index and sarcopenia associated with dose-limiting toxicity of sorafenib in patients with renal cell carcinoma. Ann Oncol. 2010;21(8):1594–98. 17. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340(6):448–54. 18. Seruga B, Zhang H, Bernstein LJ et al. Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer. 2008;8(11):887–99. 19. McMillan DC. Systemic inflammation, nutritional status and ­survival in patients with cancer. Curr Opin Clin Nutr Metab Care. 2009;12(3):223–6. 20. Elter T, Stipanov M, Heuser E et al. Is physical exercise possible in patients with critical cytopenia undergoing intensive chemotherapy for acute leukaemia or aggressive lymphoma? Int J Hematol. 2009;90(2):199–204. 21. Bayram I, Erbey F, Celik N et al. The use of a protein and energy dense eicosapentaenoic acid containing supplement for malignancyrelated weight loss in children. Pediatr Blood Cancer. 2009;52(5): 571–4. 22. Mazzotta P, Jeney CM. Anorexia-cachexia syndrome: a systematic review of the role of dietary polyunsaturated Fatty acids in the management of symptoms, survival, and quality of life. J Pain Symptom Manage. 2009;37(6):1069–77. 23. Moreira-Pfrimer LD, Pedrosa MA, Teixeira L et al. Treatment of vitamin D deficiency increases lower limb muscle strength in institutionalized older people independently of regular physical activity: a randomized double-blind controlled trial. Ann Nutr Metab. 2009;54(4):291–300. 24. Behl D, Jatoi A. Pharmacological options for advanced cancer patients with loss of appetite and weight. Expert Opin Pharmacother. 2007;8(8):1085–90. 25. Madeddu C, Macciò A, Panzone F et  al.. Medroxyprogesterone acetate in the management of cancer cachexia. Expert Opin Pharmacother. 2009;10(8):1359–66.

212 26. Pisanti S, Bifulco M. Endocannabinoid system modulation in ­cancer biology and therapy. Pharmacol Res. 2009;60(2):107–16. 27. Hugh Jones T. What should I do with a 60 year old man with a slightly low serum total testosterone concentration and normal ­levels of serum gonadotrophins. Clin Endocrinol (Oxf). 2010;72:584–8. 28. Bozzetti F, Arends J, Lundholm K et  al. ESPEN Guidelines on Parenteral Nutrition: non-surgical oncology. Clin Nutr. 2009;28(4): 445–54.

N. MacDonald and V. Baracos 29. Mackenzie ML, Gramlich L. Home parenteral nutrition in advanced cancer: where are we? Appl Physiol Nutr Metab. 2008;33(1): 1–11. 30. Okamoto Y, Okano K, Izuishi K et al. Attenuation of the systemic inflammatory response and infectious complications after gas­ trectomy with preoperative oral arginine and omega-3 fatty acids supplemented immunonutrition. World J Surg. 2009;33(9): 1815–21.

Chapter 22

Xerostomia and Dental Problems in the Head and Neck Radiation Patient Arjan Vissink, Fred K. L. Spijkervet, and Michael T. Brennan

Introduction Saliva is the “Aqua Vita” of the oral cavity. It is protective and its alimentary qualities are critical to the function of the oral and pharyngeal tissues and organs. Moreover, saliva is a sensitive indicator of oral and systemic abnormalities and diseases. Yet, this important secretion has been eschewed, neglected, and perceived as ignoble by dentists, physicians, and other keepers of our health. An example of saliva’s perceived insignificance is illustrated by the adage that items viewed as having little value are said to be worth “less than a bucket of warm spit” [1]. But might even a half bucket of warm spit not be sufficient to prevent a subject perceiving his or her mouth as dry. In other words, the important question has to be settled: how much saliva is enough saliva? This question leads to another question: enough for what? Is it how much is enough to prevent oral dryness or is it how much is enough to engage in activities that accrue as a result of normal salivary function? Ofttimes, only a minuscule amount of saliva is necessary to thwart the appearance of dry mouth – just enough to coat the mucous surfaces of the oral cavity. Probably, this coating is due to the actions of the minor salivary glands and, following a swallow, to the residual saliva. Given that the volume secreted by the minor glands is about 8% of the unstimulated flow rate, these are indeed, small amounts [1–3]. Alimentary functions of stimulated whole saliva are severely compromised with low flow rates: the ability to taste, to chew, to form a bolus, and to swallow. The unpleasant feeling of oral dryness and its related symptoms are experienced the most by patients in whom salivary secretion is suddenly decreased to negligible amounts. This includes patients who are subjected to one of the most common therapies applied within head and neck oncology, viz. head and neck radiotherapy. These patients

A. Vissink (*) Department of Oral and Maxillofacial Surgery, University Medical Center Groningen, Groningen, 9700 RB, The Netherlands e-mail: [email protected]

do not slowly adapt to a changed oral environment, but are suddenly exposed to a rather extreme oral environment: a mouth that has become dry with major changes of the oral mucosa.

Symptoms Associated with Mouth Dryness The sensation of a dry mouth (xerostomia) is rarely an isolated symptom. Xerostomia often appears in consort with hyposalivation, but a complaint of xerostomia does not always correlate well with salivary function [4]. These conditional attributes induce functional impairment of the oral cavity. A reduction in the flow of saliva frequently causes difficulties with speaking, taste, and mastication. Patients with decreased salivary function may have difficulty chewing and swallowing dry foods. They are frequently thirsty and often need to sip water to facilitate deglutition and may keep water at their bedside at night. Edentulous patients may have difficulty wearing dentures. A complaint of tingling and burning sensations of the oral mucosa, especially on the tongue, may be present. The tongue may even cleave to the roof of the mouth. Moreover, the oral mucosa may feel particularly sensitive to spicy foods [1]. In head and neck radiation patients’ mucosal problems are mostly due to the process of mucositis in combination with the changes in saliva. After cessation of the radiation therapy, the symptoms related to mouth dryness persist, including mucosal sensitivity.

The Clinical Picture of Dry Mouth Clinical signs associated with oral dryness may be observed in the soft and the hard tissues of the mouth and in the salivary glands. The oral mucosa may appear dry, atrophic, pale, or hyperemic, and there may be abundant evidence of dental caries (Fig. 22.1). The lips may be chapped or fissured, and there may be scaling and fissuring at the corners of the mouth (angular cheilosis; Fig. 22.2). The dorsum of the tongue may

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Fig. 22.1  Oral dryness is associated with abundant, rapidly progressing dental caries

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Fig. 22.3  Candidiasis of the lateral border of the tongue with some yeast colonies but predominantly erythematous

Fig. 22.2  Angular cheilosis and a dry surface of the tongue Fig. 22.4  Erythematous candiasis of the dorsum of the tongue

be dry and furrowed (Fig. 22.2), or alternatively, may appear red and hyperemic as a result of the presence of a fungal infection (erythematous candidiasis; Figs.  22.3 and 22.4). The buccal mucosa may look pale and dry (Fig. 22.5); tongue blades used to retract the cheeks may stick to the mucosa. As with the tongue, it may appear erythematous due to a yeast (Candida) infection. These changes in the oral mucosa are, in general, typical for xerostomia of any origin [1]. The principal causative factor that underlies the subjective feelings and the clinical findings associated with dry mouth is hyposalivation. Reductions in the flow of saliva, as well as qualitative changes in it, predispose a patient, either directly or indirectly, to a variety of problems. The severity of hyposalivation cannot be predicted with certainty from the patients’ complaints. In general, however, the greater the reduction in the volume of saliva, the more severe are the symptoms. After curative radiotherapy, a continuous severe reduction of salivary flow rate persists. The consequences in the radiated are: patients are awakened at night because of

Fig. 22.5  Pale and dry buccal mucosa

intense oral dryness, many suffer throughout the day with polyuria and polydipsia, oral functions like speech, chewing, and swallowing are thwarted because of insufficient wetting

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and lubrication of the mucosal surfaces, and swallowing and chewing are impeded because the decrease in the volume of saliva makes it difficult to form a bolus [1, 5]. Moreover, when lesser amounts of saliva are present, retention of the denture is often poor and more friction is produced during mastication.

Xerostomia and the Teeth There is abundant evidence that hyposalivation commonly causes a marked increase in the incidence of dental caries; in many cases it is severe and rampant (Fig. 22.1). There is conflicting evidence regarding its effect on periodontal diseases, but most authors agree that periodontal disease is not more common among dry mouth patients than among healthy subjects. The shift in the oral microflora toward increased amounts of acidogenic, cariogenic bacteria (e.g., Streptococcus mutans, Lactobacillus species, Actinomyces viscosus, and Streptococcus mitis), and the reduced salivary flow and oral clearance are accompanied by changes in the composition of saliva. Included among these changes is a reduction in the buffer capacity and pH of saliva and a decline in the presence of the caries-preventive immunoproteins. These changes can result in a rapid increase in the prevalence of hyposalivationrelated dental decay. Without special care, dental caries may progress extremely rapidly. A perfect dentition can be totally destroyed within 6 months [1]. Finally, oral candidiasis, when present, may rapidly spread to the pharynx and esophagus. In addition, these hyposalivatory changes alter the patient’s eating habits. Spicy food is a problem, so patients shift their diet to one that is blander. Patients have difficulty with mastication, so they shift to a diet that is soft, sticky, and usually laden with carbohydrates. Sometimes, the diet may be liquid. These modified, softer diets are adhered to by many drymouth patients but are particularly characteristic of the diets consumed by patients who suffer from irradiation-induced xerostomia.

Dry Mouth, Hyposalivation, and Dental Caries Dental caries is common in patients with dry mouth and hyposalivation, especially in head and neck radiated patients with a sudden onset of hyposalivation with insufficient anticaries regimens to prevent tooth decay. Three types of lesions can be observed [6–8]. All of them may be seen in the same mouth. Yet surprisingly, perhaps because of the rapid progress of the disease, there is little, if any, pain associated with

Fig. 22.6  Hyposalivation-related dental caries type 1: lesions of the cervical area. (Reprinted with permission from Stegenga B, Vissink A, de Bont LGM, eds. Mondziekten en Kaakchirurgie. Van Gorcum: Assen, the Netherlands; 2000.)

them. The histological features of early hyposalivationrelated dental carious lesions are similar to those observed in normal incipient lesions [1, 9, 10]. Erosive types of lesions can also be found [10]. A very remarkable thing about these lesions is that they occur in areas of the mouth that are normally relatively immune to dental caries. The first type of lesion usually begins on the labial surface at the cervical area of the incisors and canines (Fig. 22.6). Initially, this lesion extends superficially around the entire cervical area of the tooth, and then progresses inwardly, often resulting in complete amputation of the crown. Amputation is less frequent in the area of the molars. However, the caries tends to spread over all the surfaces of the molar teeth, changes their translucency and color, and induces an increase in their friability. Occasionally, the destruction occurs as a rapid wearing away of the incisal and occlusal surfaces of the teeth, with or without cervical lesions. The second type of lesion is a generalized superficial defect that first affects the buccal, and later, the lingual or palatal surfaces of the tooth crowns (Fig. 22.7). The proximal surfaces are less affected. When present, this lesion often begins as a diffuse, punctate defect and then progresses to a generalized, irregular erosion of the tooth surfaces. In this type of lesion, decay that is localized to the incisal or occlusal edges may often be observed. The result is a destruction of the coronal enamel and dentin, especially on the buccal and palatal surfaces. The third type is less frequently observed (Fig. 22.8). It consists of a heavy brown-black discoloration of the entire tooth crown, accompanied by wearing away of the incisal and occlusal surfaces.

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treatment modality, while other patients will require a combination of treatments. Unfortunately, some patients may not adequately achieve a response to the management of oral dryness, although much can be done to mollify the patient and guard the oral cavity against injury and disease.

Management of Dry Mouth

Fig. 22.7  Hyposalivation-related dental caries type 2: superficial defects of the crown of the tooth. (Reprinted with permission from Stegenga B, Vissink A, de Bont LGM, eds. Mondziekten en Kaakchirurgie. Van Gorcum: Assen, the Netherlands; 2000.)

Frequent sips of water during the day can be the easiest and most effective technique to improve symptoms of dry mouth in some patients. A slice of lemon or lime can be added to a glass of water to produce a mild acidic flavor that will enhance the output from the major salivary glands [11, 12]. Patients should be counseled, however, that aqueous solutions do not produce long-lasting relief from oral dryness. Water wets the mucosa, but its moisture is not retained since the mucous membranes of xerostomic patients are inadequately coated by a protective glycoprotein layer [13].

Masticatory, Gustatory, and Mild Acid Stimulation

Fig.  22.8  Hyposalivation-related dental caries type 3: brown-black discoloration of the tooth crown. (Reprinted with permission from Stegenga B, Vissink A, de Bont LGM, eds. Mondziekten en Kaakchirurgie. Van Gorcum: Assen, the Netherlands; 2000.)

Treatment The treatment of xerostomia and salivary gland hypofunction related to head and neck cancer therapy should be based on answers to the following determinations [1]: 1. If stimulation of the flow of saliva is feasible to relieve oral dryness, this approach may readily diminish the oral desiccation. 2. If the saliva cannot be adequately stimulated, it has to be determined whether one can combat the arid feeling by “coating” the surfaces of the oral mucosa. 3. Assess what else can be done to preserve and protect the teeth and the oral soft tissues and provide relief to the patient. The findings obtained from these assessments should be carefully evaluated. Some patients will respond to a single

Dry mucosal surfaces, difficulty wearing dentures, retained interproximal plaque, and difficulty with speaking, tasting, and swallowing may all benefit from the stimulation of salivary secretions. Stimulation will only work if there are residual viable salivary gland cells that are amenable to stimulation. Head and neck cancer patients, who have undergone extensive radiotherapy to their craniofacial regions, in particular to their major salivary glands, are likely to have lost many functional acinar cells and often will not benefit sufficiently from salivary stimulatory methods. Masticatory stimulation techniques are easy to implement and have few side effects. The combination of chewing and taste, as provided by gums, lozenges, or mints can be very effective in relieving symptoms for patients who have remaining salivary function. These compounds are acceptable to most patients and are generally harmless (assuming that they are all sugar free). Also, acid-containing lozenges, for example, containing malic acid, can be very helpful. Dentate patients with dry mouth must be told not to use products that contain sugars, honey, maple syrups, or sorghum as sweeteners, due to the increased risk for dental caries, or use products that contain acids.

Pharmacologic Aids Two secretagogues, pilocarpine [14, 15] and cevimeline [16, 17] have been approved by the United States Food and

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Drug Administration (FDA) for the treatment of dry mouth. Both of these drugs are muscarinic agonists that, in irradiated head and neck cancer patients who have residual functional salivary gland tissue, induce a transient increase in salivary output and decrease their feeling of oral dryness [18]. Pilocarpine is a nonselective muscarinic agonist. Cevimeline has a high affinity for M1 and M3 muscarinic receptor subtypes. Since M2 and M4 receptors are located on cardiac and lung tissues, it is likely that cevimeline’s M1 and M3 specificity will induce fewer cardiac and/or pulmonary side effects. Cevimeline, given at 45  mg t.i.d. doses, was generally well tolerated over a period of 52 weeks in subjects with xerostomia secondary to radiotherapy for cancer in the head and neck region [19]. Common side effects of both medications include sweating, flushing, urinary urgency, and gastrointestinal discomfort. These side effects are frequent, but are rarely severe or serious. Parasympathomimetics are contraindicated in patients with uncontrolled asthma, narrow-angle glaucoma, or acute iritis and should be used with caution in patients with signi­ficant cardiovascular disease, Parkinson’s disease, asthma, or chronic obstructive pulmonary disease. The best-tolerated doses for pilocarpine are 5–7.5 mg, given three or four times daily [20]. The duration of action is approximately 2–3 h. Cevimeline is currently recommended at a dosage of 30 mg t.i.d. [16, 17]; the duration of secretogogue activity is longer than pilocarpine (3–4 h) but the onset is somewhat slower. In contrast to the USA, Canada, and Japan, cevimeline is not yet licensed in Europe.

Acupuncture and Electrostimulation Acupuncture, with the application of needles in the perioral and other regions, has been proposed as a therapy for salivary gland hypofunction and xerostomia. There is some evidence that this procedure alleviates the feeling of oral dryness, but well-controlled trials are needed to fully evaluate this treatment modality [18, 21]. Electrical stimulation has also been examined as a therapy for salivary hypofunction, but it too has been inadequately investigated clinically [18, 22].

What to Do When Stimulants Fail? Water, although less effective than the patients’ natural saliva, is by far the most important fluid supplement for dry-mouth individuals. Patients should be encouraged to sip water and swish it around their mouth throughout the day. This will help to moisten the oral cavity, hydrate the mucosa, and clear debris from the mouth. Patients should be counseled, however, that aqueous solutions do not produce long-lasting relief from oral

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dryness as water wets the mucosa, but its moisture is not retained [13]. Furthermore, careful water intake with meals is very important, since this approach enhances taste perception, enhances the formation of a bolus, and improves mastication and swallowing (particularly for hard and fibrous foods). In postradiation patients, this is even more important since these patients often use diets with high sugar contents due to taste changes. It can also help prevent choking and possible pulmonary aspiration. Frequent use of sugar-free carbonated drinks is not recommended in dentate patients, as the acidic content of many of these beverages is high and may increase tooth demineralization. In edentulous patients, such drinks may irritate the oral mucous membranes and cause them to be sensitive. Finally, an increase in environmental humidity is important as the use of room humidifiers, particularly at night, may lessen discomfort markedly [1]. There are numerous oral rinses, mouthwashes, and gels available for dry-mouth patients [4, 23–26]. Patients should be cautioned to avoid products containing alcohol, sugar, or strong flavorings that may irritate the sensitive, dry oral mucosa. Moisturizing creams can also be very helpful. The frequent use of products containing aloe vera or vitamin E should be encouraged [1]. A variety of commercially available salivary substitutes have demonstrated some efficacy in dry-mouth patients [18, 27]. However, saliva replacements (saliva substitutes or “artificial salivas”) are not well accepted long term by many patients, particularly when they have not been instructed how to use them [27, 28]. As a guide to choosing the best substitute for a patient, the following recommendations for the treatment of hyposalivation can be used [1, 23]: • Severe hyposalivation. A saliva substitute with gel-like properties should be used during the night and when daily activities are at a low level. During the day, a saliva substitute with properties resembling the viscoelasticity of natural saliva such as substitutes that have xanthan gum and mucin (particularly bovine submandibular mucin) as a base should be applied. • Moderate hyposalivation. If gustatory or pharmacological stimulation of the residual salivary secretion does not ameliorate the dry mouth feeling, saliva substitutes with a rather low viscoelasticity, such as substitutes which have carboxymethylcellulose, hydroxypropylmethylcellulose, mucin (porcine gastric mucin), or low concentrations of xanthan gum as a base are indicated. During the night or other periods of severe oral dryness, the application of a gel is helpful. • Slight hyposalivation. The salivary glands of these patients usually contain viable, responsive acinar cells. Gustatory or pharmacological stimulation of the residual secretion is the treatment of choice. Little amelioration is to be expected from the use of saliva substitutes.

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Despite the limitations mentioned, the nonstimulatory techniques described in this section should be tried in nonresponsive patients. In addition, they may also be adjunctly helpful in those patients who experience persistent dry mouth and respond to stimulation techniques [1].

The Role of the Dentist And/Or Dental Hygienist Management of the patient with xerostomia and salivary gland hypofunction due to head and neck radiotherapy starts with the dentist and dental hygienist, who should be part of the oncology team. Treatment should involve a multi­ disciplinary team of health care providers. Communication among them is critical, since patients with salivary hypofunction usually have concomitant oral and medical problems and consume many drugs. Patients should be seen and evaluated frequently [29, 30]. A thorough, step-by-step, management strategy should be devised and implemented (Table 22.1) using safe and efficacious techniques [1, 22].

Oral Hygiene Patients with salivary gland disorders must maintain meticulous oral hygiene. The enamel slabs placed in the mouth of a severe dry-mouth patient whose oral hygiene is poor, can be completely destroyed by a combined carious/erosive attack within 6 weeks. On the other hand, slabs placed in the mouth of a normal patient with good oral hygiene hardly shows any decalcification in the same period of time [32, 33]. Proper oral hygiene includes tooth brushing, flossing, the use of interproximal plaque removing devices, and the use of mouth rinses. Interdental brushes and mechanical toothbrushes are helpful for those with gingival recession and oral motor or behavioral complications. Regular brushing of the tongue with a toothbrush or a tongue scraper is also recommended. The team of oral-health professionals must play an important role in providing guidance (clinical instructions, written instructions) to the dry-mouth patient, so that he or she is given every opportunity to prevent the onset of the common side effects of salivary hypofunction [1].

Topical Fluorides and Remineralizing Solutions

Dental Visits Patients with salivary gland hypofunction require frequent dental visits (usually every 3–4 months) and must work closely with their dentist and dental hygienist to maintain optimal dental health [1]. Sequenced visits might conform to the following order: dentist – dental hygienist – dentist – dental hygienist. Dentate individuals who frequently develop new and/or recurrent caries lesions should have intraoral photographs taken every 6–18 months [31]. Patients who wear prostheses should have their prosthesis-bearing mucosal regions evaluated frequently (every 3–4 months) to help identify the early onset of oral mucosal lesions and infections.

The use of topical fluorides in a patient with salivary gland hypofunction is absolutely critical to the control of dental caries [34]. There are many different fluoride therapies available, from low concentration, over-the-counter fluoride rinses, to more potent highly concentrated prescription fluorides (e.g., 1.0% sodium fluoride). These are applied by brush or in a custom carrier (Fig. 22.9). The dosage chosen

Table 22.1  Management strategies for xerostomia and salivary hypofunction Management strategies Examples Preventive therapies

Symptomatic (palliative) treatments Local or topical salivary stimulation Drug-induced stimulation

Supplemental fluoride, remineralizing solutions, optimal oral hygiene, noncariogenic diet Water, oral rinses, gels, mouthwashes, saliva substitutes, increased humidification, minimize caffeine and alcohol Sugar-free gums and mints Parasympathomimetic secretogogues: cevimeline and pilocarpine

Fig. 22.9  Custom carrier to apply a neutral fluoride gel. (Reprinted with permission from Sreebny LM, Vissink A (eds). Dry mouth. The malevolent symptom: a clinical guide, Ames: Wiley-Blackwell 2010.)

22  Xerostomia and Dental Problems in the Head and Neck Radiation Patient

and the frequency of application (from daily to once a week) should be based on the severity of the salivary hypofunction and the rate of caries development [10, 32, 33, 35]. Particu­ larly in patients with severe oral dryness, nonacidic fluoride gels and/or solutions should be used. Patients treated with acidic sodium fluoride gels often complain of sensitivity and pain in the gingiva and oral mucosa. In addition, a more rapid destruction of the teeth may occur, since there is little saliva to encourage the remineralization of the enamel dissolved by the acidic fluoride gel. Furthermore, a 5,000 ppm fluoridated toothpaste, used twice daily, has been recommended for high caries risk patients with salivary dysfunction [34]. When salivary function is compromised, the normal process of tooth remineralization is interrupted. This enhances demineralization and the consequent loss of tooth structure. Remineralizing solutions may be used to alleviate some of these changes [25].

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Fig.  22.10  Candidiasis of the tongue. (Reprinted with permission from Sreebny LM, Vissink A (eds). Dry mouth. The malevolent symptom: a clinical guide, Ames: Wiley-Blackwell 2010.)

Diet Modifications Patients should be counseled to follow a diet that avoids cariogenic foods (especially fermentable carbohydrates) and beverages. The implementation of meticulous oral hygiene procedures after each meal is critical to help reduce the risk of developing new or recurrent carious lesions. Chronic use of alcohol and caffeine can increase oral dryness and should be minimized [1]. Nonfermentable dietary sweeteners such as xylitol, sorbitol, aspartame, or saccharine are recommended [36]. So too is sucralose, a chlorinated, noncariogenic sweetener. Polyols such as xylitol, are considered to be anticariogenic since they decrease acid fermentation by S. mutans [37].

Fig.  22.11  Erythematous candidiasis of the palate. (Reprinted with permission from Sreebny LM, Vissink A (eds). Dry mouth. The malevolent symptom: a clinical guide, Ames: Wiley-Blackwell 2010.)

Oral Candida Therapy Patients with dry mouth often experience an increase in oral infections, particularly mucosal candidiasis (Fig. 22.10) [1, 26, 38, 39]. This condition often assumes an erythematous form (without the easily recognized pseudomembranous plaques). The mucosa is red and the patients complain of a burning sensation of the tongue or other oral soft tissues (Fig. 22.11). A high index of suspicion for fungal disease should be maintained, and appropriate antifungal therapies should be instituted as necessary (Table 22.2). Patients with salivary gland dysfunction may require prolonged treatment to eradicate these infections [40].

Conclusion Xerostomia is often a lifelong problem in head and neck irradiated patients. Therefore, these patients need additional supportive care by the dental team. Because of the special needs during and after head and neck radiation, the dental team should be an integral part of the head and neck team as well as take part in the regular follow-up. However, xerostomia due to cancer therapy cannot be currently prevented, but with additional oral supportive care, the complaints can be reduced or minimized.

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Table 22.2  Antifungal drugs for the management of oral candidiasis Topical agents Name Nystatin Dosage • Oral suspension (100,000 U/ml): 400,000–600,000 units 4–5 times daily (swish and swallow) • Troche (200,000 U): 200,000–400,000 units 4–5 times/day • 100,000 U/g cream and ointment: apply to the affected area 4–5 times/day • Powder (50 million U): sprinkle on the tissue contact area of denture

Clotrimazole • 10 mg troche: dissolve slowly over 15–30 min five times/daily • 1% cream: apply to the affected area bid for 7 days • Cream can be applied to the tissue contact areas of the denture

Ketoconazole • 2% cream: rub gently into the affected area 1–2 times daily Amphotericin B • 10 mg lozenge: dissolve slowly over 15–30 min in the mouth four times/ daily

Systemic agents Name Fluconazole • Tablets: 200 mg on day 1, then 100 mg daily for 7–14 days • Powder for oral suspension (10 mg/ mL); dosing is the same as for tablets

Itraconazole Ketoconazole • Tablets: 200 mg daily for 1–2 weeks; if • 200–400 mg/day as single dose for 7–14 days refractory to fluconazole, 100 mg q12h • Solution (10 mg/ml): 100–200 mg/10 ml once a day for 1–2 weeks; if refractory to fluconazole: 100 mg q12h In denture wearing individuals, the denture should overnight also be disinfected in a chlorhexidine mouth rinse to prevent reinfection of the oral cavity by Candida species residing in the denture material

References 1. Sreebny LM, Vissink A, eds. Dry mouth. The malevolent symptom: a clinical guide. Ames, Iowa: Wiley-Blackwell; 2010. 2. Ship JA, Fox PC, Baum BJ. Normal salivary gland function: how much saliva is enough? J Am Dent Assoc. 1991;122:63–69. 3. Dawes C, Odlum O. Salivary status in patients treated for head and neck cancer. J Can Dent Assoc. 2004;70:397–400. 4. Fox PC, Busch KA, Baum BJ. Subjective reports of xerostomia and objective measures of salivary gland performance. J Am Dent Assoc. 1987;115:581–584. 5. Hamlet S, Faull J, Klein B, Aref A, Fontanesi J, Stachler R et al. Mastication and swallowing in patients with postirradiation xerostomia. Int J Radiat Oncol Biol Phys. 1997;37:789–796. 6. Del Regato JA. Dental lesions observed after roentgen therapy in cancer of the buccal cavity, pharynx and larynx. Am J Roentgenol. 1939;42:404–410. 7. Frank RM, Herdly J, Philippe E. Acquired dental defects and salivary gland lesions after irradiation for carcinoma. J Am Dent Assoc. 1965;70:868–883. 8. Karmiol M, Walsh RF. Dental caries after radiotherapy of the oral regions. J Am Dent Assoc. 1975;91:838–845. 9. Jongebloed WL, ‘s-Gravenmade EJ, Retief DH. Radiation caries. A review and SEM study. Am J Dent. 1988;1:139–146. 10. Jansma J, Vissink A, Jongebloed WL. Natural and induced radiation caries. A SEM study. Am J Dent. 1993;6:130–136. 11. Mouly S, Salom M, Tillet Y et  al. Management of xerostomia in older patients: a randomised controlled trial evaluating the efficacy of a new oral lubricant solution. Drugs Aging. 2007;24:957–965. 12. Mouly SJ, Orler JB, Tillet Y et al. Efficacy of a new oral lubricant solution in the management of psychotropic drug-induced xerostomia: a randomized controlled trial. J Clin Psychopharmacol. 2007;27: 437–443. 13. Vissink A, De Jong HP, Busscher HJ. Wetting properties of human saliva and saliva substitutes. J Dent Res. 1986;65:1121–1124. 14. Johnson JT, Ferretti GA, Nethery WJ et  al. Oral pilocarpine for post-irradiation xerostomia in patients with head and neck cancer. New Eng J Med. 1993;329:390–395. 15. Vivino FB, Al-Hashimi I, Khan Z et  al. Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjögren’s syndrome: a randomized, placebo-controlled,

fixed-dose, multicenter trial. P92-01 Study Group. Arch Int Med. 1999;159:174–181. 16. Petrone D, Condemi JJ, Fife R et al. A double-blind, randomized, placebo-controlled study of cevimeline in Sjögren’s syndrome patients with xerostomia and keratoconjunctivitis sicca. Arthritis Rheum. 2002;46:748–754. 17. Fife RS, Chase WF, Dore RK et al. Cevimeline for the treatment of xerostomia in patients with Sjögren’s syndrome: a randomized trial. Arch Int Med. 2002;162:1293–1300. 18. Jensen SB, Pedersen AML, Vissink A et al. A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact. Support Care Cancer 2010;18:1061–1079. 19. Chambers MS, Jones CU, Biel MA et  al. Open-label, long-term safety study of cevimeline in the treatment of postirradiation xerostomia. Int J Radiat Oncol Biol Phys. 2007;69:1369–1376. 20. Wiseman LR, Faulds D. Oral pilocarpine: a review of its pharmacological properties and clinical potential in xerostomia. Drugs. 1995;49:143–155. 21. Jedel E. Acupuncture in xerostomia – a systematic review. J Oral Rehabil. 2005;32:392–396. 22. Brennan MT, Shariff G, Lockhart PB et al. Treatment of xerostomia: a systematic review of therapeutic trials. Dent Clin North Am. 2002;46:847–856. 23. Regelink G, Vissink A, Reintsema H. Efficacy of a synthetic polymer saliva substitute in reducing oral complaints of patients suffering from irradiation-induced xerostomia. Quintessence Int. 1998;29: 383–388. 24. Epstein JB, Emerton S, Le ND, Stevenson-Moore P. A double-blind crossover trial of Oral Balance gel and Biotene toothpaste versus placebo in patients with xerostomia following radiation therapy. Oral Oncol. 1999;35:132–137. 25. Zero DT. Dentifrices, mouthwashes, and remineralization/caries arrestment strategies. BMC Oral Health. 2006;6(Suppl 1):S9. 26. Ship JA, McCutcheon JA, Spivakovsky S et al. Safety and effectiveness of topical dry mouth products containing olive oil, betaine, and xylitol in reducing xerostomia for polypharmacy-induced dry mouth. J Oral Rehabil. 2007;34:724–732. 27. Hahnel S, Behr M, Handel G, Bürgers R. Saliva substitutes for the treatment of radiation-induced xerostomia – a review. Support Care Cancer. 2009;17:1331–1343.

22  Xerostomia and Dental Problems in the Head and Neck Radiation Patient 28. Fox PC, Brennan M, Pillemer S et al. Sjögren’s syndrome: a model for dental care in the 21st century. J Am Dent Assoc. 1998;129:719–728. 29. Atkinson JC, Wu A. Salivary gland dysfunction: causes, symptoms, treatment. J Am Dent Assoc. 1994;125:409–416. 30. Fox PC. Management of dry mouth. Dental Clin North Am. 1997;41:863–876. 31. American Dental Association Council on Scientific Affairs. The use of dental radiographs: update and recommendations. J Am Dent Assoc. 2006;137:1304–1312. 32. Jansma J, Vissink A, ‘s-Gravenmade EJ. In vivo study on the prevention of post-radiation caries. Caries Res. 1989;23:172–178. 33. Kielbassa AM, Hinkelbein W, Hellwig E et  al. Radiation-related damage to dentition. Lancet Oncol. 2006;7:326–335. 34. Chalmers JM. Minimal intervention dentistry: part 1. Strategies for addressing the new caries challenge in older patients. J Can Dent Assoc. 2006;72:427–433.

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35. Anusavice KJ. Dental caries: risk assessment and treatment solutions for an elderly population. Compend Contin Educ Dent. 2002;23 (10 Suppl):12–20. 36. Walsh L. Lifestyle impacts on oral health. In: Mount G, Hume W, eds. Preservation and restoration of tooth structure. Middlesbrough, UK: Knowledge Books and Software Ltd; 2005:83–110. 37. Van Loveren C. Sugar alcohols: what is the evidence for cariespreventive and caries-therapeutic effects? Caries Res. 2004;38: 286–293. 38. Guggenheimer J, Moore PA. Xerostomia: etiology, recognition and treatment. J Am Dent Assoc. 2003;134:61–69. 39. Tanida T, Okamoto T, Okamoto A et  al. Decreased excretion of antimicrobial proteins and peptides in saliva of patients with oral candidiasis. J Oral Pathol Med. 2003;32:586–594. 40. Daniels TE, Fox PC. Salivary and oral components of Sjogren's syndrome. Rheum Dis Clin North Am. 1992;18:571–589.

Chapter 23

Dysphagia, Reflux, and Hiccups Amy A. Shorthouse and Rebecca K. S. Wong

Introduction Dysphagia, reflux, and hiccups are common gastrointestinal symptoms in patients with cancer. Broadly speaking, they share a common theme, disruption of the function of the upper gastroesophageal tract, although their etiology is diverse and the mechanisms not fully understood. Persistent symptoms can have significant impact on nutritional status, as well as general quality of life. In fact, for patients living with advanced cancer, poor nutritional intake and performance status have been described as part of the common terminal pathway, carrying with them significant implications in prognosis [1]. Of all three symptoms, dysphagia is perhaps the best studied. Reflux is well studied in the general population, while intractable hiccups is poorly studied. In this chapter, we will review the prevalence of these symptoms, pathophysiology, and treatment options.

cancer, dysphagia is the presenting symptom in over 90% of patients. For these patients, if a curative intent is possible, local control and permanent relief of dysphagia can be expected in 30–60% (depending on the primary treatment modality) while in patients managed with a palliative intent, permanent relief of dysphagia remains challenging, often requiring repeated interventions and aggressive supportive care measures to maintain some degree of swallowing function [5]. In patients undergoing curative combination chemoradiotherapy for head and neck cancer, acute dysphagia as a side effect of treatment is expected in all patients, and in some requiring the use of prophylactic feeding tube placement [6]. In advanced lung cancer patients undergoing curative chemoradiotherapy, esophagitis and dysphagia is expected to occur in 14–49% and is one of the dose-limiting toxicities [7].

Dypshagia Prevalence of Dysphagia, Hiccups, and Reflux

Swallowing Mechanism

Dysphagia is perhaps most reliably reported, while significant dyspepsia and hiccups are more likely to be under reported. In a survey of 219 medical oncology patients focusing on symptoms with potential impact on nutritional status, dysphagia was noted in 17%, heartburn 14%, and indigestion 21% [2]. In a survey of 1,000 patients with advanced cancer attending a palliative program, Walsh et al. found dysphagia reported in 18% of patients, dyspepsia in 19%, and hiccups in 9% [3]. The corresponding estimates were 22, 56, and 15% in a survey of 406 terminally ill cancer patients [4]. For specific subgroups of patients, the expected incidence can be much higher. For example, in patients with esophageal

Swallowing involves the complex coordination of multiple muscle groups. This can be divided into three phases. The oral phase involves mastication and propulsion of the bolus to the posterior mouth. The pharyngeal phase further sends the food bolus into the oropharynx by movements of the tongue and soft palate. The esophageal phase sees the food bolus traveling through the esophagus with closure of the airway by the epiglottis, preventing aspiration of food, and closure of the palatopharynx by the soft palate, preventing regurgitation of food into the nasopharynx [8]. The neurophysiology of swallowing has not yet been fully elucidated, although it is known that a swallowing network exists in the brain stem including the nucleus tractus solitarius and nucleus ambiguous. These areas receive cortical input via the reticular formation. Imaging studies indicate that cortical involvement is multifocal and bilateral [9]. Efferent fibers of cranial nerves V, VII, IX, X, and XII are involved in sequentially co-coordinating the muscles involved in swallowing.

R.K.S. Wong (*) Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario, M5G2M9 Canada e-mail:

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_23, © Multinational Association for Supportive Care in Cancer Society 2011

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Peristalsis of the smooth muscle of the thoracic esophagus is stimulated by the autonomic nervous system via the vagus nerve [10].

Types of Dysphagia Malignant dysphagia is defined as direct cancer involvement of the esophagus, it occurs most commonly due to primary esophageal cancer, but can also occur as a result of extrinsic compression by malignant mediastinal lymphadenopathies or direct tumor extension, most commonly from lung cancer. Treatment-related dysphagia secondary to injury to the mucosal lining of the esophagus can occur in the acute phases of treatment, either with radiation therapy involving the esophagus or certain types of chemotherapy and is typically reversible. Posttreatment, injury to the esophagus resulting in scar tissue or stricture formation is typically chronic and irreversible. Neurological compromise of the swallowing pathway, located in the brain stem, and cranial nerve injuries can occur in patients with primary or metastatic tumors or from cancer treatments. Other causes of dysphagia include infection (e.g., candidiasis) and reflux esophagitis.

Clinical Assessment and Investigation For patients presenting with dysphagia, a careful history and physical examination would often reveal the potential cause and guide the appropriate choice of investigations. It is, however, important to note that not all patients with difficulty swallowing will describe it as such. For example, patients with a lower esophageal obstruction may be adamant they have no difficulty swallowing, but rather food getting stuck lower down in their chest or vomiting and pain after eating. Cough waking a patient up at night or during eating may suggest aspiration. Intractable vomiting may be the only complaint in patients who have developed a fistula, as the body struggles to protect its airway. Quantification of the severity of dysphagia is important for symptom monitoring. Several dysphagia scales have been described although all share very similar characteristics. For example, Mellow and Pinkas described a five-point scale (0–4) where 0 describes ability to eat all solids and 4 complete dsyphagia (Table 23.1) [11]. Barium swallow or computerized tomography can provide radiological information to establish the etiology of the dysphagia such as esophageal primary, extrinsic compression, benign stricture, fistula or features of complications such as aspiration pneumonia. Endoscopy provides details such as malignant mucosal involvement vs. extrinsic compression,

A.A. Shorthouse and R.K.S. Wong Table 23.1  Mellow score to describe degree of dysphagia Score Description 0 Able to eat all solids 1 Able to eat only some solids 2 Able to eat only soft foods 3 Able to drink liquids only 4 Complete dysphagia Source: Reprinted from Mellow and Pinkas [11], with permission

presence of fistula, esophageal candidiasis, reflux esophagitis, and the opportunity to obtain histology for pathological confirmation. Additional investigations such as endoscopic ultrasound and positron emission tomography are often required as part of the diagnostic work up of primary esophageal cancer. Video fluoroscopy is particularly useful in patients where dysphagia is expected to be a late sequel of treatment, allowing anatomy, swallowing function, and aspiration risk to be objectively quantified. It is particularly valuable for estimating the potential value of different behavioral strategies toward managing dysphagia.

Treatment After assessment to establish the etiology of dysphagia, management can be broadly divided into four complementary domains: supportive care measures, behavioral interventions (to facilitate the physiology of swallowing), mechanical interventions (to restore the esophageal lumen), and where appropriate antineoplastic therapies.

Supportive Interventions Supportive care measures are important and appropriate irrespective of etiology. Dysphagia is frequently accompanied by odynophagia, or painful swallowing that must be addressed concurrently. Use of systemic analgesics (e.g., opiates) and the choice of the liquid transdermal route of administration may be useful. Counseling by a dietitian in the use of pureed or liquid diets, nutrition supplement preparation, and the minimal amount of fluid intake required to maintain weight and hydration is important. For patients who are dehydrated, intravenous or subcutaneous hydration may be needed, while other more durable solutions are identified. Treatment of suspected esophageal candidiasis should be considered especially in patients receiving chemotherapy or on steroid therapy. For patients where the clinical course of the dysphagia is expected to be protracted, enteral feeding via percutaneous gastrostomy tube or total parenteral nutrition may need to be considered.

23  Dysphagia, Reflux, and Hiccups

Behavioral Interventions Behavioral measures may have a role in enhancing swallowing in some clinical situations, typically after assessment and at the recommendation of speech pathologists. These can be divided into postural techniques (e.g., chin tuck, head rotation) or the use of specific maneuvers such as the Mendelsohn maneuver, supraglottic swallow, and super-supraglottic swallow [12]. Chin tuck involves tilting the head downward toward the chest as much as possible without being extended forward. It changes the anatomic relationship between structures involved in swallowing and narrows the width of the airway entrance before swallowing. Head rotation involves rotating the head to the left of right (the weakened side) during swallowing. This results in changes in pharyngeal pressures directing the food bolus to the opposite side. The Mendelsohn maneuver requires the user to maintain hyopharyngeal elevation during swallowing for at least 2 s. This has the physiologic effect of increasing the duration of upper esophageal sphincter opening and improves airway protection. Supraglottic swallow requires the user to hold his or her breath before, during, and after swallowing, where the super supraglottic requires the additional volitional cough at the completion of the swallow. Physiological studies suggest improved airway protection at least when performed by normal subjects. While there is some evidence in support of the efficacy of these interventions in patients with neurological disorders or late effects of cancer treatments (i.e., head and neck cancer patients), the evidence is weak and requires further study.

Mechanical Interventions Narrowing of the esophageal lumen can arise due to malignant involvement with direct infiltration or extrinsic compression. Benign strictures most commonly occur in cancer patients following surgery or radiotherapy. Dilatation can provide transient relief of dysphagia and allow passage of an endoscope through an area of narrowing prior to stenting or brachytherapy. Esophageal stents can be the treatment of choice especially for patients with malignant dysphagia with a life expectancy of a few months. The placement of a stent across the region of esophageal narrowing provides a means to open the affected lumen rapidly, relieving the obstruction and dysphagia. A stent may also cover an area of tracheoesophageal fistula. While the first esophageal stents were rigid plastic stents, these have been superseded by self-expanding metal stents (SEMS). The most commonly used stents are SEMS, either covered or partially covered with an outer layer, composed of a semipermeable membrane. Covered stents have the advantage of preventing tumor growth into the lumen, but may be more prone to stent migration [13]. The location of the obstruction

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is important in the choice of stent. In particular, the placement of a stent over the gastroesophageal junction can result in significant reflux, often necessitating the use of medication such as proton pump inhibitors (PPI). Antireflux stents have an additional valve feature to reduce reflux symptoms, and removable silicone self-expanding stents are relatively new and probably have a role in selected clinical circumstances. Late complications of stents including stent migration, tumor or hyperplastic normal tissue overgrowth, or food bolus obstruction resulting in recurrent dysphagia occur in 30–40% [14].

Specific Considerations for Dysphagia Management for Incurable Esophageal Cancer For patients with potentially curable esophageal cancer, definitive therapy provides the best management of dysphagia. For others, treatment aimed at palliation can range from dilatation, laser therapy, stent insertion, brachytherapy, external beam radiotherapy, and palliative chemotherapy. Photodynamic therapy is occasionally used for selected patients. These treatments can be used sequentially or occasionally in combination. The choice of treatment approach is typically guided by feasibility, toxicity estimates, life expectancy, and of course expected efficacy. Stent therapy has already been discussed in the previous section. Brachytherapy involves the placement of a treatment catheter within the lumen of the esophagus, through an upper endoscopic procedure. Modern brachytherapy usually utilizes a high-dose-rate source (HDR brachytherapy) enabling treatment in a single dose or in 2–5 divided doses (fractionated) [15]. A recent Cochrane Review based on randomized trials supported the use of brachytherapy for patients with potential survival benefit and better quality of life, while stents can provided more rapid symptom relief and are particularly useful for patients with shorter life expectancies [16]. Palliative external beam radiotherapy is most typically given over 1–2 weeks of daily treatments although many different dose fractionation schemes are in use. In addition to the effect on restoring the esophageal lumen, it can reduce the risk of extrinsic compression or direct invasion into adjacent airways or vasculature. This is most suitable for patients with longer life expectancies (e.g., >3 months). Dysphagia relief is expected to occur in 50–70% of patients with a duration of relief in the order of 3–6 months [17]. It has not been directly compared with stenting or brachytherapy. The addition of chemotherapy to external beam radiotherapy is the subject of ongoing clinical trials (TROG 03.01 http://www. trog.com.au). The addition of external beam radiotherapy (30 Gy in ten fractions) to brachytherapy (16 Gy in two fractions) does not seem to provide additional benefit in terms of disease-free survival or overall survival [18].

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Dilatation and laser therapy have limited efficacy compared with stents and are used to complement more definitive therapies. Photodynamic therapy utilizes light of a particular wavelength to activate photosensitizing chemicals (e.g., Porphyrin based), which causes local tissue destruction. It is associated with skin photosensitivity for up to 6 weeks after delivery of the photosensitizer, fever, chest discomfort, and pleural effusion. This is seldom used as first-line therapy and may be useful in patients where other treatment options have failed. Chemotherapy typically consists of a cisplatin or 5  FU-based regimen. It is most commonly recommended when systemic disease dominates the clinical picture given its systemic toxicity profile.

Reflux The Global Consensus Group on gastroesophageal reflux disease defined GERD as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications (Montreal definition). While many symptom descriptors such as heartburn, dyspepsia, indigestion and reflux are used interchangeably, two syndromes using the nomenclature of “typical reflux syndrome” and “reflux chest pain syndrome” have been described. Typical reflux syndrome is characterized by heartburn (defined as a burning sensation in the retrosternal area) and/or regurgitation (the perception of flow of refluxed gastric content into the mouth or hypopharynx). The reflux chest pain syndrome consists of chest pain mimicking cardiac pain [19].

A.A. Shorthouse and R.K.S. Wong

Acute and chronic esophagitis can result from chemotherapy and radiotherapy [7, 22] or infective etiologies. Medications such as dexamethasone, antiinflammatories, and aspirin may result in gastritis and esophagitis, all with the potential of causing reflux symptoms.

Investigations For the majority of cancer patients with reflux symptoms, a careful history would guide further evaluations. Similar to GERD in the general population, endoscopic confirmation of esophagitis and pH studies are not always necessary and may not be cost effective. In a patient with a history suggestive of the above cancer-related etiologies, empirical treatment with a PPI may be appropriate. For patients with persistent symptoms despite appropriate use of a PPI (proton pump refractory), esophagogastroduodenoscopy, 24-h esophageal and gastric pH metry and H. pylori testing may only be appropriate for selected patients with cancer [23].

Treatment General Considerations Dietary modifications including small frequent, low fat meals, avoidance of spicy foods, and alcohol and smoking cessation should be considered. Elevation of the head of the bed is particularly important for patients with stents or gastroesophageal resection.

Pathophysiology Medical Therapy Gastroesophageal reflux disease and its symptoms, by definition, are attributed to the reflux of stomach contents into the esophagus. This can be objectively confirmed by pH studies. Patients with symptoms suggestive of gastroesophageal reflux disease can have a range of endoscopic findings, from normal, to Barrett’s esophagus (a hallmark of chronic reflux) and esophagitis (mucosal breaks). Presence of Helicobacter pylori infection may be etiologic as well as compounding the symptoms. Esophageal and gastric dysmotility can cause functional dyspepsia [20]. Patients with irritable bowel syndrome have been associated with and increased risk of reflux symptoms. In patients with cancer, malignant involvement of the stomach or esophagus can directly disrupt the anatomy and motility resulting in reflux. Similarly, surgical treatment for cancer such as gastroesophagectomy or esophageal stent placement [21] can result in reflux and is well described.

Optimal empirical use of a PPI is frequently recommended (e.g., once daily dosing). While H2 Receptor Antagonist (H2RA) (e.g., Famotidine) and prokinetic agents (e.g., domperidone) have all been shown to be effective, the effect is strongest with PPI. [24–26]. Failure of this strategy is not uncommon, occurring in about two-thirds of patients in the general population. The use of double-dose PPI has been shown to provide incremental benefit in reducing acid secretions. Switching PPI has been suggested in refractory patients, although there is no evidence to support its efficacy. The addition of an H2RA at bedtime has been shown to enhance the effect of PPI [23]. In patients who are intolerant of PPIs, H2RA and prokinetic agents should be considered. Anecdotal evidence exists for symptom response with the use of subcutaneous or intravenous omeprazole in the far advanced cancer patient where oral dosing was suboptimal [27].

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23  Dysphagia, Reflux, and Hiccups

While radioprotective agents, such as glutamine [28] and amifostine [29], have been shown to reduce esophagitis in patients undergoing high-dose chemoradiation, their use remains investigational.

Hiccups or Singultis Hiccup, (more commonly spelled “hiccough” in the UK) is created by spasmodic involuntary contraction of the ­diaphragm and intercostal muscles which is followed by closure of the glottis causing the characteristic hiccup sound. Singultis, the medical term for hiccups is of Latin origin, meaning to gasp or sign, is sometimes used for more intractable hiccups[30]. Hiccups typically occur in a pattern of 4–60 per minute and do not seem to serve a physiologic function [31]. Persistent hiccups (lasting more than 48 h) and intractable hiccups (lasting more than 2 months) can result in psychological effects, sleep disturbance, increased caloric requirements, aspiration, and even pneumomediastinum or dehiscence of surgical wounds in the postoperative setting. In patients with advanced terminal illness, they can be particularly distressing to both patient and family.

be one of the most common causes of hiccups occurring in approximately 10% of patients, while other common causes include alcohol, sudden change in temperature, gastric insufflation with gastroscopy, and stress and tympanic irritation. Hiccups have been associated with metabolic disturbance (e.g., uremia) and anesthesia (e.g., inhaled, epidural). Other rarer associations include central nervous system pathology (e.g., stroke) and myocardial infarction [30–32]. In patients with cancer, intractable hiccups may occur as a result of direct cancer involvement, medications, and anticancer therapies. Direct cancer involvement anywhere along the hiccup pathway, including the esophagus, stomach including malignant gastric-outlet obstruction, small-bowel obstruction, volvulus, diaphragm, vagus or phrenic nerve, malignant pleural effusion, and empyema, have all been associated with hiccups. Medications commonly used for supportive care, such as antibiotics, benzodiazepines, corticosteroids, perphenazine, and opioids have been described as potentially causative. Certain chemotherapy drugs such as cisplatin, carboplatin, cyclophosphamide, docetaxel, etoposide, gemcitabine, irinotecan, paclitaxel, vindesine, and vinorelbine have been linked to hiccups. In particular, the incidence of hiccups with cisplatin with an unexplained male predominance in the order of 23% has been described [33].

Mechanism

Clinical Assessment/Investigation

The mechanism of hiccup is not fully understood. The hiccupreflex arc consists of afferent and efferent arms and a central hiccup center most probably located in the upper cervical cord (C3–C5) or brainstem. The afferent arm primarily involves the vagus, phrenic and sympathetic nerves (T6–T12), however other afferent mechanisms have been reported, including stimulation of the trigeminal nerve. The efferent limb of the reflex arc is mediated principally by the phrenic nerve, causing diaphragmatic contraction, often unilateral with the left diaphragm involved more frequently than the right. The external intercostal (T1–T11) and scalenus anticus nerves, as well as the accessory respiratory muscles are involved. Finally, the recurrent laryngeal nerve stimulates closure of the glottis after contraction of the diaphragm [31].

History and physical examination should include neurological assessment, external auditory canal, head and neck, thorax and abdomen examination looking for features suggestive of a causative etiology. Imaging of the head and neck, thorax and abdomen (including chest X-ray, CT, or MRI) depending on physical findings may reveal or confirm a likely cause. Endoscopy of the upper GI tract may be indicated. In selected cases, complementary investigations could include complete blood count, electrolytes, and renal function.

Etiologies Hiccups may be caused by a large number of stimuli with more than 100 being reported in the literature. Benign hiccup bouts often follow gastric distension (such as with large meals or ingestion of carbonated beverages), which is believed to stimulate vagal afferent activity. Gastroesophageal reflux may

Treatments Beyond removing any possible contributing factors (such as steroid medications), a large number of nonpharmacological (“folk remedies”) and pharmacological interventions have been described to treat hiccups, as well as a smaller number of more invasive interventions. As intractable hiccups are relatively uncommon, most treatments are supported only by level IV evidence. Many unproven “folk remedies” exist for hiccups, sharing a common theme aimed at stimulating either the phrenic or vagal nerves (Table 23.2) [30, 31].

228

A.A. Shorthouse and R.K.S. Wong Table 23.2  Folk remedies suggested to terminate hiccups Selected folk remedies for hiccup Stimulation of palate or pharynx Lifting uvula with a spoon Valsalva maneuver Traction on tongue Pressure over eyebrow area Gargling or drinking ice water Spoonful of sugar or peanut butter Drinking from opposite side of a cup Biting a lemon Black pepper-induced sneezing Sudden fright Breathing into a paper bag Source: Data from Marinella [31]

review of the anesthetic literature found several remedies suggested for the prevention and treatment of anesthesiaassociated hiccups in case series [39]. Phrenic nerve blockade, initially achieved by long-acting anesthetic, can be rendered a permanent intervention by phrenic nerve transection in the absence of respiratory compromise [31]. Breathing pace makers, designed to control diaphragmatic contraction via stimulation of the phrenic nerve, have been reported in a case series for intractable neurogenic hiccups [40]. These more invasive procedures are typically considered only after careful multidisciplinary assessment and reserved for patients with longer-term life expectancies.

Pharmacology

Summary

Chlorpromazine is the only medication with US Food and Drug Administration (FDA) approval for hiccups. It is thought to act centrally, via dopamine antagonism, to suppress the hiccup reflex and is considered to be more effective when given intravenously. Adverse effects include hypotension urinary retention, glaucoma, and delirium [30, 31]. Baclofen is a gamma-aminobutyric acid (GABA) analog thought to activate an inhibitory neurotransmitter and block the hiccup stimulus [34]. Ramirez performed a crossover randomized study involving only four patients. While no difference in hiccup frequency was seen, baclofen was associated with a longer hiccup-free period [35]. Gabapentin maybe efficacious in terminating persistent hiccups by increasing the levels of GABA, mediated by neural Ca channel blockade modulating diaphragmatic excitability, [31] with some recent evidence in support of its efficacy. Given the favorable toxicity and interaction profile of gabapentin, it may be the medication of choice in oncology patients who are often taking multiple pharmaceutical agents and in whom adverse effects may not be tolerated well [30, 31]. Chlorpromazine, baclofen, and gabapentin are reasonable pharmacological agents of choice, depending on the anticipated tolerance to potential side effects. Other agents that have been used include metoclopramide, benzodiazepines, carvedilol, and steroids [31]. Where reflux esophagitis may be a contributory factor, treatment with PPI is a sound initial strategy [36]. If single agent therapy is not successful, combinations have been used including cisapride, omeprazole and baclofen [37], and gabapentin and baclofen [38].

Dysphagia, reflux, and hiccups are common gastrointestinal symptoms in cancer patients. They can all result from direct tumor involvement or be secondary to adverse effects from cancer treatments, with a negative impact on the optimal function of the gastroesophageal tract and impairment in nutritional status and quality of life. The etiology may be obvious, given what is known about the disease or treatment status of the patient, or may require careful assessment to deduce. The cause would, in turn, guide optimal management, which frequently includes a combination of nutritional support and medical therapies in addition to more specialized modalities depending on the circumstances. Multidisciplinary approaches to the assessment and management of these symptoms are warranted.

Other Strategies Alternative therapies in the management of hiccups including acupuncture and cupping have been reported. A systematic

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23  Dysphagia, Reflux, and Hiccups 7. Werner-Wasik M, Werner-Wasik M. Treatment-related esophagitis. Seminars in Oncology 2005;32:S60–S66. 8. Nguyen NP, Smith HJ, Sallah S, et al. Evaluation and management of swallowing dysfunction following chemoradiation for head and neck cancer. Current Opinion in Otolaryngology & Head and Neck Surgery 2007;15:130–133. 9. Ertekin C, Aydogdu I. Neurophysiology of swallowing. Clinical Neurophysiology 2003;114:2226–2244. 10. Goyal RK, Chaudhury A, Goyal RK, et al. Physiology of normal esophageal motility. Journal of Clinical Gastroenterology 2008; 42:610–619. 11. Mellow MH, Pinkas H. Endoscopic laser therapy for malignancies affecting the esophagus and gastroesophageal junction. Analysis of technical and functional efficacy. Archives of Internal Medicine 1985;145:1443–1446. 12. Wheeler-Hegland KP, Ashford JP, Frymark TM, et al. Evidence-based systematic review: oropharyngeal dysphagia behavioral treatments. Part II-Impact of dysphagia treatment on normal swallow function. Journal of Rehabilitation Research and Development 2009;46:185. 13. Yakoub D, Fahmy R, Athanasiou T, et al. Evidence-based choice of esophageal stent for the palliative management of malignant dysphagia. World Journal of Surgery 2008;32:1996–2009. 14. Homs MY, Kuipers EJ, Siersema PD, et  al. Palliative therapy. Journal of Surgical Oncology 2005;92:246–256. 15. Sur RK, Levin CV, Donde B, et al. Prospective randomized trial of HDR brachytherapy as a sole modality in palliation of advanced esophageal carcinoma–an International Atomic Energy Agency study.[see comment]. International Journal of Radiation Oncology, Biology, Physics 2002;53:127–133. 16. Sreedharan A, Harris K, Crellin A, et al. Interventions for dysphagia in oesophageal cancer. Cochrane Database of Systematic Reviews 2009;(4):CD005048. 17. Wong R, Malthaner R. Esophageal cancer: a systematic review. Current Problems in Cancer 2000;24:297–373. 18. Sur R, Donde B, Falkson C, et al. Randomized prospective study comparing high-dose-rate intraluminal brachytherapy (HDRILBT) alone with HDRILBT and external beam radiotherapy in the palliation of advanced esophageal cancer. Brachytherapy 2004;3:191–195. 19. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. [see comment]. American Journal of Gastroenterology 2006;101:1900–1920; quiz 1943. 20. Talley NJ, Talley NJ. How to manage the difficult-to-treat dyspeptic patient. Nature Clinical Practice Gastroenterology and Hepatology 2007;4:35–42. 21. Neale JC, Goulden JW, Allan SG, et al. Esophageal stents in malignant dysphagia: a two-edged sword? Journal of Palliative Care 2004;20:28–31. 22. Rose J, Rodrigues G, Yaremko B, et al. Systematic review of dosevolume parameters in the prediction of esophagitis in thoracic radiotherapy. Radiotherapy and Oncology 2009;91:282–287. 23. Yuan Y, Hunt RH, Yuan Y, et al. Evolving issues in the management of reflux disease? Current Opinion in Gastroenterology 2009;25:342–351.

229 24. van Pinxteren B, Numans ME, Bonis PA, Lau J. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database of Systematic Reviews 2006;19;3:CD002095. Review. 25. Moayyedi P, Soo S, Deeks J, Delaney B, Innes M, Forman D. Pharmacological interventions for non-ulcer dyspepsia. Cochrane Database of Systematic Reviews 2006;18;(4):CD001960. Review. 26. Donnellan C, Sharma N, Preston C, Moayyedi P. Medical treatments for the maintenance therapy of reflux oesophagitis and endoscopic negative reflux disease. Cochrane Database of Systematic Reviews 2005;18;(2):CD003245. Review. Update in: Cochrance Database of Systematic Reviews 2010;2:CD003245. PMID: 15846653. 27. Agar M, Webster R, Lacey J, et al. The use of subcutaneous omeprazole in the treatment of dyspepsia in palliative care patients. Journal of Pain and Symptom Management 2004;28:529–531. 28. Algara M, Rodriguez N, Vinals P, et al. Prevention of radiochemotherapy-induced esophagitis with glutamine: results of a pilot study. International Journal of Radiation Oncology, Biology, Physics 2007;69:342–349. 29. Sasse AD, Clark LG, Sasse EC, et  al. Amifostine reduces side effects and improves complete response rate during radiotherapy: results of a meta-analysis. International Journal of Radiation Oncology, Biology, Physics 2006;64:784–791. 30. Lewis JH. Hiccups: causes and cures. Journal of Clinical Gastroen­ terology 1985;7:539–552. 31. Marinella MA. Diagnosis and management of hiccups in the patient with advanced cancer. The Journal of Supportive Oncology 2009; 7:122–127, 130. 32. Rousseau P. Hiccups. Southern Medical Journal 1995;88:175–181. 33. Liaw CC, Wang CH, Chang HK, et al. Gender discrepancy observed between chemotherapy-induced emesis and hiccups. Supportive Care in Cancer 2001;9:435–441. 34. Smith HS, Busracamwongs A. Management of hiccups in the palliative care population. American Journal of Hospice and Palliative Medicine 2003;20:149–154. 35. Ramirez FC, Graham DY. Treatment of intractable hiccup with baclofen: results of a double-blind randomized, controlled, cross-over study. American Journal of Gastroenterology 1992;87:1789–1791. 36. Dore MP, Pedroni A, Pes GM, et al. Effect of antisecretory therapy on atypical symptoms in gastroesophageal reflux disease. Digestive Diseases and Sciences 2007;52:463–468. 37. Petroianu G, Hein G, Petroianu A, et al. Idiopathic chronic hiccup: combination therapy with cisapride, omeprazole, and baclofen. Clinical Therapeutics 1997;19:1031–1038. 38. Hernández JL, Pajarón M, García-Regata O, et al. Gabapentin for intractable hiccup. The American Journal of Medicine 2004;117:279–281. 39. Kranke P, Eberhart LH, Morin AM, et al. Treatment of hiccup during general anaesthesia or sedation: a qualitative systematic review. European Journal of Anaesthesiology 2003;20:239–244. 40. Dobelle WH. Use of breathing pacemakers to suppress intractable hiccups of up to thirteen years duration. ASAIO Journal 1999;45:524–525.

Chapter 24

Nausea and Vomiting Ian N. Olver

Nausea and vomiting occur as symptoms associated with cancer in many settings. Raised intracranial pressure, liver or renal impairment are examples that can be direct conse­ quences of cancer and its metastases or paraneoplastic effects causing metabolic disturbances, such as hypercalcemia, which result in these symptoms. Concomitant medication, particularly opiate analgesia, may also cause patients with cancer to experience nausea or vomiting. It was, however, when cytotoxic chemotherapy was intro­ duced to treat cancer and some drugs were associated with severe emesis, which limited their use, that research into the mechanisms of emesis was boosted. Subsequently, two new classes of antiemetics, the 5 hydroxytryptamine 3 receptor antagonists (5HT3 RA) and the neurokinin 1 receptor anta­ gonist (NK1 RAs) were developed, and these made a signifi­ cant impact on both the acute and delayed vomiting associated with chemotherapy. The most common nausea and vomiting that patients experience after chemotherapy occurs in the first 24 h and is called acute post-chemotherapy emesis [1]. Delayed emesis commences from about 18 h and can last for at least 5 days [2]. Anticipatory emesis is a conditioned response that occurs prior to subsequent cycles of chemotherapy, after vomiting. Anticipatory emesis can occur with subsequent cycles of chemotherapy as a conditioned response to vomiting in a previous cycle [3]. Patient characteristics and the drugs and their dose and schedule determine the likelihood of emesis post-chemother­ apy [4]. Younger patients are more prone to vomiting than older, as are women compared to men. Patients who have had previous vomiting with chemotherapy or motion sickness or vomiting with pregnancy are more likely to vomit post-che­ motherapy. Those patients with a prolonged history of heavy alcohol consumption vomit less after chemotherapy. Drugs are classified as having a high emetic potential if patients have a 90% or greater chance of experiencing ­emesis, I.N. Olver (*) University of Sydney Medical School, Cancer Council Australia, Surry Hills, Sydney, NSW 2010, Australia e-mail: [email protected]

if no antiemetic prophylaxis is given [5]. The best example is cisplatin that when given over an hour at greater than 60 mg/ m2 will cause acute and delayed vomiting in almost all patients. It is often used in trials to test new antiemetic drugs. Drugs such as anthracyclines or cyclophosphamide are clas­ sified as of moderate emetic potential (between 30 and 90% chance of emesis). Drugs of low emetic potential (10–30% chance of vomiting) include the taxanes and oral agents such as capecitabine, and newer targeted therapies such as the vinca alkaloids, bleomycin, procarbazine and erlotinitib (Tables 24.1 and 24.2). Most drugs are not given as single agents. The emetic poten­ tial of drug combinations can be judged by the drug with the highest emetic potential. Combinations of drugs of moderate emetic potential have not always been assessed for their overall emetic potential but the commonly used combination of cyclo­ phosphamide and an anthracycline would induce emesis in 90% or more of patients not given prophylactic antiemetics and so should be considered as having high emetic potential. In patient surveys ranking side effects, nausea and vomit­ ing are still amongst the most distressing side effects of che­ motherapy and have been so in surveys dating back to the early 1980s [6, 7]. One of the reasons for this is not just the discomfort of the side effect itself but its impact on the quality of life, and association with other symptoms such as fatigue, anorexia and insomnia [8]. Despite this, doctors and nurses underestimate nausea and vomiting, particularly in the delayed phase, as compared with the patients’ experiences, and often do not use aggressive enough prophylaxis [9].

Nausea In studies that have been used to demonstrate the antiemetic efficacy of the major antiemetic drugs, the 5HT3 RAs and the NK1 RAs, nausea is not as well controlled as vomiting and is still reported as a distressing side effect. One reason is that what is reported as nausea may be associated with a cluster of symptoms with different biological origins [10]. When we had interviewed patients about nausea, the associated symptoms

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_24, © Multinational Association for Supportive Care in Cancer Society 2011

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232 Table 24.1  Emetic potential of intravenous antineoplastic agents Degree of emetogenicity (incidence) Agent High (>90%)

Cisplatin Mechlorethamine Streptozotocin Cyclophosphamide ≥1,500 mg/m2 Carmustine Dacarbazine Moderate (30–90%) Oxaliplatin Cytarabine >1 g/m2 Carboplatin Ifosfamide Cyclophosphamide <1,500 mg/m2 Doxorubicin Daunorubicin Epirubicin Idarubicin Irinotecan Azacitidine Bendamustine Clofarabine Alemtuzumab Low (10–30%) Paclitaxel Docetaxel Mitoxantrone Doxorubicin HCl liposome injection Ixabepilone Topotecan Etoposide Pemetrexed Methotrexate Mitomycin Gemcitabine Cytarabine ≤1,000 mg/m2 5-Fluorouracil Temsirolimus Bortezomib Cetuximab Trastuzumab Panitumumab Catumaxumab Minimal (<10%) Bleomycin Busulfan 2-Chlorodeoxyadenosine Fludarabine Vinblastine Vincristine Vinorelbine Bevacizumab Source: Data from the Multinational Society for Supportive Care in Cancer (MASCC) antiemetic group guidelines are available at www.mascc.org

were vomiting, dry retching, loss of appetite, dizziness and indigestion (described as ranging from queasiness to intense abdominal churning). Most patients described psychological symptoms as either difficulty in concentrating, restlessness or anxiety and negative emotions that could also trigger nausea

I.N. Olver Table 24.2  Emetogenic potential of oral antineoplastic agents Degree of emetogenicity (incidence) Agent High (>90%)

Hexamethylmelamine Procarbazine Moderate (30–90%) Cyclophosphamide Temozolomide Vinorelbine Imatinib Low (10–30%) Capecitabine Tegafur Uracil Fludarabine Etoposide Sunitinib Everolimus Lapatinib Lenalidomide Thalidomide Minimal (<10%) Chlorambucil Hydroxyurea l-Phenylalanine mustard 6-Thioguanine Methotrexate Gefitinib Erlotinib Sorafenib Considerable uncertainty prevails for the emetogenic risk of oral agents Source: Data from the MASCC antiemetic group guide­ lines are available at www.mascc.org

(Jaklin Eliott, personal communication). It maybe that many of the symptoms in the cluster require treatment to alleviate nausea. Certainly non-pharmacological treatments including acupressure and hypnosis have been tried. In addition, drugs that have shown some efficacy include gabapentin and ginger. In a small study, gabapentin was reported by Guttuso and colleagues as reducing delayed post-chemotherapy nausea in patients being treated for breast cancer with a combination of doxorubicin and cyclophosph­ amide [11]. Ginger (Zingiber officinale), a spice used for centuries for nausea associated with pregnancy, has been shown to reduce the nausea of patients receiving chemother­ apy who had nausea in a previous cycle, when it was added to a 5HT3 RA [12].

The Initial Drugs Used to Control Chemotherapy-Induced Nausea and Vomiting When emesis was first encountered with chemotherapy, the antiemetics used to treat a range of other conditions associ­ ated with nausea were used for treatment and prophylaxis, but had limited efficacy, particularly against cytotoxics with high

24  Nausea and Vomiting

emetic potential such as cisplatin. Common antiemetics were the dopamine antagonists, domperidone, the substituted benzamides such as metoclopramide or alizapride, phenothi­ azines, particularly prochlorperazine or metopimazine and butyro­phenones, particularly haloperidol or droperidol. Higher doses of metoclopramide were more successful against cisplatin-induced emesis probably because such doses impacted on the serotonin receptors rather than the dopamine receptors [13]. Prochlorperazine was similarly more effective at higher doses but also exhibited more toxicity particularly postural hypotension and extrapyramidal effects [14]. Other drugs investigated at that time included the cannabi­ noids, tetrahydrocannabinol and the synthetic nabilone and dronabinol, based on reports from marijuana smokers of relief from chemotherapy-induced emesis. Some antiemetic effi­ cacy was found, but many patients did not tolerate the dys­ phoric side effects [15]. Anticholinergics such as scopolamine patches, which were useful for motion sickness, had little antiemetic efficacy with cisplatin, but antihistamines given in addition to dopamine antagonists reduced their extrapyrami­ dal side effects and added some antiemetic efficacy. Dexamethasone and methylprednisolone were amongst the earliest agents to be used for chemotherapy-induced emesis, including showing efficacy in decreasing cisplatin-induced emesis [16]. Prior to the introduction of NK1 RAs, dexame­ thasone was arguably the best available agent for delayed emesis [17]. The Italian Group for Antiemetic Research evalu­ ated the role of dexamethasone alone or combined with ondansetron on days 2–5 in 618 patients who had no emesis and either no or mild nausea in the first 24 h post-chemotherapy of moderate emetic potential. Dexamethasone was statistically significantly superior to placebo in controlling delayed vomiting or moderate to severe nausea (87 vs. 77%), and the combina­ tion of dexamethasone and ondansetron was not significantly superior to dexamethasone alone (92 vs. 87%) [18]. Dexamethasone is now used as part of triple therapy with 5HT3 RAs and NK1 RAs, and doses range between 8 mg to prevent moderate emesis and 20  mg for chemotherapy of high emetic potential but the optimal dose for delayed emesis is unknown [19]. Benzodiazepines such as lorazepam were used as adju­ vants to other antiemetics. Lorazepam has anxiolytic effects and is associated with retrograde amnesia, which improved the control of post-chemotherapy emesis and lessened the potential for anticipatory emesis [20]. More recently olan­ zepine, a thienobenzodiazepine, which can act on multiple receptors including dopamine (D1, D2, D3, D4) and the serotonin receptors (5HT2a, 5HT2c, 5HT3, 5HT6) as well as adrenergic, muscurinic and histamine receptors have shown activity in small studies with 5HT3 RAs and dexamethasone, in both acute, and delayed emesis [21, 22]. These drugs are now mainly used for cases refractory to 5HT3 RAs, NK1 RAs and steroids, or for breakthrough

233

emesis when other strategies such as changing 5HT3 RAs or using NK1 RAs to gain a response after a 5HT3 RA fail.

5HT3 Receptor Antagonists The first major breakthrough in the control of chemotherapyinduced emesis came with the introduction of the 5HT3 receptor antagonists. These resulted from the discovery that chemotherapy caused the release of 5-hydroxytryptamine from the enterochromaffin cells in the small intestine, which stimulated the vagal afferents that connect to the dorsal brainstem, the nucleus tractus solitarius and the area pos­ trema (which is in contact with blood and cerebrospinal fluid), and then efferent fibres go to the central pattern gen­ erator more ventrally in the brain stem and the vomiting reflex is initiated [23, 24]. Ondansetron was the first of the 5HT3 RAs. When com­ bined with dexamethasone prior to chemotherapy of high emetic potential, it achieved control of acute post-chemotherapy emesis in over 80% of patients with a rate of around 65%, if used as a single agent [25]. It was well tolerated, the side effects being mild headache, constipation and transient eleva­ tion in liver transaminases. Ondansetron, however, had much less efficacy against cisplatin-induced delayed emesis [17]. Other 5HT3 RAs have been marketed since but a meta-analysis of randomised studies did not demonstrate major differences in the therapeutic effect between ondansetron, granisetron, tropisetron or dolasetron [26]. Currently, the 5HT3 RAs are given by single daily dosing rather than the initial multiple day schedules, and oral formulations have been shown to be as effective as intravenous dosing [27, 28]. A second generation 5HT3 RA, palonosetron, has a lon­ ger mean elimination half-life of approximately 40 h as com­ pared to 4–9 h, and a 30-fold higher binding affinity for the receptor than first generation 5HT3 RAs, but is as well toler­ ated [29]. Single agent comparisons with intravenous ondansetron and dolasetron suggested non-inferiority in the control of acute emesis and superiority in the control of delayed emesis associated with chemotherapy of moderate emetic potential [30, 31]. A third trial showed non-inferiority for acute, delayed and overall emesis in the prophylaxis of chemotherapy of high emetic potential when palonosetron was compared to ondanstetron [32]. Palonosetron and dexamethasone was subsequently com­ pared to granisetron and dexamethasone in 1,114 patients receiving chemotherapy of high emetic potential (including the AC combination). The complete response rate for acute emesis was 75.3% in the palonosetron arm vs. 73.3% in the granisetron arm of the study [33]. Palonosetron can be safely given over multiple days and its efficacy is sustained over multiple cycles [34–36].

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The NK1 Receptor Antagonists The major issue persisting after the introduction of the 5HT3 RAs was the challenge of controlling delayed post-chemo­ therapy emesis. Substance P is a neurotransmitter with a strong affinity for the neurokinin1 (NK1) receptor and is con­ centrated in areas of the brain associated with nausea and vomiting such as the nucleus tractus solitarius and the area prostrema [37]. The NK1 RAs prevent the binding to this receptor. The first of the NK1 RAs on the market was aprepitant, as a nanoparticle oral formulation [38]. Of many potential drug interactions with aprepitant, because it is both a substrate and inhibitor of CYP 3A4, when aprepitant is given with oral dexamethasone it increases the area under the curve (AUC) of dexamethasone twofold, necessitating halving the dose when given with aprepitant [39]. There have been no clini­ cally important interactions found with 5HT3 RA’s or cyto­ toxic drugs however that decreases in the AUC of ethinyl estradiol, phenytoin and decreases in the international nor­ malised ratio (INR) with warfarin that occur when given with aprepitant should be recognised [40–43]. Given that the combination of a 5HT3 RA and dexametha­ sone had become the standard antiemetic regimen to prevent emesis from chemotherapy of high emetic potential, the two major trials tested added it to this combination. Aprepitant (125 mg) was given with ondansetron (32 mg) and dexame­ thasone (20 mg) on day 1 where it could have impact on the acute phase of the emesis and then days 2 and 3 (80 mg) with dexamethasone (8 mg) from days 2 to 4. The dexamethasone dose was halved because of the pharmacokinetic interaction. The two trials evaluated 1,099 patients and showed sig­ nificant improvement when aprepitant was added, with over­ all rates of no emesis and no rescue being 52.7 vs. 43.3% on one study and 72.7 vs. 52.3% on the other (p < 0.001). The greatest difference was in the delayed phase of emesis, with complete response rates of 67.7 vs. 45.8% and 74.4 vs. 55.8% respectively [44, 45]. Fewer patients experienced nausea in the overall and delayed phases. The efficacy of the triple therapy is maintained over six cycles [46]. Aprepitant was well tolerated; the main side effects being asthenia, anorexia and hiccoughs, and the quality of life was improved. In a subsequent trial with a more intense control arm of 5 days of ondansetron and dexamethasone, the aprepitant arm was still superior in all phases of emesis the overall complete response being 72 vs. 61% (p = 0.003) [47]. The aprepitant triple therapy was superior with non-cisplatin combinations such as breast cancer patients receiving cyclo­ phosphamide and anthracyclines, with the control of vomit­ ing without rescue over 5 days being 51 vs. 42% [48]. Similarly, in a study with chemotherapy of moderate emetic potential, those not receiving AC recorded no vomiting

I.N. Olver

overall as 83.2 vs. 71.3% in favour of aprepitant [49]. In a small study, when palonosetron was the 5HT3 RA in triple therapy with chemotherapy of moderate emetic potential, an 83% response rate was recorded [50]. The original trials were done with fosaprepitant dimeglu­ mine (L-758298), an intravenous water-soluble prodrug of aprepitant, whose antiemetic properties are attributable to aprepitant, as it is rapidly converted to aprepitant with a plasma half-life of 2.3 min and complete conversion within 30 min. A dose of 115 mg intravenously is bioequivalent to 125 mg of aprepitant orally [51]. The efficacy and safety data are just those of aprepitant with the addition of venous irrita­ tion at 25 mg/ml, at doses of 50 or 100 mg infused over 30 s, and therefore fosaprepitant provides a safe and effective intravenous alternative to oral dosing of aprepitant. Of several other NK1 RAs, the trials with casopitant pro­ vided insights into possible dose optimisation and efficacy, although GlaxoSmithKline has discontinued regulatory fil­ ings for this drug. A double blinded phase II trial with ­chemotherapy of moderate emetic potential, compared a dexamethasone (8  mg IV day 1) and ondansetron (8  mg twice daily days 1–3) control with three arms, which added a 3-day regimen of casopitant at three different doses of 50, 100 and 150 mg daily, and two arms exploring single day 1 dosing of casopitant (150 mg) [52]. Casopitant significantly increased the control of vomiting in the overall and delayed phases (84.2% for 150 mg vs. 69.4% control), but the rates of nausea control did not differ. On day 1 only dosing of caso­ pitant showed similar rates of control of vomiting to the 3-day regimen (79.2%). Similarly, results were recorded in a subset analysis of a phase II study with chemotherapy of high emetic potential comparing, adding a single dose of casopitant (150 mg) on day 1 to ondansetron and dexametha­ sone or 3 days of aprepitant. Complete response rates at 120 h were 75 and 72%, respectively [53]. Nausea, however, was not as well controlled as vomiting. Likewise single day dosing was effective in phase III studies with women receiv­ ing predominantly AC and another with chemotherapy of high emetic potential [54–56].

Antiemetic Guidelines The Multinational Society For Supportive Care In Cancer (MASCC) antiemetic group regularly updates its guidelines and last met for a major review of the literature and consen­ sus meeting in June 2009. Studies reporting at least 10% improvement in outcome were considered as warranting changing a guideline, and a consensus was reached with 66% agreement. The information referred to in this chapter and any updated guidelines and the authors responsible can be accessed at www.mascc.org.

235

24  Nausea and Vomiting

Prevention of Acute Nausea and Vomiting Following Chemotherapy of High Emetic Potential The MASCC group recommended, with a high level of confidence and consensus, triple antiemetic therapy with a 5HT3 RA, dexamethasone and aprepitant. The 5HT3 RA should be given at the lowest fully effective dose tested as a single dose prior to chemotherapy either orally or intrave­ nously, and any of the agents can be used. It is not known whether palonosetron will be superior to the other 5HT3 RAs when an NK1 RA is used. Regarding the NK1 RA, fosaprepi­ tant intravenously could be substituted for oral aprepitant, but no randomised studies have been done to support this.

Prevention of Delayed Nausea and Vomiting Following Chemotherapy of High Emetic Potential The MASSC panel recommended, with a high level of con­ fidence and moderate level of consensus, that in patients receiving cisplatin treated with a combination of aprepitant, a 5HT3 RA and dexamethasone to prevent acute vomiting and nausea, a combination of dexamethasone and aprepitant is suggested to prevent delayed nausea and vomiting, on the basis of its superiority to dexamethasone alone. The major issue here is that the incidence of delayed eme­ sis is influenced by the control of acute emesis. Aprepitant’s role has been tested in the delayed phase only after it has been administered prior to the acute phase and some of its efficacy in the delayed phase has been postulated as a carry­ over effect. However, an analysis of the database from two phase III aprepitant trials suggested that aprepitant protected against delayed vomiting regardless of response in the acute phase [57]. There remains the question raised by the casopi­ tant trials of the need for the NK1 RA dose beyond day 1. The optimal dose of dexamethasone for delayed emesis is also not known.

Prevention of Acute Nausea and Vomiting Following Chemotherapy of Moderate Emetic Potential The MASCC recommendation, with a high level of con­ fidence and moderate level of consensus, for the prevention of acute nausea and vomiting induced by non-AC moderately emetogenic chemotherapy is a combination of palonosetron

plus dexamethasone as standard prophylaxis. However, an exception is made for women receiving the combination AC that has high emetic potential, and so, with a high degree of confidence and consensus, a triple regimen of single doses of a 5HT3 RA, NK1 RA and dexamethasone is recommended prior to chemotherapy. With moderate confidence and con­ sensus, palonosetron and dexamethasone in combination was recommended where aprepitant is not available. The 5HT3 RA can be given orally or intravenously, and there are no data that show a difference between these drugs.

Prevention of Delayed Nausea and Vomiting Following Chemotherapy of Moderate Emetic Potential The MASCC panel recommended, with a high degree of confidence and consensus, that patients who receive chemo­ therapy of moderate emetic potential known to be associated with a significant incidence of delayed nausea and vomiting should receive antiemetic prophylaxis for delayed emesis. For non-AC chemotherapy where palonosetron was rec­ ommended on day 1, the recommendation with a moderate degree of confidence and consensus is that multiple day oral dexamethasone be given for delayed emesis. Again AC has been treated separately because of it having high emetic potential. Therefore, the panel updated the rec­ ommendation and with moderate levels of confidence and consensus stated that in these patients aprepitant should be used to prevent delayed nausea and vomiting. This is under­ pinned by the Warr study in patients with breast cancer [48].

Prevention of Nausea and Vomiting Induced by Multiple Day Cisplatin The MASCC recommendation, with a high level of con­ fidence and consensus, for patients receiving multiple day cisplatin should receive a 5HT3 receptor antagonist plus dexamethasone for acute nausea and vomiting and dexame­ thasone for delayed nausea and vomiting. There is a paucity of data in this area, and daily acute emesis and delayed emesis coinciding has meant that in the commonly used 5-day cisplatin regimens, nausea and ­vomiting are worse towards the end of the 5 days and the subsequent 2 days. It is known that a 5HT3 RA with dexametha­sone is superior to dopamine antagonists and dexamethasone with control rates of over 80% reported [58]. The optimal daily doses of both ondansetron and dexametha­ sone are unknown and yet it would be desirable to reduce the

236

toxicities of daily dosing of both of these drugs. There are also no randomised trials to ascertain whether adding aprepi­ tant would be useful in this setting.

Prevention of Nausea and Vomiting Following Chemotherapy of Low and Minimal Emetic Potential The MASCC recommendation, with moderate consensus but no level of confidence possible, is that patients with no prior history of nausea and vomiting who receive chemotherapy of low emetic potential in an intermittent schedule should be treated with a single antiemetic agent such as dexametha­ sone, a 5HT3 receptor antagonist or a dopamine receptor antagonist, as prophylaxis. A high level of consensus was reached in not treating such patients with no prior history of nausea and vomiting and not treating patients receiving che­ motherapy of minimal emetic potential. No prophylactic treatment for delayed emesis was recommended. The problem here is that there is little data on the emetic potential of many of these cytotoxic drugs or when agents are administered in schedules such as prolonged oral dosing schedules. Single-agent antiemetic therapy can be used if vomiting occurs, as recommended prior to using cytotoxics of low emetic potential with a prior history of emesis.

Niche Areas in the Control Of Nausea and Vomiting Anticipatory Nausea and Vomiting The best strategy to counter anticipatory nausea and vomi­ ting is to achieve better control of post-chemotherapy nausea and vomiting. If it does occur, behavioural therapies such as desensitisation, hypnosis or relaxation are the most promis­ ing treatments. Benzodiazepines such as lorazepam that is associated with amnesic effects can be used but with limited success that reduces over multiple cycles.

I.N. Olver

dexamethasone in this setting and small randomised studies to support the use of a 5HT3 RA and dexamethasone over older antiemetic regimens [58, 59]. A 5HT3 RA with dexam­ ethasone represents the current standard of care. Randomised studies evaluating the efficacy of aprepitant added to the standard therapy are necessary.

Radiation-Induced Emesis This is a complex area because the emetic potential will depend on the total dose, dose per fraction and number of fractions, field size and site of the radiation, which is often administered over several weeks. The patients’ general health, age, gender and concomitant treatment also influence the likelihood of emesis. As many as 50–80% of patients undergoing radiotherapy will experience nausea and/or vomiting, depending on the site of irradiation. Fractionated radiotherapy may involve up to 40 fractions over a 6–8 weeks period, and prolonged symptoms of nausea and vomiting could adversely affect the quality of life. Furthermore, uncontrolled nausea and vomiting may result in patients delaying or refusing further radiotherapy. The MASCC guidelines attempt to ascribe a risk category and recommend prophylactic treatment accordingly (Table 24.3). Also, there are subgroups of patients receiving radiotherapy such as the elderly where prescribing antiemet­ ics maybe problematic due to comorbid conditions and polypharmacy [60].

Children Receiving Chemotherapy Adult antiemetic studies cannot simply be extrapolated to children, and yet there are limited antiemetic studies specific to the paediatric population. For example, children were much less tolerant of dopamine inhibitors because of the extrapyramidal reactions and did not respond as well. The control of emesis has improved with the use of a 5HT3 RA and dexamethasone with chemotherapy of severe-to-moderate emetic potential. Other drugs such as aprepitant have been subjected to very small trials in adolescents but not younger children [61, 62].

High Dose Chemotherapy There is little data to guide the treatment of the acute or late emesis, which is often multifactorial and which follows high dose chemotherapy regimens, prior to bone marrow transplant or stem cell rescue. There is phase II data support­ ing the use of triple therapy of a 5HT3 RA, NK1 RA and

Conclusions Triple therapy with a 5HT3 RA, an NK1 RA and dexame­ thasone has made a major impact on the prevention of chemotherapy-induced acute and delayed emesis. Strong

237

24  Nausea and Vomiting Table 24.3  Radiotherapy-induced emesis Risk level Irradiated area High (>90%) Moderate (60–90%)

Low (30–60%)

Total body irradiation, total nodal irradiation Upper abdomen, HBI, UBI

Cranium, craniospinal, H&N, lower thorax region, pelvis Extremities, breast

Antiemetic guidelinesa

MASCC level of confidence/consensus

Prophylaxis with 5HT3 antagonists + DEX Prophylaxis with 5HT3 antagonists + optional DEX Prophylaxis or rescue with 5HT3 antagonists

High/high (for the addition of DEX: moderate/high) High/high (for the addition of DEX: moderate/high) Moderate/high For rescue: low/high

Low/high Rescue with dopamine receptor antagonists or 5HT3 antagonist HBI half body irradiation; UBI upper body irradiation; H&N head and neck; DEX dexamethasone Source: Data from the MASCC antiemetic group guidelines are available at www.mascc.org a In concomitant radiochemotherapy the antiemetic prophylaxis is according to the chemotherapy-related antiemetic guidelines of the corresponding risk category, unless the risk of emesis is higher with radiotherapy than chemotherapy Minimal (<30)

recommendations can be made for administering such treatment prior to receiving chemotherapy containing drugs of high emetic potential and regimens such as AC. Good control of emesis occurs with drugs of moderate emetic potential, but more research is needed to optimise drugs and dosing. With drugs of low or minimal emetic potential, or those given by prolonged oral dosing regimens, more data are required on the incidence, intensity and patterns of emesis before evidencebased recommendations can be considered. Niche areas such as which antiemetic regimens best prevent emesis with high dose chemotherapy, with radiotherapy and in children and adolescents, require more research.

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239 and delayed vomiting: Analysis of pooled data from two phase III studies of the NK-1 antagonist aprepitant. Proc Am Soc Clin Oncol. 2003; 22:2931a. 58. Herrstedt J, Roila F. Chemotherapy-induced nausea and vomiting: ESMO clinical recommendations for prophylaxis. Ann Oncol. 2009;20(Suppl 4):156–158. 59. Paul B, Trovato JA, Thompson J, et  al. Efficacy of aprepitant in patients receiving high-dose chemotherapy with hematopoietic stem cell support. J Oncol Pharm Pract. 2010 Mar;16(1):45–51. Epub 2009 Jun 12. 60. Horiot JC, Aapro M. Treatment implications for radiation-induced nausea and vomiting in specific patient groups. Eur J Cancer. 2004; 40:979–987. 61. Dupuis LL, Nathan PC. Optimizing emetic control in children receiv­ ing antineoplastic therapy: beyond the guidelines. Pediatr Drugs. 2010;12(1):51–61. doi: 10.2165/11316190-000000000-00000. 62. Gore L, Chawla S, Petrilli A, et al. Aprepitant in adolescent patients for prevention of chemotherapy-induced nausea and vomiting: a randomized, double-blind, placebo-controlled study of efficacy and tolerability. Pediatr Blood Cancer. 2009;52(2):242–247.

Chapter 25

Mucositis (Oral and Gastrointestinal) Rajesh V. Lalla and Dorothy M. K. Keefe

Introduction Alimentary mucositis refers to inflammatory, erosive, and ulcerative lesions of any part of the gastrointestinal (GI) tract that occur secondary to cancer therapy. Thus, the term alimentary mucositis encompasses both oral and GI mucositis. Mucositis can be classified according to the type of cancer therapy involved as chemotherapy-induced mucositis, radiation-induced mucositis, or a combination of the two. More recently, mucositis following targeted anticancer therapies has been described, but our understanding of that is only beginning to develop. Oral mucositis occurs in approximately 10–40% of patients receiving conventional chemotherapy for solid tumors [1], 80% of patients receiving head and neck radiotherapy [2], and 89% of patients undergoing high-dose chemotherapy prior to hematopoietic stem cell transplantation [3]. In one study, it was reported that 303 of 599 patients (51%) receiving chemotherapy for solid tumors or lymphoma developed oral and/or GI mucositis [4]. Oral mucositis developed in 22% of 1,236 cycles of chemotherapy, GI mucositis in 7% of cycles, and both oral and GI mucositis in 8% of cycles.

Morbidity and Economic Impact Mucositis can be very painful and can significantly affect nutritional intake, mouth care, and quality of life [5]. For patients receiving high-dose chemotherapy prior to hematopoietic cell transplantation, mucositis has been reported to be the single most debilitating complication of transplantation [6].

R.V. Lalla (*) Section of Oral Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA e-mail: [email protected]

Infections associated with mucositis lesions can cause lifethreatening systemic sepsis during periods of profound immunosuppression [7]. Moderate to severe mucositis has been correlated with systemic infection and transplant-related mortality [8]. In patients receiving chemotherapy for solid tumors or lymphoma, the rate of infection during cycles with mucositis was more than twice that during cycles without mucositis and was directly proportional to the severity of mucositis [4]. Infection-related deaths were also more common during cycles with both oral and GI mucositis. In addition, the average duration of hospitalization was significantly longer during chemotherapy cycles with mucositis. Importantly, a reduction in the next dose of chemotherapy was twice as common after cycles with mucositis than after cycles without mucositis [4]. Patients receiving head and neck radiation therapy who develop mucositis are significantly more likely to have severe pain and a weight loss of ≥5% [9]. In one study, approximately 16% of patients receiving radiation therapy for head and neck cancer were hospitalized due to mucositis [2]. Further, 11% of the patients receiving radiation therapy for head and neck cancer had unplanned breaks in radiation therapy due to severe mucositis [2]. Thus, mucositis can be a dose-limiting toxicity of cancer therapy with direct effects on patient survival. Patients who have significant mucositis require supportive care measures such as pain management, liquid diet supplements, placement of gastrostomy tubes or delivery of total parenteral nutrition, fluid replacement, and prophylaxis/treatment against infections. These can add substantially to the total cost of care. For example, in patients receiving chemotherapy for solid tumors or lymphoma, the estimated cost of hospitalization was $3,893 per chemotherapy cycle without mucositis, $6,277 per cycle with oral mucositis, and $9,132 per cycle with both oral and GI mucositis [4]. In one study of patients receiving radiation therapy for head and neck cancer, oral mucositis was associated with an increase in costs ranging from $1,700 to $6,000 per patient, depending on the grade of oral mucositis [9].

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_25, © Multinational Association for Supportive Care in Cancer Society 2011

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Pathogenesis and Risk Factors Although direct damage to basal epithelial cells plays a role in the pathogenesis of mucositis, multiple additional mechanisms are also believed to be involved [10]. A model (Fig.  25.1) has been described [11] that consists of the following five stages: 1. Initiation of tissue injury. Radiation and/or chemotherapy induce cellular damage resulting in death of basal epithelial cells. The generation of free oxygen radicals by radiation or chemotherapy is also believed to play a role in the initiation of mucosal injury. These small highly reactive molecules are byproducts of oxygen metabolism and can cause significant cellular damage. 2. Upregulation of inflammation via generation of messenger signals. In addition to causing direct cell death, free radicals activate second messengers that transmit signals from cell-surface receptors to the nucleus, leading to increased expression of proinflammatory cytokines, tissue injury, and cell death. 3. Signaling and amplification. Upregulation of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-a), produced mainly by macrophages, injures mucosal cells, and also activates molecular pathways that intensify mucosal injury. 4. Ulceration and inflammation. A significant inflammatory cell infiltrate is associated with the mucosal ulcerations, partly in reaction to the metabolic byproducts of the colonizing oral microflora. Production of proinflammatory cytokines is also further increased due to this secondary infection [12].

Fig. 25.1  Five-stage model of oral mucositis (courtesy of Dr. Stephen T. Sonis, DMD, DMSc. Reprinted from Sonis [39])

R.V. Lalla and D.M.K. Keefe

5. Healing. This phase involves epithelial proliferation as well as cellular and tissue differentiation [13], leading to the restoration of the integrity of the epithelium. The various stages are likely to have significant overlap and are thought to involve multiple cell types and various classes of mediators including reactive oxygen species, proinflammatory cytokines, and transcription factors. Recent studies have used a bioinformatics approach to identify gene expression changes associated with mucositis development and should lead to an increased understanding of its pathogenesis [14, 15]. The severity and extent of mucositis that develops in any patient is dependent on both treatment-related and host-related risk factors. Treatment-related risk factors include the specific type and dose of cancer therapy (e.g., certain chemotherapy drugs such as 5-fluorouracil are particularly ­mucotoxic, especially at high doses). Host-related risk ­factors include genetic polymorphisms and systemic disease. Polymorphisms in genes for enzymes involved in drug metabolism have been found to result in an increased risk of mucositis. For example, patients who carry the 677 TT ­genotype for methylenetetrahydrofolate reductase have more severe mucositis in response to methotrexate use [16]. Similarly, patients with a polymorphism resulting in increased production of the proinflammatory cytokine TNF were reported to have a significantly increased risk of ­chemotherapy-related toxicity including mucositis [17]. Certain ­systemic diseases associated with increased ­apoptosis  (e.g., Addison’s disease) may increase the risk of mucositis, while others associated with reduced apoptosis (e.g., Psoriasis) may be protective. The effects of general host-related factors such as age and gender on risk for mucositis are not clear [18].

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Clinical Signs and Symptoms Oral mucositis initially presents as erythema of the oral mucosa, with subsequent progression to erosion and ulceration, depending on the intensity of the cancer therapy. The ulcerations may be covered by a white pseudomembrane. Oral mucositis lesions are usually limited to nonkeratinized areas of the mouth such as the lateral and ventral tongue (Fig.  25.2), buccal mucosa, and soft palate. In radiationinduced oral mucositis, lesions are limited to the tissues in the field of radiation. Most patients who have received more than 50 Gy to the oral mucosa will develop severe ulcerative oral mucositis. The time required for healing is proportional to the extent and severity of the lesions. Oral mucositis in patients receiving conventional chemotherapy may resolve between 10 and 18 days after cessation of chemotherapy, while in patients who have received high-dose radiation, several weeks may be needed for healing. The most common symptom of oral mucositis is pain, which impacts on nutrition, oral hygiene, and speech. GI mucositis may present as abdominal pain, bloating, nausea, or diarrhea. It usually starts within 3–7 days of chemotherapy and resolves by about day 14. Again, it can be prolonged in high-dose chemotherapy or pelvic radiotherapy patients, and can impact on nutrition.

Diagnosis and Complicating Factors The diagnosis of mucositis is based on a recent history of cancer therapy and the presence of clinical signs (for oral mucositis) or symptoms (for GI mucositis). However, lesions of oral mucositis

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may be resembled or secondarily infected by other conditions including fungal infection (most commonly candidiasis), viral infection (most commonly HSV) and graft vs. host disease (in transplant recipients). An alternative diagnosis or secondary infection should especially be suspected when lesions occur in unusual sites or last for longer than expected. Symptoms similar to those of GI mucositis may be caused by infection, peptic ulcer disease, inflammatory bowel disease, and motility disorders. Transient lactose intolerance can occur post chemotherapy so that dairy foods can worsen the symptoms.

Measurement A number of different scales are available to record the ­severity of mucositis. The World Health Organization (WHO) scale is a simple, easy to use scale that is suitable for daily use in clinical practice. This scale combines both subjective and objective measures of oral mucositis (Table 25.1). The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 includes separate ­clinical and functional/symptomatic scales for mucositis at upper and lower GI tract sites [19]. The Oral Mucositis Assessment Scale (OMAS), suitable for research purposes, measures erythema and ulceration at nine different sites in the oral cavity. This scale has been validated in a multicenter trial with highinterobserver reproducibility and strong correlation of objective mucositis scores with patient symptoms [20]. There is a need for the development of a new scale for GI mucositis that could better delineate the problem.

Management The Mucositis Study Group of MASCC/ISOO has published evidence-based clinical practice guidelines for the management of oral and GI mucositis [21]. These guidelines are listed in Table  25.2 and are referred to in the sections below as applicable.

Table 25.1  World Health Organization (WHO) scale for oral mucositis

Fig. 25.2  Radiation-induced Oral Mucositis on the lateral tongue of a patient who had received 4,600 cGy of a total planned dose of 6,200 cGy, without concurrent chemotherapy, for treatment of squamous cell carcinoma of the tongue (reprinted with permission from Lalla et al. [40])

Grade 0 = No oral mucositis Grade 1 = Erythema and soreness Grade 2 = Ulcers, able to eat solids Grade 3 = Ulcers, requires liquid diet (due to mucositis) Grade 4 = Ulcers, alimentation not possible (due to mucositis) Source: Reprinted with permission from the WHO [41]

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Table 25. 2  Summary of MASCC/ISOO evidence-based clinical practice guidelines for the management of patients with oral and gastrointestinal mucositis I. Oral mucositis Basic oral care and good clinical practices   1. The panel suggests multidisciplinary development and evaluation of oral care protocols, and patient and staff education in the use of such protocols to reduce the severity of oral mucositis from chemotherapy and/or radiation therapy. As part of the protocols, the panel suggests the use of a soft toothbrush that is replaced on a regular basis. Elements of good clinical practice should include the use of validated tools to regularly assess oral pain and oral cavity health. The inclusion of dental professionals is vital throughout the treatment and follow-up phases   2. The panel recommends patient-controlled analgesia with morphine as the treatment of choice for oral mucositis pain in patients undergoing HSCT. Regular oral pain assessment using validated instruments for self-reporting is essential Radiotherapy: prevention   3. The panel recommends the use of midline radiation blocks and three-dimensional radiation treatment to reduce mucosal injury   4. The panel recommends benzydamine for the prevention of radiation-induced mucositis in patients with head and neck cancer receiving moderate-dose radiation therapy   5. The panel recommends that chlorhexidine not be used to prevent oral mucositis in patients with solid tumors of the head and neck who are undergoing radiotherapy   6. The panel recommends that antimicrobial lozenges not be used for the prevention of radiation-induced oral mucositis Radiotherapy: treatment   7. The panel recommends that sucralfate not be used for the treatment of radiation-induced oral mucositis Standard-dose chemotherapy prevention   8. The panel recommends that patients receiving bolus 5-FU chemotherapy undergo 30 min of oral cryotherapy to prevent oral mucositis   9. The panel suggests the use of 20–30 min of oral cryotherapy to decrease mucositis in patients treated with bolus doses of edatrexate 10. The panel recommends that acyclovir and its analogs not be used routinely to prevent mucositis Standard-dose chemotherapy: treatment 11. The panel recommends that chlorhexidine not be used to treat established oral mucositis High-dose chemotherapy with or without total body irradiation plus HCST: prevention 12. In patients with hematologic malignancies who are receiving high-dose chemotherapy and total body irradiation with autologous stem cell transplantation, the panel recommends the use of keratinocyte growth factor-1 (palifermin) in a dose of 60 g/kg/day for 3 days prior to conditioning treatment and for 3 day posttransplantation for the prevention of oral mucositis 13. The panel suggests the use of cryotherapy to prevent oral mucositis in patients receiving high-dose melphalan 14. The panel does not recommend the use of pentoxifylline to prevent mucositis in patients undergoing HSCT 15. The panel suggests that GM-CSF mouthwashes not be used for the prevention of oral mucositis in patients undergoing HSCT 16. The panel suggests the use of LLLT to reduce the incidence of oral mucositis and its associated pain in patients receiving high-dose chemotherapy or chemoradiotherapy before HSCT, if the treatment center is able to support the necessary technology and training, because LLLT requires expensive equipment and specialized training. Because of interoperator variability, clinical trials are difficult to conduct, and their results are difficult to compare; nevertheless, the panel is encouraged by the accumulating evidence in support of LLLT II. GI mucositis Basic bowel care and good clinical practices 17. The panel suggests that basic bowel care should include the maintenance of adequate hydration, and that consideration should be given to the potential for transient lactose intolerance and the presence of bacterial pathogens Radiotherapy: prevention 18. The panel suggests the use of 500 mg sulfasalazine orally twice daily to help reduce the incidence and severity of radiation-induced enteropathy in patients receiving external beam radiotherapy to the pelvis 19. The panel suggests that amifostine in a dose of 340 mg/m2 may prevent radiation proctitis in patients who are receiving standard-dose radiotherapy for rectal cancer 20. The panel recommends that oral sucralfate not be used to reduce related side effects of radiotherapy; it does not prevent acute diarrhea in patients with pelvic malignancies undergoing external beam radiotherapy; and, compared with placebo, it is associated with more GI side effects, including rectal bleeding 21. The panel recommends that 5-amino salicylic acid and its related compounds mesalazine and olsalazine not be used to prevent GI mucositis Radiotherapy: treatment 22. The panel suggests the use of sucralfate enemas to help manage chronic radiation-induced proctitis in patients who have rectal bleeding Standard-dose and high-dose chemotherapy: prevention 23. The panel recommends either ranitidine or omeprazole for the prevention of epigastric pain after treatment with cyclophosphamide, methotrexate, and 5-FU or treatment with 5-FU with or without folinic acid chemotherapy 24. The panel recommends that systemic glutamine not be used for the prevention of GI mucositis Standard-dose and high-dose chemotherapy: treatment 25. When loperamide fails to control diarrhea induced by standard-dose or high-dose chemotherapy associated with HSCT, the panel recommends octreotide at a dose of 100 mg subcutaneously, twice daily (continued)

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Table 25. 2  (continued) Combined chemotherapy and radiotherapy: prevention 26. The panel suggests the use of amifostine to reduce esophagitis induced by concomitant chemotherapy and radiotherapy in patients with nonsmall-cell lung cancer HSCT hematopoietic stem cell transplantation; 5-FU 5-fluorouracil; GM-CSF granulocyte-macrophage-colony stimulating factor; LLLT low-level laser therapy; GI gastrointestinal Source: Keefe et al. [21]. Reprinted with permission from John Wiley & Sons, Inc.

Preventive Measures The maintenance of good oral hygiene can result in reduced incidence and severity of oral mucositis [22–24]. The MASCC/ISOO mucositis guidelines recommend as good clinical practice, the use of a standardized oral care protocol including brushing with a soft toothbrush, flossing, and the use of nonmedicated rinses (e.g., saline, sodium bicarbonate rinse). It is important that patients, staff, and caregivers be educated about the importance of good oral hygiene [25]. The use of cryotherapy in patients receiving bolus doses of chemotherapeutic agents with short half-lives reduces the severity of oral mucositis. Ice chips are placed in the mouth, beginning 5 min before administration of chemotherapy and replenished as needed, usually for up to 30 min. This effect is likely to be mediated through local vasoconstriction and reduced blood flow, resulting in decreased delivery of the chemotherapeutic agent to the oral mucosa. The MASCC/ ISOO guidelines recommend the use of cryotherapy to reduce oral mucositis in patients receiving bolus doses of 5-fluorouracil, melphalan, and edatrexate [26]. For patients undergoing head and neck radiation therapy, the guidelines recommend the use of midline radiation blocks and three dimensional radiation treatment to reduce mucosal injury [21]. To minimize the likelihood of developing GI mucositis, maintenance of adequate hydration is recommended, and the presence of transient lactose intolerance and bacterial pathogens should be considered. Sulfasalzine may reduce radiationinduced GI mucositis, and amifostine may prevent radiation proctitis. The MASCC/ISOO guidelines also recommend the use of either ranitidine or omeprazole for the prevention of epigastric pain following chemotherapy [21].

Inc., Fremont,  MI). A number of other topical mucosal ­bioadherent agents are also available that are postulated to reduce pain by forming a protective coating over the ulcerated mucosa. Of these, sucralfate is the most widely studied. The MASCC/ISOO guidelines recommend against the use of sucralfate in radiation-induced oral mucositis due to lack of efficacy. No recommendation was made for the use of sucralfate in chemotherapy-induced oral mucositis due to lack of consistent results [27]. In addition to the use of topical agents, most patients with severe mucositis require systemic analgesics, often including opioids, for satisfactory pain relief. The MASCC/ISOO guidelines recommend patient-controlled analgesia with morphine for patients undergoing hematopoetic cell transplantation [27]. Likewise, the pain of GI mucositis should be treated symptomatically, with the added benefit that the opioids can improve diarrhea.

Nutritional Support Nutritional intake can be severely compromised by mucositis. Furthermore, taste changes can also occur secondary to chemotherapy and/or radiation therapy [28, 29]. The patient’s nutritional intake and weight should be monitored regularly over the course of cancer therapy. A soft diet and liquid diet supplements are often more easily tolerated than a normal diet. A gastrostomy tube is sometimes placed prophylactically, especially in patients receiving head and neck radiotherapy. In patients undergoing hematopoietic cell transplantation, total parenteral nutrition is usually given via an indwelling catheter such as a Hickman line.

Therapeutic Interventions for Oral Mucositis Pain Control

Growth Factors

Pain is the most distressing symptom experienced by patients due to mucositis. Many centers use topical mouth rinses ­containing an anesthetic such as 2% viscous lidocaine for short-term relief. The lidocaine may be mixed with equal ­volumes of diphenhydramine and a soothing covering agent such as Maalox (Novartis Consumer Health,

Recombinant human keratinocyte growth factor-1 (Palifermin, Biovitrum, Stockholm, Sweden) significantly reduced the incidence of WHO grade 3 and 4 oral mucositis in patients with hematologic malignancies (e.g., leukemia, lymphoma, and multiple myeloma) receiving high-dose chemotherapy and total body irradiation before autologous hematopoetic

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cell transplantation [30]. Based on this, the MASCC/ISOO guidelines recommend the use of this growth factor in this specific population [31]. Palifermin has also been approved by the United States (US) Food and Drug Administration (FDA) for patients with hematologic malignancies receiving myelotoxic therapies requiring hematopoietic cell support. Additional studies are ongoing to confirm the safety of this agent in the solid tumor setting.

Laser Therapy Several clinical trials have reported that intraoral low-level laser therapy (LLLT) reduces the severity of oral mucositis. Recent studies suggest that LLLT has an anti-inflammatory effect [32]. The optimal parameters for laser use have not been established since trials differ in wavelength, energy density, and administration schedules used. Nevertheless, due to the promising data to date, the MASCC/ISOO guidelines for chemotherapy patients suggest the use of laser therapy at centers able to support the necessary technology and training [26].

Promoters of Healing Saforis (MGI Pharma) is an oral suspension of l-glutamine in a vehicle that enhances the uptake of this amino acid into epithelial cells. A Phase III study demonstrated efficacy in reducing the incidence and severity of ≥ WHO Grade 2 oral mucositis in breast cancer patients receiving anthracyclinebased chemotherapeutic regimens [33]. The US FDA has requested an additional Phase III study of this agent. By comparison, the MASCC/ISOO guidelines recommend that systemically administered glutamine not be used for the prevention of GI mucositis [27]. Caphosol (EUSA Pharma) is a supersaturated calcium/ phosphate rinse that is thought to act via beneficial effects of calcium and phosphate ions on inflammation and tissue repair. A double-blind, randomized trial compared Caphosol rinse and fluoride tray treatments with fluoride rinse and placebo tray treatments in 95 cancer patients receiving various chemotherapy regimens for hematopoetic stem cell transplant. The Caphosol group demonstrated significant decreases in days of mucositis and severity of peak mucositis as compared to the control group [34]. Caphosol is currently available on the US market as a prescription device. Additional clinical studies are ongoing.

Anti-Inflammatory Agents Benzydamine hydrochloride (MGI Pharma) is a nonsteroidal anti-inflammatory drug that inhibits proinflammatory cytokines,

R.V. Lalla and D.M.K. Keefe

including TNF-a. In one Phase III trial, benzydamine hydrochloride mouth rinse reduced the severity of mucositis in patients with head and neck cancer undergoing radiation therapy of cumulative doses up to 50 Gy radiation therapy [35]. Based on this and previous studies, the MASCC/ISOO guidelines recommended use of this agent in patients receiving moderate-dose radiation therapy [36]. However, this agent has not received approval for this use from the US FDA; furthermore, most patients with head and neck cancer receive well over 50  Gy radiation therapy with concomitant chemotherapy. A more recent Phase III trial of this agent in radiation-induced oral mucositis in patients with head and neck cancer was halted based on negative results of an interim analysis.

Antioxidants Amifostine (Ethylol, MedImmune, Gaithersburg, MD) is thought to act as a scavenger for harmful reactive oxygen species. However, due to insufficient evidence of benefit, a MASCC/ISOO guideline could not be established regarding the use of this agent in oral mucositis in chemotherapy or radiation therapy patients. The use of amifostine was recommended for the prevention of esophagitis in patients receiving chemoradiation for nonsmall-cell lung cancer [37].

Therapeutic Interventions for GI Mucositis In chronic radiation-induced proctitis with bleeding, the use of sucralfate enemas is suggested [21]. Loperamide, the nonanalgesic opioid, is the mainstay of treatment for radiation or chemotherapy-induced diarrhea. It can be given in a dose of up to 11 2.1 mg tablets per 24 h (i.e., 2.1 mg every 2 h during the day and every 4 h overnight) [21]. However, when this does not work, octreotide, in a dose of at least 100 mg subcutaneously, twice a day, should be added. A lactose-free diet may also help.

Targeted Anticancer Therapies Many of the molecularly targeted anticancer agents cause stomatitis, oral ulceration, and diarrhea. The mechanism is under investigation, and treatment will be determined by that. Simple mouth care and analgesics remain the mainstay of treatment of the oral lesions. In the absence of evidence-based guidelines in this area, GI mucositis secondary to ­targeted therapies is treated in the same way as chemotherapy-induced GI mucositis. However, given that there is

25  Mucositis (Oral and Gastrointestinal)

some ­evidence of tachyphylaxis with the targeted agents, and even some suggestion of a similarity to ischemic colitis, withdrawal and reintroduction of treatment has been tried with some success, and the use of steroids has likewise been ­suggested. More research in this area is clearly required [38].

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247 regions reveals activation of common cell regulatory pathways following cytotoxic chemotherapy. Int J Cancer. 2007;121: 1847–56. 15. Sonis S, Haddad R, Posner M, Watkins B, Fey E, Morgan TV, et al. Gene expression changes in peripheral blood cells provide insight into the biological mechanisms associated with regimen-related toxicities in patients being treated for head and neck cancers. Oral Oncol. 2007;43(3):289–300. 16. Robien K, Schubert MM, Bruemmer B, Lloid ME, Potter JD, Ulrich CM. Predictors of oral mucositis in patients receiving hematopoietic cell transplants for chronic myelogenous leukemia. J Clin Oncol. 2004;22(7):1268–75. 17. Bogunia-Kubik K, Polak M, Lange A. TNF polymorphisms are associated with toxic but not with aGVHD complications in the recipients of allogeneic sibling haematopoietic stem cell transplantation. Bone Marrow Transplant. 2003;32(6):617–22. 18. Barasch A, Peterson DE. Risk factors for ulcerative oral mucositis in cancer patients: unanswered questions. Oral Oncol. 2003;39(2): 91–100. 19. National Cancer Institute. Common Terminology Criteria for Adverse Events v3.0 (CTCAE); 2006. Available from: http://ctep. info.nih.gov/reporting/ctc_v30.html. 20. Sonis ST, Eilers JP, Epstein JB, LeVeque FG, Liggett WH, Jr., Mulagha MT, et  al. Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Mucositis Study Group. Cancer. 1999;85(10):2103–13. 21. Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, et al. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer. 2007;109(5): 820–31. 22. Cheng KK, Molassiotis A, Chang AM, Wai WC, Cheung SS. Evaluation of an oral care protocol intervention in the prevention of chemotherapy-induced oral mucositis in paediatric cancer patients. Eur J Cancer. 2001;37(16):2056–63. 23. Levy-Polack MP, Sebelli P, Polack NL. Incidence of oral complications and application of a preventive protocol in children with acute leukemia. Spec Care Dentist. 1998;18(5):189–93. 24. Borowski B, Benhamou E, Pico JL, Laplanche A, Margainaud JP, Hayat M. Prevention of oral mucositis in patients treated with highdose chemotherapy and bone marrow transplantation: a randomised controlled trial comparing two protocols of dental care. Eur J Cancer B Oral Oncol. 1994;30B(2):93–7. 25. McGuire DB, Correa ME, Johnson J, Wienandts P. The role of basic oral care and good clinical practice principles in the management of oral mucositis. Support Care Cancer. 2006;14(6):541–7. 26. Migliorati CA, Oberle-Edwards L, Schubert M. The role of alternative and natural agents, cryotherapy, and/or laser for management of alimentary mucositis. Support Care Cancer. 2006;14(6): 533–40. 27. Barasch A, Elad S, Altman A, Damato K, Epstein J. Antimicrobials, mucosal coating agents, anesthetics, analgesics, and nutritional supplements for alimentary tract mucositis. Support Care Cancer. 2006;14(6):528–32. 28. Cheng KK. Oral mucositis, dysfunction, and distress in patients undergoing cancer therapy. J Clin Nurs. 2007;16:2114–21. 29. Raber-Durlacher J, Barasch A, Peterson DE, Lalla RV, Schubert MM, Fibbe WE. Oral complications and management considerations in patients treated with high-dose cancer chemotherapy. Supportive Cancer Ther. 2004;1(4):219–29. 30. Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med. 2004;351(25): 2590–8. 31. von Bultzingslowen I, Brennan MT, Spijkervet FK, Logan R, Stringer A, Raber-Durlacher JE, et al. Growth factors and cytokines

248 in the prevention and treatment of oral and gastrointestinal ­mucositis. Support Care Cancer. 2006;14(6):519–27. 32. Lopes NN, Plapler H, Chavantes MC, Lalla RV, Yoshimura EM, Alves MT. Cyclooxygenase-2 and vascular endothelial growth ­factor expression in 5-fluorouracil-induced oral mucositis in hams­ ters: evaluation of two low-intensity laser protocols. Support Care Cancer. 2009;17:1409–15. 33. Peterson DE, Jones JB, Petit RG, II. Randomized, placebo-­ controlled trial of Saforis for prevention and treatment of oral mucositis in breast cancer patients receiving anthracycline-based chemotherapy. Cancer. 2007;109(2):322–31. 34. Papas AS, Clark RE, Martuscelli G, O’Loughlin KT, Johansen E, Miller KB. A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003;31(8):705–12. 35. Epstein JB, Silverman S, Jr., Paggiarino DA, Crockett S, Schubert MM, Senzer NN, et al. Benzydamine HCl for prophylaxis of radiation-induced oral mucositis: results from a multicenter, randomized,

R.V. Lalla and D.M.K. Keefe double-blind, placebo- controlled clinical trial. Cancer. 2001;92(4):875–85. 36. Lalla RV, Schubert MM, Bensadoun RJ, Keefe D. Anti-inflammatory agents in the management of alimentary mucositis. Support Care Cancer. 2006;14(6):558–65. 37. Bensadoun RJ, Schubert MM, Lalla RV, Keefe D. Amifostine in the management of radiation-induced and chemo-induced mucositis. Support Care Cancer. 2006;14(6):566–72. 38. Al-Dasooqi N, Gibson R, Bowen J, Keefe D. HER2 targeted therapies for cancer and the gastrointestinal tract. Curr Drug Targets. 2009;10(6):537–42. 39. Sonis ST. A biological approach to mucositis. J Support Oncol. 2004;2:21–36. 40. Lalla RV, et al. Management of oral mucositis in patients who have cancer. Dent Clin North Am. 2008;52(1):61–77, viii. 41. World Health Organization. Handbook for reporting results of ­cancer treatment. Geneva: World Health Organization; 1979: 15–22.

Chapter 26

Diarrhea, Constipation, and Obstruction in Cancer Management Lowell B. Anthony

Introduction Gastrointestinal symptoms are frequently encountered in cancer patients and are commonly present not only as initial symptoms but also as side effects from cancer treatments. Diarrhea is an expected and manageable side effect from some cytotoxic and targeted agents. While constipation can be severe from analgesics, thalidomide, lenalidomide and vinca alkaloids, management may vary depending upon anatomical considerations. The latter may include obstruction from adhesions, the underlying malignancy or a combination of etiologies. The management of these adverse effects is reviewed.

Diarrhea Diarrhea induced by cytotoxic chemotherapy (CID) involving 5-fluorouracil (5-FU), capecitabine, irinotecan, and docetaxel can be dose limiting. CID incidence ranges from 30 to 87% depending upon the NCI Common Toxicity Criteria Grade (1–4) and whether single or combination regimens are present [1]. Severe diarrhea can be significantly debilitating leading to dehydration, electrolyte abnormalities, secondary infections, and malnutrition. CID may lead to chemotherapy dose reductions resulting in shorter survival in some clinical investigations [2]. Loose stool frequency exceeding 3 per 24 h is considered by the NCI CTC as diarrhea [3].

Etiology and Specific Agents 5-Fluorouracil Cytotoxic therapies can damage the intestinal mucosa resulting in a loss of epithelium [4]. Repair of the damaged mucosa is L.B. Anthony (*) LSUHSC New Orleans, Professor of Medicine, Department of Medicine, Ochsner Kenner Medical Center, 200 West Esplanade, Ste 200, Kenner, LA 70065, USA e-mail: [email protected]

impacted upon by 5-FU that induces mitotic arrest of the crypt cells [5]. Intestinal secretion exceeds the colonic resorptive capacity resulting in clinically significant diarrhea, electrolyte abnormalities, and dehydration. Efficacy and toxicity of 5-FU are increased when given as a bolus with or without the biochemical modulator, leucovorin (LV) and used in many regimens and schedules [6]. Diarrhea from weekly 5-FU/LV has been reported with up to 50% of patients requiring IV fluids with elderly patients with myelosuppression and sepsis [7]. With palliative-intent chemotherapy, treatment is usually withheld for >grade 2 diarrhea. Factors increasing the risk for 5-FU toxicity include an unresected primary tumor, prior CID, bolus 5-FU and LV with oxaliplatin, female gender and being in the summer months [8–10]. Various pheno- and genotypic markers predicting life-threatening toxicity to 5-FU have been evaluated but none have been incorporated into routine patient care. Dihydropyrimidine dehydrogenase (DPD) is the initial catabolic enzyme for 5-FU. Partial DPD deficiency can produce life-threatening side effects to 5-FU therapy [11, 12]. DPD activity is more of a continuum rather than an absolute with complete DPD deficiency rare. Decreased DPD activity is more common in blacks and females [13]. Testing for DPD deficiency prospectively has been evaluated [14, 15]. In a 5-FU monotherapy prospective study, the sensitivity of DPYD*2A genotyping for overall toxicity was 5% with a positive predictive value for grade 3/4 toxicity of 46% [16]. Based on these findings, most cases of DPD deficiency are diagnosed following a severe 5-FU reaction. Management of these patients includes aggressive supportive care with vasopressors, parenteral nutrition, antibiotics, and granulocyte colony stimulating factors. 5-FU is usually dosed according to body surface area (BSA). An alternative dosing method, to improve the therapeutic index, is pharmacokinetically guided (PK). In one prospective study, 208 metastatic colorectal cancer patients received 1,500 mg/m2 5-FU over 8 h and LV. Patients were randomly assigned to either continue weekly BSA-based fixed dosing or PK individualized dosing based upon a single 5-FU plasma concentration measurement at steady state [17]. Patients who were randomized to the PK-guided dosing regimen had

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significantly higher response rates (34 vs. 18%), longer median survival (22 vs. 16 months) and less toxicity, including diarrhea. While incorporating PK-guided dosing into daily clinical practice seems intriguing, certain barriers remain. As the 5-FU/LV regimen chosen for this trial is not typical, additional data are needed regarding the potential benefits of PK-based dosing patients receiving more common 5-FU regimens either as a single agent or in combination with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI). Also, drug monitoring is labor-intensive and requires rapid processing. The latter may limit its incorporation into smaller clinical practices. The combination of oxaliplatin and 5-FU (FLOX, FOLFOX) has become one of the most commonly used adjuvant and first-line regimens in colorectal cancer. The enterotoxicity associated with these regimens is dependent on the schedule of 5-FU administration. The incidence of grades 3 and 4 diarrhea is <20% when 5-FU is administered as a short-term infusion rather than daily or weekly boluses. Being females or aged more than 60 years are additional risk factors in predicting enterotoxicity [9, 18, 19]. Capecitabine, a prodrug, is considered an oral 5-FU equivalent. Following near complete intestinal absorption, capecitabine undergoes hepatic first-pass metabolism and is converted to its active moiety in three sequential enzymatic reactions. Its dose-limiting toxicities include diarrhea, hand-foot syndrome (HFS), and myelosuppression. Capecitabine’s initially approved dose for the treatment of metastatic breast cancer was 2,500 mg/m2/day for 14 of every 21 days. Later studies combined with postmarketing surveillance suggested that a lower dose (starting at 2,000 mg/m2/day for 14 of every 21 days) offered improved tolerability without compromising efficacy. Large regional differences in capecitabine’s therapeutic index exist [20]. These differences include populationspecific pharmacogenomics, diet, and differences in lifestyle. Because of these issues, optimal capecitabine dosing for North American patients remains to be determined with titration to tolerability an option in its clinical usage. Combining oxaliplatin with capecitabine (CAPOX, XELOX) has become intensely investigated. XELOX (capecitabine 1,000 mg/m2 b.i.d. for 14 days plus oxaliplatin 130  mg/m2 on day 1 every 3 weeks) was compared to FOLFOX (continuous infusion of 5-FU at 2,250 mg/m2 over 48 h on days 1, 8, 15, 22, 29, and 36 plus oxaliplatin 85 mg/m2 on days 1, 15, and 29 every 6 weeks) in a phase III trial of patients with metastatic colorectal cancer. A significantly lower rate of grades 3 and 4 diarrhea was observed with XELOX (14 vs. 24%; however, a significantly higher rate of grade 1 or 2 hyperbilirubinemia (37 vs. 21%) occurred. Capecitabine combinations with epirubicin and either cisplatin or oxaliplatin have been evaluated in esophageal and gastric cancers. A phase III comparison of regimens containing

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epirubicin with either cisplatin or oxaliplatin and either 5-FU or capecitabine reported a rate of grade 3/4 diarrhea of 12% EOX (day 1 epirubicin 50 mg/m2, day 1 oxaliplatin 130 mg/m2, and b.i.d. capecitabine 625 mg/m2) [21].

Irinotecan (CPT-11) Immediate side effects occurring during or several hours following irinotecan infusion is cholinergically mediated [22]. Late effects from irinotecan result from its metabolite’s, SN-38, toxic effect on the intestinal mucosa [23]. This metabolite is formed by hepatic glucuronidation followed by biliary excretion. Deconjugation by intestinal bacteria results in a direct toxic effect on the colonic mucosa [24, 25]. Altered hepatic glucuronidation as present in Gilbert’s syndrome patients results in severe irinotecan intestinal toxicity [26]. Antibiotics inhibiting intestinal deconjugation protect against the mucosal injury and common genetic polymorphisms of the UDP-glucuronyltransferase enzyme influence diarrhea severity [27]. Irinotecan’s dose-limiting toxicities are diarrhea and leucopenia. Grades 3/4 CID occurred in 31% of patients with all grades of diarrhea developing in 50–88%. Primary prophylaxis with loperamide lowered the incidence of CID and allowed irinotecan to become the second cytotoxic agent approved in the management of colorectal cancer. Adherence to aggressive use of loperamide is imperative in irinotecan’s use. The median onset of late diarrhea is 6–11 days following irinotecan’s dosing with the 3-week (350  mg/m2) and weekly (125  mg/m2) schedules, respectively [28, 29]. Comparing two dosing schedules in a randomized trial, irinotecan’s antitumor efficacy was similar between the every 3 weeks vs. the every week schedule, but the incidence of severe CID was significantly less for the 3-week regimen (19 vs. 36%). Cholinergic symptoms were, however, significantly lower with the weekly schedule (31 vs. 61%) [30]. Irinotecan’s active metabolite, SN-38, is hepatically glucuronidated by the polymorphic enzyme uridine diphosphoglucuronosyltransferase 1A1 (UGT1A1). Intratumoral UGT1A1 enzymatic activity is reduced in 10% of the North American population who inherit genetic polymorphisms such as the UGT1A1*28 allele (Gilbert’s syndrome). Some studies have shown that both homozygotes and heterozygotes to this specific allele have had significantly higher rates of toxicity to irinotecan [30]. Even though genetic testing is available, the clinical relevance of identifying homozygotes remains unclear as the absolute risk of increased treatmentrelated toxicity in homozygotes is small. Combination irinotecan regimens such as FOLFIRI (short-term infusional 5-FU/LV) result in less severe GI and bone marrow toxicity than IFL (bolus 5-FU/LV) [31].

26  Diarrhea, Constipation, and Obstruction in Cancer Management

Large and Small Molecule EGFR Inhibitors Epidermal growth factor receptor (EGFR)-directed monoclonal antibodies (MoAb) such as cetuximab (IgG1 class) and panitumumab (IgG2 class) bind to the extracellular domain of the receptor and competitively inhibit ligand binding. In contrast to the small molecule EGFR inhibitors that act intracellularly, MoAb-related diarrhea is generally not as severe. Single agent cetuximab treatment in 346 metastatic colorectal cancer patients caused any grade diarrhea in 12.7% [32]. In a lung cancer phase II trial, 22.7% of patients reported diarrhea (all grades) without regard to attribution to 1.5% experiencing grade 3 or 4 [33]. The incidence of any grade diarrhea in the panitumumab phase III registration trial of best supportive care (BSC) with or without panitumumab was 21 vs. 11%, respectively. Grade 3 diarrhea incidence was 1 vs. 0% (BSC + panitumumab vs. BSC) [34]. These data have been confirmed by other investigators evaluating panitumumab as monotherapy [35]. Combining MoAb that target the vascular endothelial growth factor receptor (VEGF) with EGFR-targeted MoAb and cytotoxic chemotherapy resulted in grade 3/4 diarrhea as being the dose-limiting event (24% double MoAb + FOLFOX vs. 13% VEGF-MoAb + FOLFOX). Dose reductions and delays were observed with the double MoAb therapy and were most likely the cause of the significant decrease in the median survival [2]. Small molecule tyrosine kinase inhibitors (TKIs) such as erlotinib, lapatinib, and gefitinib (available outside of the USA) that target the intracellular epidermal growth factor pathway(s) have diarrhea as a predictable and manageable adverse event in up to 60% of patients [36–39]. All diarrheal grades have been reported in up to 60% with grades 3 and 4 <10% of patients. In general, the diarrhea is easily managed with loperamide followed by dose reduction and/or treatment delay. Combining targeted agents such as the small molecule TKIs with cytotoxic chemotherapy or radiotherapy may result in overlapping toxicities with diarrhea having been a significant dose-limiting toxicity in several clinical trials [40, 41].

Multikinase Inhibitors Agents that target multiple intracellular signaling pathways include sorafenib, sunitinib, and imatinib. These oral agents are indicated for multiple neoplasms as monotherapy. Sorafenib, a VEGF pathway multikinase inhibitor (MKI), causes all grade diarrhea in 30–45% of patients treated at the approved dose of 400  mg twice daily. Grades 3/4 diarrhea occurred in <5% [42]. In the sorafenib registration trial for renal cell cancer, the incidence of all grade diarrhea (sorafenib

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vs. placebo) was 43 vs. 13% and 3/4 2 vs. 1% [43]. In other disease states such as hepatocellular cancer, all grade diarrhea incidence from sorafenib ranges from 66 to 73% for Child’s class B and A, respectively, and 100% in Child’s class C, though the patient numbers were small [44]. Another oral MKI is sunitinib, a VEGF and plateletderived growth factor (PDGF) receptor TKI. Sunitinib is typically dosed at 50  mg daily for 4 weeks followed by a 2-week rest. All grade diarrhea from sunitinib in various solid tumor patients ranged from 30 to 60% with grade 3 diarrhea incidence range of 3–6% [45–47]. Therapy with imatinib, a Bcr-Abl protein TKI, active in CML and gastrointestinal stromal tumors, causes all grade diarrhea in approximately 30% of patients [48].

Other Targeted Inhibitors Sirolimus, temsirolimus, and everolimus are inhibitors of the mammalian target of rapamycin (mTOR). The renal cell cancer everolimus registration trial reported an incidence of grades 1 and 2 diarrhea of 17% (vs. 3% in the placebo group) and grade 3 was only 1% (vs. 0% placebo) [49]. In a phase II everolimus clinical trial in pancreatic neuroendocrine cancer, the incidence of all grades diarrhea was 39% and grade 3 or 4 was 4%; in the group that also received octreotide with everolimus, the incidence of all grades diarrhea was 14% with no grade 3 or 4 events [50]. Bortezomib, a proteasome inhibitor, induced diarrhea in approximately half of the multiple myeloma patients enrolled in the registrational trial. The incidence of grade 3 or 4 diarrhea in this trial was 8% [51]. Vorinostat, a histone deacetylase inhibitor active in cutaneous T cell-lymphoma, induced all grade diarrhea in 52% of the patients enrolled in the registration trial. Severe diarrhea was rarely observed [52].

Clinical Assessment The algorithm for CID evaluation and management is shown in Fig. 26.1a. The initial assessment of CID focuses on the history not only to begin formulating a differential diagnosis but also to assess diarrhea severity according to the NCI CTC grading system [3]. The quantity, quality, and duration of the diarrhea should be determined. Specific questions directed toward diet, drugs (including OTC and nutritional supplements), recent illnesses, and hospitalizations will provide insight into possible etiologies and exclude osmotic agents. Specific diets need to be considered as a temporary lactase deficiency may develop because the loss of the intestinal brush border is part of the pathophysiology of the cytotoxic agent-induced mucosal damage. Other food groups such as

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a

Fig. 26.1  (a) Diarrhea management algorithm; (b) octreotide protocol for refractory diarrhea

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26  Diarrhea, Constipation, and Obstruction in Cancer Management

b

Fig. 26.1  (continued)

fruits may be taken with good intention but aggrevate the underlying condition. The history may also uncover some issues relative to the cancer patient such as concomitant radiation, prior surgical procedures, and intestinal infections (e.g., Clostridium difficile, Helicobacter pylori). Finally, identifying the presence of pain, fever, dizziness, nausea, emesis, or bleeding should assist in triaging to establish the urgency and classifying the illness as self-limiting or of major complexity. The physical examination should be focused on the vital signs with special attention to signs of volume depletion as indicated by hypotension, orthostatic blood pressure, pulse rate, skin “tenting,” low jugular venous pressure, and nutritional status (temporal muscle wasting, etc.). Laboratory assessment includes a standard complete metabolic profile inclusive of blood glucose, albumin, complete blood count, and stool culture. Radiologic tests such as plain X-rays, ultrasound, CT/MRI scanning would be determined according to the clinical scenarios. Consultative assistance with gastroenterology, infectious diseases, surgery, and other medical specialties would be driven by the illness’ severity including comorbidities and response to initial empiric intervention(s).

Treatment Prior to initiating definitive or empiric treatment, establishing the CID diagnosis is not only dependent upon identifying the specific antineoplastic agent(s) but also on the timing of treatment. In general, with the first occurrence of CID, outpatient management for the first 24  h is appropriate as the diet modification (nonpharmacologic) and OTC antimotility agents (pharmacologic) may be prescribed. Once CID symptoms are refractory to first-line (outpatient) intervention, physician assessment becomes important. In palliative settings, the antineoplastic treatment may be either delayed or dose(s) reduced. Should hospitalization be required, initiating the octreotide protocol (see Fig.  26.1b) within the first 24 h of admission may shorten the hospital stay. With response to either low- or high-dose octreotide, the patient’s hospital stay is usually limited to 2–3 days. For patients not responding within 48–72 h of admission, the differential diagnosis should be broadened, further work-up and nutritional support considered. Patients relapsing after initially improving usually do so by advancing the diet too quickly or discontinuing octreotide. To prevent conditioning

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and to improve quality of life, the use of depot octreotide should be considered in patients with more than one additional chemotherapy cycle [53]. The initial drug therapy for CID is the opiates including loperamide (Imodium), diphenoxylate/atropine (Lomotil), paregoric and deodorized tincture of opium (DTO). Loperamide and diphenoxylate/atropine are FDA-approved for diarrhea management and have a short onset of action. Treatment guidelines recommend loperamide initially as it is obtained OTC and may be more effective [54, 55]. Loperamide is initially administered at 4 mg followed by 2 mg every 4 h or after every loose stool. Higher-dose loperamide is 4 mg initially followed by 2  mg every 2  h or 4  mg every 4  h until CID has resolved for at least 12 h. Octreotide acetate, a synthetic somatostatin congener, slows intestinal motility, decreases intestinal secretions, and stimulates intestinal absorption of water and electrolytes [56]. Octreotide is effective in the management of CID with dose titration as the optimal dose remains undetermined [57, 58]. The starting octreotide dose is 100–150 mg subcutaneously every 8–12  h [59]. Should symptoms not respond within 24 h, higher doses (500 mg SC every 8 h) may be more effective [60]. Octreotide is generally well tolerated with expected adverse effects being steattorhea, abdominal cramping, and flatulence. The use of the long-acting formulation (LAR) of octreotide offers choices for patients having additional chemotherapy cycles. Similar to the immediate acting octreotide, the optimal octreotide LAR dose remains uncertain [53].

Constipation Constipation is the slow movement of feces through the intestinal tract resulting in a decreased defecation frequency and is a common (50–87%) symptom in advanced cancer patients [61]. In 462 cancer patients, constipation was the third most common symptom (prevalence of 16% with 5% severe and 11% moderate) reported during cytotoxic chemotherapy [62]. Stool frequency of fewer than 3 per week and accompanied by pain or strain is considered pathologic. The etiology of constipation in the cancer patient is more likely to be multifactorial as primary, secondary, and iatrogenic causes are likely to be present. Primary causes include decreased fluid intake secondary to the debilitating illness, nausea, malaise, and depression. Low fiber diets may also contribute to these primary causes. Secondary causes may be obstructive lesions from adhesions, strictures, impaction, or masses. Dysmotility from an autonomic neuropathy, physical inactivity, diabetes, metabolic derangements (hypercalcemia, hypokalemia) or from hypothyroidism or spinal cord impairment is an additional

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secondary etiology of constipation. Iatrogenic causes are from the expected complications of specific pharmacologic agents such as analgesics, antiemetics (ondansetron), and certain chemotherapy drugs. Presenting symptoms of constipation include headache, abdominal pain and swelling, malaise, nausea, emesis, anorexia, and hemorrhoids. The pain from constipation may be of such severity that further analgesic therapy is significantly reduced or discontinued. The clinician should consider withdrawal symptoms as a potential additional complication of constipation management.

Vinca Alkaloids Even though constipation is present in approximately half of all cancer patients, constipation from chemotherapy is uncommon except for the vinca alkaloids such as vincristine, vinblastine, and vinorelbine. The vincas will induce constipation in approximately 25–30% of patients with grade 3 or 4 symptoms occurring infrequently (2–3%). The vinca alkaloids’ gut motility shortly after administration (3–10 days) usually resolves but is not cumulative [63]. Up to one-third of cancer patients will experience constipation [64]. Grades 3 and 4 constipations are uncommon with hospitalization of patients suffering from adynamic ileus occurring infrequently (2–3%) [64, 65]. Vinca-induced constipation is dose-related with the greatest incidence occurring at doses above 2 mg. An example of the severity of vincristine-induced constipation is Hodgkin and non-Hodgkin lymphoma patients (N = 104) treated with 90% of patients receiving doses >2 mg [66]. Severe constipation developed in 10% with improvement occurring within a few weeks after completing therapy.

Thalidomide Thalidomide therapy has a clinically significant incidence of constipation that is dose-related. In a clinical trial of patients with refractory myeloma and other diseases, constipation developed in approximately one-third of patients treated with 200 mg daily doses vs. 60% of those receiving 800 mg/day [67]. In a phase II clinical trial of thalidomide in high-grade glioma, constipation occurred in 19% without severe episodes [68]. Thalidomide-induced constipation is dose-dependent and develops within 2–4 days of drug initiation. Its severity is greatest in those patients older than 70 years and those receiving concomitant opiod therapy [69]. For patients developing constipation later in their treatment course, thalidomideinduced hypothyroidism should be considered.

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Therapy Prevention through prophylaxis and patient education is critical in constipation management. The NCCN palliative care guidelines recommend screening for the presence of constipation during routine symptom assessment and placing it in the context of life expectancy [70]. Increasing fluid intake and physical activity may also improve bowel function. Increasing dietary fiber to 20–25  g/day for several weeks may assist some patients. Laxatives should be administered concomitantly with narcotics and at the initial signs and symptoms of constipation. Initiating laxative therapy with senna, bisacodyl, and docusate is common. Should resistance to these first-line agents develop, then magnesium salts, polyethylene glycol, sorbitol, and lactulose are therapeutic options [71, 72]. In one small study, colchicine was effective in improving bowel function in chronic constipation patients who had failed other therapies [73]. Prokinetic agents such as metoclopramide may be effective in patients without physical obstruction. Recent advances in the management of analgesic-induced constipation include the 2008 FDA approval of methylnaltrexone, a pure peripherally acting opiate antagonist, for patients with advanced illnesses receiving palliative care. Blocking the opiate m-receptor in the peripheral nervous system compartment alone, methylnaltrexone does not reverse the analgesic effect of opiates or induce withdrawal. The methylnaltrexone registration trial randomized patients between subcutaneous methylnaltrexone (0.15 mg/kg subcutaneous, every other day) and placebo. The methylnaltrexonetreated group exhibited significant efficacy (48% of methylnaltrexone-treated patients experienced laxation within 4 h vs. 15% on the placebo arm) without altering central analgesia or inducing withdrawal [74]. Additional data are required to use this agent either prophylactically or reactively for analgesic-induced constipation. Should medical therapy fail, total colectomy with ileorectal anastomosis can be considered [75]. See Fig. 26.2 for an algorithm for managing constipation.

Obstruction Malignant bowel obstruction (MBO) occurs in approximately 3–15% of patients and usually signifies a short prognosis [76]. The symptoms are generally distressing with the diagnosis made clinically and confirmed with imaging modalities such as plain films or CT scans. Intervention is dependent upon lifeexpectancy. For those patients with months to years to live, appropriate screening should be performed with reversible causes treated appropriately. Total parenteral nutrition may be considered prior to surgical intervention. Even though surgery

is the primary treatment for obstruction from malignant disease, it is appropriate in selected patients with advanced disease and poor performance status to offer medical intervention only. This latter patient group generally has only days to weeks to live. Medical intervention includes the use of opiod analgesics, antiemetics, anticholinergics, somatostatin congeners, and steroids. Using these agents in combination may offer improved symptom control [76–78]. The NCCN guidelines suggest an algorithm directed by the patient’s expected survival in the context of the initial assessment and establishment of specific goals followed by appropriate intervention(s) followed by reassessment [70] (Fig. 26.3).

Corticosteroids By reducing the peritumoral inflammation and edema, intestinal transit improves. Reduction in water and salt secretion also occurs with steroid therapy. Because of the low cost, convenience, and good tolerability, corticosteroids are frequently prescribed in the palliative care setting for MBO [79].

Anticholinergics The antisecretory effects of the anticholinergics are desirable pharmacologic effects in MBO management. Even though mostly used in combinations, the anticholinergics, such as hyoscine butylbromide, hyoscine hydrobromide, and glycopyrrolate, are frequently used in improving MBO symptoms through muscarinic receptor inhibition producing ganglionic neural transmission impairment.

Octreotide Somatostatin congeners, such as octreotide, reduce intestinal secretions and slow motility through their direct and indirect actions [56]. The initial report of using octreotide in MBO was in a 40 patient cohort with only two patients surgically managed [80]. Subsequent prospective randomized trials compared octreotide therapy to hyoscine butylbromide. These trials all reported outcomes favoring octreotide [81–83]. Combining octreotide with other supportive care agents may offer improved outcomes, but its optimal use in the MBO setting remains undefined [77, 84]. The use of the LAR of octreotide for MBO management has been reported in small numbers of patients but for patients with an anticipated longer survival (>45–60 days), depot octreotide may offer advantages [85, 86].

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Fig. 26.2  Constipation management algorithm (data from NCCN guidelines) [70]

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26  Diarrhea, Constipation, and Obstruction in Cancer Management Fig. 26.3  Malignant bowel obstruction algorithm (data from NCCN guidelines) [70]

Summary An algorithm for MBO management is shown in Fig.  26.3. Following MBOs initial assessment and decision to proceed with medical intervention, the decision regarding the best route(s) of drug administration is necessary. As the oral route is generally contraindicated, sublingual, intravenous, subcutaneous, rectal, transdermal and intramuscular routes are the options depending upon specific drug formulations. Analgesic choices are usually the opiod class that could worsen a partial obstruction and constipation symptoms. Antiemetic choices should exclude the promotility agents such as metoclopramide that may be of benefit in partial bowel obstruction. Octreotide should be considered early in MBO management with initial subcutaneous doses at 150 mg every 8–12 h with dose titration to 300 mg every 8–12 h. Alternatively, continuous intravenous or subcutaneous infusions are options and with more chronic use, octreotide LAR at 20–30  mg intramuscularly every 30 days is suggested. Combining analgesics, antiemetics, and octreotide with the anticholinergics and corticosteroids would be considered the maximal medical effort in relieving MBO symptoms. Corticosteroids administered up to 60 mg/day of dexamethasone or its equivalent should be discontinued if no improvement is noted in 3–5 days.

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L.B. Anthony 26. Wasserman E, Myara A, Lokiec F et al. Severe CPT-11 toxicity in patients with Gilbert’s syndrome: two case reports. Annals of Oncology 1997;8(10):1049–1051. 27. Maitland ML, Vasisht K, Ratain MJ. TPMT, UGT1A1 and DPYD: genotyping to ensure safer cancer therapy? [Review] [67 refs]. Trends in Pharmacological Sciences 2006;27(8):432–437. 28. Abigerges D, Armand JP, Chabot GG et  al. Irinotecan (CPT-11) high-dose escalation using intensive high-dose loperamide to control diarrhea. Journal of the National Cancer Institute 1994; 86(6):446–449. 29. Hecht JR. Gastrointestinal toxicity or irinotecan [Review] [77 refs]. Oncology (Williston Park) 1998;12(8 Suppl 6):72–78. 30. Fuchs CS, Moore MR, Harker G et al. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. Journal of Clinical Oncology 2003;21(5): 807–814. 31. Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in firstline treatment of metastatic colorectal cancer: updated results from the BICC-C study. Journal of Clinical Oncology 2008;26(4): 689–690. 32. Lenz HJ, Van CE, Khambata-Ford S et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. Journal of Clinical Oncology 2006;24(30):4914–4921. 33. Hanna N, Lilenbaum R, Ansari R et al. Phase II trial of cetuximab in patients with previously treated non-small-cell lung cancer. Journal of Clinical Oncology 2006;24(33):5253–5258. 34. Van CE, Peeters M, Siena S et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic ­colorectal cancer. Journal of Clinical Oncology 2007;25(13): 1658–1664. 35. Hecht JR, Patnaik A, Berlin J et al. Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer 2007;110(5):980–988. 36. Moy B, Goss PE. Lapatinib-associated toxicity and practical management recommendations [Review] [58 refs]. Oncologist 2007; 12(7):756–765. 37. Carter CA, Kelly RJ, Giaccone G. Small-molecule inhibitors of the human epidermal receptor family [Review] [105 refs]. Expert Opinion on Investigational Drugs 2009;18(12):1829–1842. 38. Shepherd FA, Rodrigues PJ, Ciuleanu T et  al. Erlotinib in previously treated non-small-cell lung cancer. New England Journal of Medicine 2005;353(2):123–132. 39. Thatcher N, Chang A, Parikh P et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced nonsmall-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366(9496):1527–1537. 40. Messersmith WA, Laheru DA, Senzer NN et al. Phase I trial of irinotecan, infusional 5-fluorouracil, and leucovorin (FOLFIRI) with erlotinib (OSI-774): early termination due to increased toxicities. Clinical Cancer Research 2004;10(19):6522–6527. 41. Czito BG, Willett CG, Bendell JC et al. Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: phase I trial results. Journal of Clinical Oncology 2006;24(4): 656–662. 42. Clark JW, Eder JP, Ryan D et al. Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clinical Cancer Research 2005;11(15): 5472–5480. 43. Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clearcell renal-cell carcinoma [Erratum appears in N Engl J Med 2007 Jul 12;357(2):203]. New England Journal of Medicine 2007; 356(2):125–134.

26  Diarrhea, Constipation, and Obstruction in Cancer Management 44. Worns MA, Weinmann A, Pfingst K et  al. Safety and efficacy of sorafenib in patients with advanced hepatocellular carcinoma in consideration of concomitant stage of liver cirrhosis. Journal of Clinical Gastroenterology 2009;43(5):489–495. 45. Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. New England Journal of Medicine 2007;356(2):115–124. 46. Demetri GD, van Oosterom AT, Garrett CR et  al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006;368(9544):1329–1338. 47. Socinski MA, Novello S, Brahmer JR et al. Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer. Journal of Clinical Oncology 2008;26(4):650–656. 48. Deininger MW, O’Brien SG, Ford JM et al. Practical management of patients with chronic myeloid leukemia receiving imatinib [Review] [35 refs]. Journal of Clinical Oncology 2003;21(8): 1637–1647. 49. Motzer RJ, Escudier B, Oudard S et  al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebocontrolled phase III trial. Lancet 2008;372(9637):449–456. 50. Yao JC, Lombard-Bohas C, Baudin E et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. Journal of Clinical Oncology 2010;28(1):69–76. 51. Kane RC, Farrell AT, Sridhara R et al. United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy. Clinical Cancer Research 2006;12(10):2955–2960. 52. Mann BS, Johnson JR, He K et al. Vorinostat for treatment of cutaneous manifestations of advanced primary cutaneous T-cell lymphoma. Clinical Cancer Research 2007;13(8):2318–2322. 53. Rosenoff SH, Gabrail NY, Conklin R et al. A multicenter, randomized trial of long-acting octreotide for the optimum prevention of chemotherapy-induced diarrhea: results of the STOP trial. The Journal of Supportive Oncology 2006;4(6):289–294. 54. Benson AB, III, Ajani JA, Catalano RB et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. Journal of Clinical Oncology 2004;22(14):2918–2926. 55. Maroun J, Anthony L, Blais N et  al. Prevention and management of chemotherapy-induced diarrhea in patients with colorectal cancer: a consensus statement by the Canadian Working Group on ChemotherapyInduced Diarrhea. Current Oncology 2007;14:13–20. 56. Lamberts SW, van der Lely AJ, de Herder WW et  al. Octreotide [Review] [76 refs]. New England Journal of Medicine 1996; 334(4):246–254. 57. Cascinu S, Fedeli A, Fedeli SL et al. Octreotide versus loperamide in the treatment of fluorouracil-induced diarrhea: a randomized trial. Journal of Clinical Oncology 1993;11(1):148–151. 58. Kornblau S, Benson AB, Catalano R et al. Management of cancer trea­tment-related diarrhea. Issues and therapeutic strategies [Review] [63 refs]. Journal of Pain and Symptom Management 2000;19(2):118–129. 59. Harris AG, O’Dorisio TM, Woltering EA et al. Consensus statement: octreotide dose titration in secretory diarrhea. Diarrhea Management Consensus Development Panel [Review] [39 refs]. Digestive Diseases and Sciences 1995;40(7):1464–1473. 60. Goumas P, Naxakis S, Christopoulau A et al. Octreotide acetate in the treatment of fluorouracil-induced diarrhea. The Oncologist 1998;3:50–53. 61. Abernethy AP, Wheeler JL, Zafar SY. Detailing of gastrointestinal symptoms in cancer patients with advanced disease: new methodologies, new insights, and a proposed approach [Review] [39 refs]. Current Opinion in Supportive and Palliative Care 2009;3(1):41–49. 62. Yamagishi A, Morita T, Miyashita M et  al. Symptom prevalence and longitudinal follow-up in cancer outpatients receiving chemo-

259 therapy. Journal of Pain and Symptom Management 2009;37(5): 823–830. 63. Legha SS. Vincristine neurotoxicity. Pathophysiology and management [Review] [45 refs]. Medical Toxicology 1986;1(6): 421–427. 64. Holland JF, Scharlau C, Gailani S et  al. Vincristine treatment of advanced cancer: a cooperative study of 392 cases. Cancer Research 1973;33(6):1258–1264. 65. Hohneker JA. A summary of vinorelbine (Navelbine) safety data from North American clinical trials. Seminars in Oncology 1994; 21(5 Suppl 10):42–46. 66. Haim N, Epelbaum R, Ben-Shahar M et  al. Full dose vincristine (without 2-mg dose limit) in the treatment of lymphomas. Cancer 1994;73(10):2515–2519. 67. Singhal S, Mehta J, Desikan R et al. Antitumor activity of thalidomide in refractory multiple myeloma [Erratum appears in N Engl J Med 2000 Feb 3;342(5):364]. New England Journal of Medicine 1999;341(21):1565–1571. 68. Fine HA, Figg WD, Jaeckle K et al. Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent highgrade gliomas. Journal of Clinical Oncology 2000;18(4): 708–715. 69. Dimopoulos MA, Eleutherakis-Papaiakovou V. Adverse effects of thalidomide administration in patients with neoplastic diseases [Review] [91 refs]. American Journal of Medicine 2004;117(7): 508–515. 70. National Comprehensive Cancer Network. NCCN: Palliative Care. In NCCN Clinical Practice Guidelines Version 1.2010. 1–52. 2010. 71. Weed HG. Lactulose vs sorbitol for treatment of obstipation in hospice programs. Mayo Clinic Proceedings 2000;75(5):541. 72. Reville B, Axelrod D, Maury R. Palliative care for the cancer patient [Review] [146 refs]. Primary Care 2009;36(4):781–810. 73. Verne GN, Davis RH, Robinson ME et  al. Treatment of chronic constipation with colchicine: randomized, double-blind, placebocontrolled, crossover trial. American Journal of Gastroenterology 2003;98(5):1112–1116. 74. Thomas J, Karver S, Cooney GA et al. Methylnaltrexone for opioidinduced constipation in advanced illness. New England Journal of Medicine 2008;358(22):2332–2343. 75. Nyam DC, Pemberton JH, Ilstrup DM et al. Long-term results of surgery for chronic constipation [Erratum appears in Dis Colon Rectum 1997 May;40(5):529]. Diseases of the Colon and Rectum 1997;40(3):273–279. 76. Mercadante S, Casuccio A, Mangione S. Medical treatment for inoperable malignant bowel obstruction: a qualitative systematic review [Review] [14 refs]. Journal of Pain and Symptom Management 2007;33(2):217–223. 77. Weber C, Zulian GB. Malignant irreversible intestinal obstruction: the powerful association of octreotide to corticosteroids, antiemetics, and analgesics. American Journal of Hospice & Palliative Medicine 2009;26(2):84–88. 78. Mangili G, Aletti G, Frigerio L et  al. Palliative care for intestinal obstruction in recurrent ovarian cancer: a multivariate analysis. International Journal of Gynecological Cancer 2005;15(5):830–835. 79. Feuer DJ, Broadley KE. Systematic review and meta-analysis of corticosteroids for the resolution of malignant bowel obstruction in advanced gynaecological and gastrointestinal cancers. Systematic Review Steering Committee. Annals of Oncology 1999;10(9): 1035–1041. 80. Baines M, Oliver DJ, Carter RL. Medical management of intestinal obstruction in patients with advanced malignant disease. A clinical and pathological study. Lancet 1985;2(8462):990–993. 81. Mercadante S, Ripamonti C, Casuccio A et al. Comparison of octreotide and hyoscine butylbromide in controlling gastrointestinal symptoms due to malignant inoperable bowel obstruction. Supportive Care in Cancer 2000;8(3):188–191.

260 82. Ripamonti C, Mercadante S, Groff L et al. Role of octreotide, scopolamine butylbromide, and hydration in symptom control of patients with inoperable bowel obstruction and nasogastric tubes: a prospective randomized trial. Journal of Pain and Symptom Management 2000;19(1):23–34. 83. Mystakidou K, Tsilika E, Kalaidopoulou O et  al. Comparison of octreotide administration vs conservative treatment in the management of inoperable bowel obstruction in patients with far advanced cancer: a randomized, double-blind, controlled clinical trial. Anticancer Research 2002;22(2B):1187–1192.

L.B. Anthony 84. Mercadante S, Ferrera P, Villari P et al. Aggressive pharmacological treatment for reversing malignant bowel obstruction. Journal of Pain and Symptom Management 2004;28(4):412–416. 85. Massacesi C, Galeazzi G. Sustained release octreotide may have a role in the treatment of malignant bowel obstruction. Palliative Medicine 2006;20(7):715–716. 86. Matulonis UA, Seiden MV, Roche M et al. Long-acting octreotide for the treatment and symptomatic relief of bowel obstruction in advanced ovarian cancer. Journal of Pain and Symptom Management 2005;30(6):563–569.

Chapter 27

Ascites Rohit Joshi

Introduction Ascites is the pathological accumulation of fluid in the abdominal cavity caused by an imbalance of fluid in and out of the blood and lymphatic vessels. Cirrhosis leading on to portal hypertension accounts for nearly 80% of the cases of ascites [1]. However, malignant and infectious causes are also common. Cancer-induced ascites is present in about 10% of all patients [2]. Ascites in patients with cancer is caused by the metastatic spread to the peritoneum in 50% of the cases, lymphatic invasion in 20%, portal venous compression and liver invasion in 15%, and the combined effect of metastatic spread and liver invasion in 15% [3]. Advanced cancer accounts for about 10% of ascites, and the 1-year survival is less than 10% [4]. Palliation of ascites is vital for holistic patient management. Multivariate analyses show significantly shortened survival in patients with liver metastases and elevated serum bilirubin, while ovarian cancer is a significant independent predictor of prolonged survival [5]. The median survival after the diagnosis of malignant ascites was only 20 weeks from the time of diagnosis of ascites. However, tumors of ovarian and lymphatic origin have better mean survivals (32 and 58 weeks, respectively) [6].

Anatomy The peritoneum lines the abdominal and pelvic cavity (parietal peritoneum) and covers the intra-abdominal organs (visceral peritoneum). It consists of mesothelial tissue with squamous epithelium facing the abdominal cavity, which is supported by an inner layer of tissue, called the lamina propria. The squamous epithelium is not a closed layer but contains foramina allowing macromolecules and cells to enter the abdominal cavity. Furthermore, plasma filters into the

abdominal cavity via the peritoneal capillaries, and drains off via open endings of lymphatic channels in the serosa. In the healthy state, approximately 50–100 mL of fluid fills the peritoneal cavity allowing the organs to slide freely over each other.

Etiology and Pathogenesis Chronic liver disease with portal hypertension, congestive cardiac failure, tuberculosis, and malignancy are important causes of ascites. Various causes of ascites are shown in Table 27.1 [7]. The most common cancers associated with ascites are adenocarcinomas of the ovary, breast, colon, stomach, and pancreas. The cancer type largely influences the sites of abdominal metastases and the cause of the ascites. Potential causes of ascites in patients with cancer include peritoneal carcinomatosis, malignant obstruction of draining lymphatics, portal vein thrombosis, elevated portal venous pressure from cirrhosis, congestive heart failure, and peritoneal infections [8, 9]. Studies have shown that malignant effusions arise in part from increased production and activity of vascular endothelial growth factors (VEGFs). VEGFs increase vascular permeability and establish an ideal environment for the accumulation of malignant effusions [10]. The presence of portal hypertension also contributes to the development of ascites in patients who have cirrhosis. Hypoalbuminemia (common in cancer patients due to poor dietary history and catabolic effects of the malignancy) reduces plasma oncotic pressure and may lead to transudation from the vascular to peritoneal compartment. This also causes loss of fluid from the vascular compartment into the peritoneal cavity.

Clinical Manifestations R. Joshi (*) Medical Oncology, Christian Medical College & Hospital, Ludhiana 141012, Punjab, India e-mail: [email protected]

The manifestation of symptoms depends on the amount of fluid, rapidity of fluid accumulation, and the cause of ascites.

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_27, © Multinational Association for Supportive Care in Cancer Society 2011

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262 Table 27.1  Causes of ascites Venous hypertension

Cirrhosis of liver Congestive cardiac failure Constrictive pericarditis Hepatic venous outflow obstruction Acute portal vein thrombosis Hypoalbuminemia Cirrhosis of liver Nephrotic syndrome Malnutrition Infections Tuberculosis Parasitic (strongyloidosis, entamoeba) Malignancies Peritoneal carcinomatosis Lymphomas and leukemias Primary mesothelioma Miscellaneous Chylous ascites Systemic lupus erythematosus Ovarian disease Pancreatic ascites Pseudomyxoma peritonei Chylous ascites Source: From McIntyre and Burroughs [7], reprinted with permission

Patients often notice an increase in abdominal girth, peripheral swelling, and edema, after at least 1–2 L of fluid has accumulated in the abdomen. Patients with massive ascites are often malnourished, have muscle wasting, weight loss, and excessive fatigue. Patients often first seek medical attention because of abdominal discomfort, pain, breathing difficulty, or early satiety. They may also complain of reduced appetite, nausea, vomiting, lower extremity edema, weight gain, and reduced mobility [9]. If present, an umbilical nodule (Sister Mary Joseph nodule) suggests cancer as a possible cause of ascites. Abdominal pain may be due to a combination of factors including nerve invasion by the tumor, stretching of the liver capsule, or stretching of the abdominal wall.

Diagnosis The diagnosis is based upon the clinical setting, imaging tests, and ascitic fluid analysis [11]. Patients with malignancy may have minimal fluid, which is picked up during workup. Ascites needs to be differentiated from abdominal distension due to causes like gross obesity, gaseous distention, bowel obstruction, abdominal cysts, or masses. The diagnosis may be obvious in a patient with massive ascites, but when only a small or moderate amount of fluid is present, the accuracy of physical assessment is only about 50%, even by experienced gastroenterologists [12]. Flank dullness that is present in nearly 90% of the patients with nonloculated ascites, is the most sensitive physical sign.

R. Joshi

Shifting dullness on percussion is more specific but less sensitive than flank dullness for the detection of ascites. A fluid thrill or wave may be demonstrable in cases of tense ascites. Occasionally, massive ovarian or hydatid cysts and pregnancy with hydramnios can masquerade as ascites. The puddle sign (the patient is examined while placed in a kneeelbow position; one flank is percussed while a stethoscope is placed over the most dependent portion of the abdomen and gradually moved toward the flank opposite to the percussion; a sharp increase in the intensity of the sound indicates the level of fluid) reported to detect as little as 120 mL of fluid clinically requires the patient to be in the knee-elbow position during examination. The utility of puddle sign and auscultatory percussion for detecting ascites has been assessed using ultrasound of the abdomen as gold standard. It was observed that auscultatory percussion has a greater sensitivity (66 vs. 45%) but a lower specificity (48 vs. 68%) than the puddle sign [13]. Radiologic studies are useful in detecting small amounts of ascitic fluid as well as helpful in assessing the etiology of ascites. Ultrasonography is the commonest and most convenient investigation for diagnosing ascites [11]. It does not require exposure to radiation or use of contrast and may detect as little as 100 mL of intraperitoneal fluid. Depending on the clinical setting, computed tomography (CT) or magnetic resonance imaging (MRI) scans are excellent investigations. CT or MRI scans provide much more detailed information about the abdomen and pelvis, which may be difficult to obtain on ultrasonography. In patients with carcinomatosis or inflammatory peritonitis, a contrast enhanced CT or MRI scan may demonstrate enhancement of the peritoneal lining. Clear ascitic fluid (translucent or yellow) is usually caused by portal hypertension and cirrhosis, infections cause the fluid to turn cloudy (due to the presence of high number of cells), milky fluid indicates chyle (triglyceride concentration greater than serum and greater than 200 mg/dL), and bloodstained fluid (red cell concentration of >10,000  cells/mm3) may suggest cancer (Table 27.2). The next step in the evaluation of the patient with ascites of unknown etiology is to differentiate those causes arising from portal hypertension (usually cirrhosis) or from other causes

Table 27.2  Tests performed on ascitic fluid Routine tests

Other tests

Total protein Albumin Cell count

Gram’s stain & culture AFB smear & culture Malignant cytology Amylase Lactate dehydrogenase Triglycerides Glucose Adenosine deaminase

27  Ascites

(including malignancy). This is supported by the serumto-ascites albumin gradient (SAAG) that is the difference between serum albumin and ascitic fluid albumin [14]. A SAAG value of less than 1.1 signifies a nonportal hypertension etiology of the ascites. An ascites-to-serum ratio of LDH greater than 1 indicates that the enzyme is actively being produced in the ascitic fluid and suggests malignancy. The detection of tumor cells by cytology remains the gold standard for the detection of malignancy. For patients with peritoneal carcinomatosis due to cellular exfoliation into the ascitic fluid, malignant cells can be detected nearly 100% of the time [15]. The overall sensitivity for cytology smears for the detection of malignancy-related ascites is between 40–75 and 58–75% [16]. A more definitive diagnosis can also be ascertained by performing immunohistochemistry studies on the malignant cells or a cell block. Ascites in the setting of probable cancer of an unknown primary may require biopsies via laparoscopy or laparotomy, as both are extremely sensitive for picking up peritoneal carcinomatosis. Omental biopsies can also be performed under ultrasound or CT guidance. Patients with a known malignancy who develop ascites, in the setting of a nonovarian cancer, have a very poor prognosis [17]. Patients with fever or abdominal pain along with ascites should also be evaluated for infectious causes of ascites [18].

Treatment In most instances, the treatment of metastatic cancer with ascites is palliative. Symptoms such as breathlessness, abdominal discomfort, fatigue, or loss of appetite may indicate a need for initiating treatment. Therapies to manage fluid overload such as diuresis and abdominoparacentesis are relatively simple and can be combined with chemotherapy. While diuretics are well tolerated, inexpensive, and simple to use [19], their use in the management of malignant ascites is controversial. Diuretics are not a definitive treatment option in malignant ascites as mechanisms affecting renal handling of excess fluid, and sodium may not be very effective in cancer treatment[20]. Also, malignant ascites results from increased fluid production due to the presence of tumor cells in the peritoneum and not from increased portal pressure [21]. A distal tubule diuretic such as spironolactone may be used alone or along with furosemide. Patients should weigh themselves daily to check for weight changes [8]. Excessive diuresis may cause hypotension, volume depletion, renal failure, and electrolyte abnormalities.

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Paracentesis Large-volume paracentesis is the most commonly used lowrisk method for palliation of malignant ascites [22]. It may rapidly improve shortness of breath and early satiety temporarily. Paracentesis provides relief in up to 90% of patients of malignant ascites [23]. Complications of large-volume paracentesis include dehydration, intravascular volume depletion, hypotension, and renal failure. Repeated paracentesis may lead to bleeding, pain, infection, loss of protein, electrolyte loss, and bowel perforation [8].

Peritoneovenous Shunting Peritoneovenous shunting, introduced by LeVeen for alcoholic liver disease, is an option in managing malignant ascites [24]. Patients do not lose protein and thus maintain or improve intravascular oncotic pressures, which allow management of the ascites without hospitalization. Rapid increase in intravascular volume from the infusion of a large amount of ascitic fluid may result in congestive heart failure, immediately after the placement of the pump. Performing a large-volume paracentesis immediately prior to the procedure can minimize this risk. Patients with peritonitis or those not able to handle large, rapid fluid shifts (patients with significant cardiac or renal dysfunction) would not be candidates for shunt placement. Peritoneovenous shunting is effective in controlling ascites between 62 and 88% of the time [25]. However, there was no survival or quality of life advantage when peritoneovenous shunting was compared with repeated paracentesis [26].

Drainage Catheters External drainage catheters are used for repeated fluid drainage that does not require repeated needle insertion. Patients are therefore offered the ability to perform repeated paracentesis by themselves. Protein loss and infections are the main problems with this method [27].

Surgery Peritonectomy is performed to remove various parts of the peritoneum, omentum, and some intra-abdominal organs, as a method of tumor cytoreduction [28]. Studies show modest success with this procedure in increasing survival time and in

264

the prevention or recurrence of the development of malignant ascites, its use in the treatment of ascites, however, has not been well evaluated [29]. Peritonectomy is unlikely to help in patients with advanced, malignant ascites, as patients in this setting often have chemotherapy-refractory disease. Surgery is very helpful for conditions like ovarian and primary peritoneal cancer.

Intraperitoneal Therapy Intraperitoneal (IP) therapy is often administered in an attempt to deliver higher doses of chemotherapy locally [30]. The response to IP therapy to treat ascites and abdominal malignancies depends on the primary cancer and prior chemotherapy. IP administration of Cisplatin has been studied extensively in the setting of ovarian cancer and there is a suggestion that IP therapy has better efficacy than intravenous chemotherapy [31].

Tumor-Targeted Treatment For women with ovarian cancer – surgical debulking and chemotherapy are the best options available. More than onehalf of patients with advanced ovarian cancer will have a complete remission from initial therapy, although only 10–30% will remain progression-free long term. VEGF appears to have an important role in permitting tumors to attach to the peritoneum; some VEGF inhibitors have been reported to provide some palliation. There are some data to suggest that intraperitoneal bevacizumab is a relatively safe and effective way to palliate the symptoms of refractory malignant ascites [10]. There have also been reports of complete remission of ovarian cancer-induced intractable malignant ascites with intraperitoneal bevacizumab. Immunological analyses showed an initial increase in the proportion and function of CD8(+) effector T cells and a reduction of circulating T(reg) cells. Intraperitoneal administration induces an immune activation and appears promising in the treatment of malignant ascites [32]. Gemcitabine infusions may benefit patients with ascites from pancreatic cancer. There are reports with good results of intraperitoneal administration of Imatinib mesylate for ascites due to chronic myeloid leukemia [33] and Rituximab for ascites due to lymphoma [34]. Patients with peritoneal mesothelioma may benefit from aggressive cytoreductive therapy combined with intraperitoneal hyperthermic chemotherapy [35].

R. Joshi

Patients with malignant ascites due to epithelial cancer treated with the trifunctional antibody Catumaxomab resulted in a clinically relevant prolongation of puncture-free survival, defined as the time to the next therapeutic puncture or the time to death, whichever occurred first. Catumaxomab demonstrated a significant clinical benefit in patients with malignant ascites independent of the primary tumor or other prognostic factors [36]. In chemorefractory ovarian cancer patients, Catumaxomab was the only medication that could achieve an improvement [37]. Acknowledgments  Dr. Joseph Thomas, MD: Professor and Head of Medical Oncology, Shirdi Sai Baba Cancer Hospital and Research Centre, Kasturba Medical College, Manipal. Karnataka 576104. Mr. Ashok VK, Product Manager, Dr. Reddy’s Laboratories, Hyderabad, Andhra Pradesh.

References 1. Runyon BA. Management of adult patients with ascites due to cirrhosis. Hepatology. 2004;39(3):841–856. 2. Becker G, Galandi D, Blum HE. Malignant ascites: systematic review and guideline for treatment. Eur J Cancer. 2006;42(5):589–597. 3. Adam RA, Adam YG. Malignant ascites: past, present, and future. J Am Coll Surg. 2004;198(6):999–1011. 4. Runyon BA. Care of patients with ascites. N Engl J Med. 1994; 330(5):337–342. 5. Mackey JR, Venner PM. Malignant ascites: demographics, therapeutic efficacy and predictors of survival. Can J Oncol. 1996;6(2): 474–480. 6. Garrison RN, Kaelin LD, Galloway RH, Heuser LS. Malignant ascites. Clinical and experimental observations. Ann Surg. 1986;203(6): 644–651. 7. McIntyre N, Burroughs AK. Cirrhosis, Portal hypertension, and Ascites. In: Weatherall DJ, Ledingham J, Warrell DA, ed. Oxford Textbook of Medicine, 3rd Edition. Oxford University Press, Oxford; 1996:2085–2100. 8. Lifshitz S. Ascites, pathophysiology and control measures. Int J Radiat Oncol Biol Phys. 1982;8(8):1423–1426. 9. Saif MW, Siddiqui IA, Sohail MA. Management of ascites due to gastrointestinal malignancy. Ann Saudi Med. 2009;29(5):369–377. 10. El-Shami K, Elsaid A, El-Kerm Y. Open-label safety and efficacy pilot trial of intraperitoneal bevacizumab as palliative treatment in refractory malignant ascites. J Clin Oncol. 2007;25(18S):9043. 11. Runyon BA. Management of adult patients with ascites due to cirrhosis: an update. Hepatology. 2009;49(6):2087–2107. 12. Cattau EL, Jr., Benjamin SB, Knuff TE, Castell DO. The accuracy of the physical examination in the diagnosis of suspected ascites. JAMA. 1982;247(8):1164–1166. 13. Chongtham DS, Singh MM, Kalantri SP, Pathak S. A simple bedside manoeuvre to detect ascites. Natl Med J India. 1997;10(1): 13–14. 14. Runyon BA, Montano AA, Akriviadis EA, Antillon MR, Irving MA, McHutchison JG. The serum-ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites. Ann Intern Med. 1992;117(3):215–220. 15. Akriviadis EA. Hemoperitoneum in patients with ascites. Am J Gastroenterol. 1997;92(4):567–575. 16. Kielhorn E, Schofield K, Rimm DL. Use of magnetic enrichment for detection of carcinoma cells in fluid specimens. Cancer. 2002;94(1):205–211.

27  Ascites 17. Ayantunde AA, Parsons SL. Pattern and prognostic factors in patients with malignant ascites: a retrospective study. Ann Oncol. 2007;18(5):945–949. 18. Runyon BA. Management of adult patients with ascites caused by cirrhosis. Hepatology. 1998;27(1):264–272. 19. Sharma S, Walsh D. Management of symptomatic malignant ascites with diuretics: two case reports and a review of the literature. J Pain Symptom Manage. 1995;10(3):237–242. 20. Greenway B, Johnson PJ, Williams R. Control of malignant ascites with spironolactone. Br J Surg. 1982;69(8):441–442. 21. Lee CW, Bociek G, Faught W. A survey of practice in management of malignant ascites. J Pain Symptom Manage. 1998;16(2):96–101. 22. Rosenberg SM. Palliation of malignant ascites. Gastroenterol Clin North Am. 2006;35(1):189–199, xi. 23. Smith EM, Jayson GC. The current and future management of malignant ascites. Clin Oncol (R Coll Radiol). 2003;15(2):59–72. 24. Straus AK, Roseman DL, Shapiro TM. Peritoneovenous shunting in the management of malignant ascites. Arch Surg. 1979;114(4):489–491. 25. Schumacher DL, Saclarides TJ, Staren ED. Peritoneovenous shunts for palliation of the patient with malignant ascites. Ann Surg Oncol. 1994;1(5):378–381. 26. Parsons SL, Lang MW, Steele RJ. Malignant ascites: a 2-year review from a teaching hospital. Eur J Surg Oncol. 1996;22(3):237–239. 27. Belfort MA, Stevens PJ, DeHaek K, Soeters R, Krige JE. A new approach to the management of malignant ascites; a permanently implanted abdominal drain. Eur J Surg Oncol. 1990;16(1):47–53. 28. Sugarbaker PH. Peritonectomy procedures. Ann Surg. 1995;221(1): 29–42. 29. Sugarbaker PH, Jablonski KA. Prognostic features of 51 colorectal and 130 appendiceal cancer patients with peritoneal carcinomatosis

265 treated by cytoreductive surgery and intraperitoneal chemotherapy. Ann Surg. 1995;221(2):124–132. 30. Dedrick RL, Myers CE, Bungay PM, DeVita VT, Jr. Pharmaco­ kinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Cancer Treat Rep. 1978;62(1):1–11. 31. 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(26):1950–1955. 32. Bellati F, Napoletano C, Ruscito I, et  al. Complete remission of ovarian cancer induced intractable malignant ascites with intraperitoneal bevacizumab. Immunological observations and a literature review. Invest New Drugs. 2009; doi 10.1007/s10637-009-9351-4. 33. Aleem A, Siddiqui N. Chronic myeloid leukemia presenting with extramedullary disease as massive ascites responding to imatinib mesylate. Leuk Lymphoma. 2005;46(7):1097–1099. 34. Ng T, Pagliuca A, Mufti GJ. Intraperitoneal rituximab: an effective measure to control recurrent abdominal ascites due to non-Hodgkin’s lymphoma. Ann Hematol. 2002;81(7):405–406. 35. Sugarbaker PH. Managing the peritoneal surface component of gastrointestinal cancer. Part 1. Patterns of dissemination and treatment options. Oncology (Williston Park). 2004;18(1):51–59. 36. Parsons S, Hennig M, Linke R, Klein A, Lahr A, Lindhofer H, Heiss M. Clinical benefit of catumaxomab in malignant ascites in patient subpopulations in a pivotal phase II/III trial. J Clin Oncol. 2009; ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 27, No. 15S (May 20 Supplement), 2009:e14000. 37. Woopen H, Sehouli J. Current and future options in the treatment of malignant ascites in ovarian cancer. Anticancer Res. 2009;29(8): 3353–3359.

Chapter 28

Hepatotoxicity and Hepatic Dysfunction Ahmet Taner Sümbül and Özgür Özyilkan

Introduction It is believed that “Primum non nocere” should be the main aim for clinicians. Most drugs combined in chemotherapeutic regimens have a narrow therapeutic index which can be narrower in patients with preexisting liver or other chronic systemic diseases. It is known that many of the cytotoxic drugs are metabolized by the liver, resulting in either inactivating drugs or activating prodrugs. Therefore, in patients with preexisting liver disease, these drugs may cause more toxicity than usual or be less effective than usual. The interaction between chemotherapy and the liver can be divided into three groups: 1 . Drug related direct hepatotoxicity 2. Aggravating the underlying liver disease such as steatohepatitis and viral hepatitis 3. Affecting the metabolism and excretion of the drugs due to underlying liver disease Prediction of these effects can be achieved by careful assessment of the patient before initiating the therapeutic modality. A detailed patient history and physical examination for underlying liver disease should be the initial step, after which laboratory tests for assessing the liver’s synthetic function (serum albumin, bilirubin, prothrombin time), tests for cellular injury (aspartate aminotransferase (AST), alanine aminotransferase (ALT)), tests helpful for assessing duct injury or cholestasis (alkaline phosphatase (ALP), gammaglutamyltransferase (gGT), and direct reacting billuribin), and tests showing underlying viral hepatitis (HBsAg, AntiHBs, AntiHCV) should be performed [1] (Table 28.1).

A.T. Sümbül () Department of Medical Oncology, Baskent University School of Medicine, Baskent Universitesi Adana Hastanesi Kisla Yerleskesi Tibbi Onkoloji BD Kazim Karabekir cadYuregir, Adana, 01120, Turkey e-mail: [email protected]

Radiologic imaging such as ultrasonography, computerized tomography, and magnetic resonance imaging could be useful in certain groups of patients. But we should be aware that nearly 3% of the healthy population has abnormal liver function tests despite having a normal functioning liver. They are outside a standard deviation (SD) of 2 compared with the normal distribution for laboratory reference ranges [2]. The other important issue is that liver function tests can fall into the normal range in patients with histopathologically proven liver disease. It has been reported that nearly 16% of patients with chronic hepatitis C infection and 13% with non-alcoholic fatty liver disease with proven histopathological damage have normal liver function tests [3, 4]. During the evaluation period, the effects of cancer on liver function should be considered. Primary liver tumors, metastatic liver disease, or tumors next to the liver or biliary tree can affect liver function either by invading the normal liver tissue or by obstructing the bile tract. And also thrombosis of big vessels of the liver such as the portal vein or hepatic vein might occur because of a hypercoagulable state or compression or by direct infiltration of the vein.

Underlying Liver Disease At the initial evaluation of oncologic patients, considering the underlying liver disease is an important issue. Both chemotherapy and other therapeutic modalities may cause exacerbation of underlying liver disease and also these patients may be more susceptible to drug induced hepatotoxicity. Avoiding these risks can be achieved by a full diagnostic work up before deciding upon the therapeutic management of these patients. This approach will help clinicians to make realistic choices and avoid using or making dose reductions of certain drugs because of their possible side-effects. Chronic infection with hepatitis B, hepatitis C, and nonalcoholic steatohepatitis are the most encountered preexisting liver diseases.

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_28, © Multinational Association for Supportive Care in Cancer Society 2011

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268 Table. 28.1  Common nonmalignant causes of abnormal serum liver enzymes Increased alkaline phosphatase Bone disease (e.g., Paget’s disease; hyperparathyroidism – any cause of increased bone turnover) During fracture repair Increased parathyroid hormone (via effects on bone) Cirrhosis, especially during the course of primary biliary cirrhosis Pregnancy associated (plesental) Increased gammaglutamyltransferase Chronic alcoholism Drug associated (e.g., phenytoin, barbituates) Iron overload Fatty liver or obesity associated Diabetes mellitus Myocardial infarction Increased alkaline phosphatase and gammaglutamyltransferase Marker of extrahepatic cholestasis (multiple causes) Cholecystitis or cholelithiasis Drug associated Increased aspartate aminotransferase Rhabdomyolysis (cardiac or skeletal) Haemolysis (aspartate aminotransferase present in erythrocytes) Alcohol-associated hepatitis Chronic liver disease or cirrhosis Increased aspartate aminotransferase and alanine aminotransferase Markers of hepatocellular injury Alcohol associated hepatitism Hepatitis (i.e., viral, autoimmune or drug-induced) Drug associated (e.g., isoniazid, statins, and amiodarone) Non-alcoholic steatohepatitis Ischaemic or hypoxic liver injury Increased bilirubin Prehepatic (i.e., unconjugated hyperbilirubinaemia) Haemolysis Gilbert’s syndrome Crigler–Najjar syndrome (types I and II) Intrahepatic cholestasis (i.e., conjugated hyperbilirubinaemia) Drug associated (e.g., capecitabine and mitomycin) Posthepatic (i.e., conjugated hyperbilirubinaemia) Biliary obstruction (any cause) Decreased albumin Decreased production   Malnutrition   Malabsorption   Liver failure (any cause, usually chronic)   Inflammatory states Increased loss   Nephrotic syndrome   Protein-losing enteropathy   Burns   Congestive heart failure Redistribution   Negative acute-phase protein (i.e., serum level decreases with intercurrrent illness)   Ascites Increased international normalized ratio (INR) or prothrombin time Vitamin K deficiency Warfarin administration Coagulopathy (e.g., disseminated intravascular coagulation) Liver disease or cirrhosis (any cause)

A.T. Sümbül and Ö. Özyilkan

Hepatitis B Infection Hepatitis B is a chronic viral infection that may lead to cirrhosis and hepatocellular cancer. In the absence of prophylaxis, chemotherapy can cause hepatitis B reactivation in HbsAg (+) patients. Reactivation may cause serious liver failure that can end in fatal complications [5]. There have been many reports about HBV reactivation during the course of chemotherapy and chemoradiotherapy in different hematologic and solid organ malignancies [6]. The risk of reactivation reported in these series ranged between 20 and 50%. It is known that the risk is highest in patients who have stopped their therapy [7]. Studies focused on HbsAg (+) patients have shown that the risk is highest in men, younger age groups, HbeAg (+) patients, patients with high HBV DNA levels, lymphoma, or hematologic malignancies, and patients using corticosteroids, anthracyclines, and rituximab therapy [8]. These studies have also shown that there was no association between reactivation status and pretreatment serum ALT or bilirubin values. Reactivation of HBV during the course of chemotherapy can manifest itself by the development of jaundice, non-fatal hepatic failure, and death in 22, 4, and 4%, respectively [9] (Table 28.2). Management of patients with HBV infection has been investigated in these studies and it has been shown that prophylactic usage of lamivudine is associated with fewer exacerbations and hepatic failure, although other nucleoside and nucleotide analogues such as adefovir dipivoxil, entecavir, telbivudine, and tenofovir have shown similar effects in these patients [10, 11]. It is not recommended to use interferon in this setting because it may cause much more bone marrow suppression and also can cause exacerbation of hepatitis. Patients should use these drugs at the beginning of chemotherapy and they should be maintained for at least 6 months after the chemotherapy has ended.

Hepatitis C Infection Hepatitis C virus (HCV) infection may also cause cirrhosis and related complications. It often stays undiagnosed in asymptomatic carriers, but may become clinically relevant during periods of immunosuppression or severe illness. Reactivation of HBV is well documented in patients receiving chemotherapy, but this relationship for HCV is less clear.

Table. 28.2  Risk factors associated with HBV reactivation in oncology patients Male sex Younger age HbeAg positive or high levels of HBV DNA Corticosteroid, anthracycline, rituximab-containing chemotherapies Hematologic malignancies

28  Hepatotoxicity and Hepatic Dysfunction

In the literature, there are a growing number of case reports docu­menting fulminant hepatitis after chemotherapy in patients with HCV infection [12, 13]. Most of these reports are related to haematologic malignancies; reactivation or exacerbation in patients being treated for solid tumors is rare. Because the clinical course of HCV infection differs from patient to patient and the mainstay of therapy consists of interferon, there is no current recommendation about the preemptive therapy of HCV (+) patients concurrent with chemotherapy. Often, carefully following transaminase levels and the patient clinically is the mainstay of management.

Non-alcoholic Steatohepatitis Non-alcoholic steatohepatitis is another important condition, which can be a preexisting disease that could be exacerbated by chemotherapy or could develop after chemotherapy. It is associated with fatty accumulation in hepatocytes and necroinflammatory activity [14]. Its prevalence increases in parallel with insulin resistance and obesity. Many case reports and studies demonstrate that chemotherapy is associated with steatosis and steatohepatitis [15]. Most of these reports are from patients with colorectal disease who were treated with neoadjuvant chemotherapy. In most of them, this situation is found to be related to increased postoperative morbidity and mortality [16].

269 Table. 28.3  Common causes of abnormality in liver biochemical tests in cancer patients Direct toxic effect or interactions of chemotherapeutics Viral hepatitis Infiltration of the liver by tumor Compressing bile ducts or big vessels Radiotherapy-related injury Sepsis or fungal liver disease related Total parenteral nutrition and supportive care related Paraneoplastic (e.g., Stauffer Syndrome, associated with renal cell carcinoma) Hemolysis Cardiac failure related (congestive hepatopathy) Graft vs. host disease

Drug induced hepatocellular injury is considered in two groups: 1. Predictable: Direct toxic effect of offending drug on liver tissue. 2. Unpredictable: This type of reaction is usually idiosyncratic. Many of the chemotherapeutic drugs can affect liver function by idiosyncratic reactions [18]. These kinds of reactions are unpredictable and not dose dependent. Also, the latent period between exposure to the drug and the seriousness of the reaction varies between individuals (Table 28.3).

Selected Cytotoxic Agents and their Effects Chemotherapy Induced Hepatotoxicity Alkylating Agents Many drugs can cause alterations in liver biochemical tests, but most of them are not associated with progressive decline in liver function and can be ignored. If the elevation in serum alanine transferase (ALT) is greater than three times the upper limit of the normal value, it is accepted as drug induced liver injury (DILI) [17]. The time of onset and the response to rechallenge are important factors in diagnosing DILI. Most of the DILIs start between 5 and 90 days after starting therapy and decreases of more than 50% of serum liver transferase concentrations are usually seen within 10 days of cessation. DILI usually resolves in 30 days but it can be prolonged to 6 months. Rechallenging with the drug after resolution as well as observing the elevation in liver enzymes again is another sign of DILI. Liver biopsy is needed in rare conditions; this is for persistent liver enzyme elevation for more than 6 months and for distinguishing Sinusoidal Obstruction Syndrome (Hepatic Venoocclusive Syndrome) from hyperacute graft vs. host disease in bone marrow transplants. Hepatocyte necrosis and related hepatocellular failure are the most commonly seen scenarios of many toxic chemotherapeutics at the late stage. Some of the toxic effects are related to damage to the bile system (especially intrahepatic) or harmful effects on endothelial and stellate cells.

Nitrogen mustards, ethylenemines, alkylsulfonates, nitrosoureas, and triazenes are members of this group. Currently commonly used agents of this family are nitrogen mustards: cyclophosphamide, ifosfamide, melphalan, chlorambucil, and mechlorethamine. These groups of drugs are uncommonly related to hepatotoxicity. Mechanisms of hepatotoxicity are less clear. Possible offending causes are reduction in glutathione levels and increased oxidative stress.

Cyclophosphamide Cyclophosphamide is metabolized by liver by the CYP2C9 and 3A4 enzyme systems and converted to 4-hydroxycyclo­ phosphamide. This form appears in the circulation and the blood concentration of this form is in equilibrium with ­aldophosphamide (the other metabolic product). Aldo­phos­ phamide can be ­metabolized by aldehyde dehydrogenase 1 and the end products can be either carboxyethyl phosphoramide mustard or phosphoramide mustard and acrolein by

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s­ pontaneous cleavage. Phosphoramide mustard is the cytotoxic end molecule and acrolein is the toxic metabolite especially for the endothelial cells. This molecule is blamed in both hepatic venoocclusive disease and hemorrhagic cystitis. Despite the metabolism of cyclophosphamide by the liver, at usual doses it is an unusual cause of drug induced liver injury. Rare case reports report cyclophosphamide associated liver toxicity. In most of them, this effect is attributed to an idiosyncratic reaction rather than direct toxicity [19]. Giving cyclophosphamide with azathioprine in the treatment of vasculitis has been associated with serious liver injury. Four cases are reported in the literature and three of them were reported as serious liver injury with hepatic necrosis. In two of them, cyclophosphamide had been used in treatment previously without any toxic effect and elevations in liver enzymes started after adding azathioprine to the therapy [20]. Hepatic venoocclusive disease associated with cyclophosphamide is usually related to higher doses especially in bone narrow transplants. Also other synergistic molecules and modalities such as busulfan, carmustine (BCNU), and total body irradiation can have some additive effect. Susceptibility to hepatic toxicity is not increased in patients with underlying liver disease and hepatic dysfunction. A 25% dose reduction is recommended in patients with serum bilirubin concentration between 50 and 85 mmol/L or alanine aminotransferase higher than 180 IU/ml. The drug is not recommended in patients with serum bilirubin levels higher than 85 mmol/L [21].

Ifosfamide Ifosfamide is another alkylating agent that requires the hepatic p450 oxidase enzyme system for activation. It is very rarely associated with DILI. The liver dysfunction related to ifosfamide is found in only 3% in a metaanalysis of 30 studies including more than 2,000 patients [22]. There is no recommendation about dose reduction in patients with mild to moderate hepatic dysfunction but 75% dose reduction can be recommended in patients with severe hepatic dysfunction (serum ALT >300 IU or bilirubin >50 mmol/L).

Melphalan Melphalan is an agent which is rapidly hydrolyzed in plasma. Nearly 15% of the unchanged drug is excreted in the urine and the remaining part of the drug is excreted through stool. At standard doses, it is not hepatotoxic. But high doses of melphalan (140 mg/m2), which can be used in high dose regimens

A.T. Sümbül and Ö. Özyilkan

for bone marrow transplants, are reported to be associated with mild and transient elevations of serum aminotransferase and billuribin [23]. No serious liver injury associated with melphalan is reported and there is no recommendation for dose modification of this drug in patients with hepatic dysfunction.

Chlorambucil Chlorambucil is another derivate of nitrogen mustard and a rare cause of hepatotoxicity. An autopsy series of patients with leukemia and lymphoma showed that three of six patients with cholestatic hepatitis were reported to have this associated with chlorambucil [24]. But it is important to keep in mind that this is an old review and at the time of publication there were no tests for chronic hepatitis. In another case, reported liver enzymes rose and skin rashes recurred after rechallenging with cholarambucil [25]. There is no recommendation about the dose reduction of chlorambucil in patients with hepatic dysfunction.

Busulfan Busulfan is a weak alkylating agent which is rapidly cleared from the plasma by excretion in the urine as methanesulfonic acid. Hepatic metabolism of the drug seems to be unimportant. Busulfan associated hepatotoxicity is related with oxidative stresses and this is mostly due to depletion of liver glutathione levels. In case reports as a single agent, high dose busulfan toxicity is associated with cholestatic hepatitis [26]. Two case reports have described standard doses of busulfan associated with cholestatic hepatitis. The toxicity of busulfan can be increased with concomitant usage of cyclophosphamide or melphalan which are both glutathione detoxified. Busulfan is also associated with hepatic venoocclusive disease when used in high doses or in combination with cyclophosphamide. Also there is no dose modification recommendation for busulphan in patients with hepatic impairment.

Dacarbazine Dacarbazine is a prodrug activated by microsomal liver enzymes. As with busulphan, dacarbazine is also toxic for endothelial cells through glutathione depletion. It can also cause hepatic venoocclusive syndrome at standard doses and is associated with peripheral eosinophilia and thrombosis of the central venules and veins.

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Temozolomide Temozolomide is an orally active alkylating agent which is commonly used in patients with CNS tumors and malignant melanomas. Metabolism and the toxicity of the drug are not affected by hepatic function. There is no recommendation about dose modification.

Other Alkylating Agents Carmustine, Lomustine, and streptozocin are other alkylating agents which have both alkylating and carbomylating activity. Their hepatotoxic effect is usually associated with glutathione depletion related oxidative injury. Streptozocin can be associated with a cholestatic pattern of hepatic injury. Toxicities of all of these agents are related to mild or moderate elevation of liver function and this toxicity usually resolves after cessation of the causative drug. There is no recommendation about dose modification with hepatic impairment, but close monitoring of liver function tests may be necessary during the therapy.

Antimetabolites The main antimetabolites that are commonly used in ­chemotherapeutic regimens are cytosine arabinoside (ara-c), 5-fluorouracil (5-Fu), 6-mercaptopurine, azothiopurine, 6-thioguanine, methotrexate, and gemcitabine. Their hepatoxic effects are variable but the common features of these drugs are their metabolism in the liver. Therefore, dose reduction is usually needed in patients with hepatic dysfunction.

Cytosine Arabinoside Cytosine arabinoside (ARA-C) is a major drug for treating hematological malignancies. ARA-C is mainly metabolized intracellularly by phosphorylation to the ARA-CTP and this end product inhibits DNA synthesis. The effect of the drug is limited to cells actively proliferating and synthesizing DNA. The liver plays a major role in detoxification of the cytarabine and doses of the drug must be reduced in patients with hepatic dysfunction. Otherwise, toxic effects occur, mainly in the nervous system [27].

There were several case reports which showed cytarabine to be associated with abnormal liver function tests. Most of the cases in the literature have hematologic malignancies, and establishing a diagnosis of drug induced liver injury is very difficult because of confounding risk factors such as sepsis, a multiple transfusion history, and combined use with other drugs. Cytarabine related histologically proven cholestasis was reported as a case report [28, 29]. In conclusion, cytarabine may cause transient elevations in liver tests and this abnormality is generally dose limiting and usually resolves after ending of the therapy [30]. This drug should be used cautiously in patients with severe hepatic dysfunction (ALT > 150 IU and/or total bilirubin > 50 mmol/L) and a 25 % dose modification is recommended in order to avoid drug-associated myelosuppression and neurotoxicity.

Fluorouracil and Capecitabine Fluorouracil (5-FU) is a uracil analogue and mainly eliminated by the liver and peripheral degradation by dihydropyrimidine dehydrogenase enzyme activity. Nearly 15% of the drug is excreted in the urine without change. The active form of the drug (5-fluorodeoxyuridine monophosphate) inhibits thymidylate synthesis in proliferating tissues. Capecitabine is an oral fluoropyrimidine which is in prodrug form. After absorption from the intestinal system, this prodrug is converted to the active form by thymidine phosphorylase. This enzyme’s concentration is higher in tumor tissues than in normal tissues. This feature of the drug is associated with a higher tumor selectivity and better tolerability. 5-FU is shown to be associated with hepatic steatosis [31, 32]. In spite of steatohepatitis, this effect is not related with morbidity or mortality [33]. There are some reports about the relation between bilirubin levels and 5-FU clearance. These data have shown that 5-FU doses should be reduced in patients with hepatic dysfunction. It is recommended to omit the drug if bilirubin levels are more than four times the upper limit of normal. An important point for both 5-FU and capecitabine is their interaction with warfarin; this issue is reported in several case reports [34, 35]. Another caution for 5-FU is for its use in combination with levamisole, oxaliplatin, and irinotecan because of the risk of potentiation of their hepatotoxic effects. Despite these data, there is no relation between capecitabine and liver function, so there is no dosage adjustment in case of hepatic dysfunction.

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Floxuridine Floxuridine (FUdr) is a metabolite of 5-FU and commonly used for intra-arterial treatment of isolated liver metastasis in colorectal cancer. FUdr is a much more potent drug than 5-FU and this is usually associated with more hepatotoxicity. The adverse effects can be developed in two ways: −− Direct toxic effects of the drug to the hepatic cells and these effects are associated with elevations in liver enzymes. −− Damage in the intra or extrahepatic bile ducts. The toxicity of the drug seems to be related to the dose and its duration. Liver transaminase elevations associated with the drug usually resolve after cessation of the drug. It is recommended that liver enzymes be followed at least weekly during therapy with intrahepatic intra-arterial FUdr.

Gemcitabine Gemcitabine is a pyrimidine analogue that inhibits DNA synthesis in proliferating cells. It is commonly used in different cancer types such as breast carcinoma, non-small cell lung carcinoma, and pancreatic cancer. It is mainly eliminated by the hepatic cytochrome p450 enzyme system and 10% of the drug is excreted in the urine without being changed. The drug may cause transient elevations of liver enzymes in up to 60% of patients but these adverse effects are seldom of clinical significance and rarely associated with severe hepatotoxicity [36, 37]. There is no dose recommendation in this setting, but patients with elevated bilirubin levels at the beginning of the therapy have an increased risk of toxicity and caution is advised.

Mercaptopurine Mercaptopurine is a purine analogue mainly used in the maintenance therapy of acute lymphocytic leukemia. The drug is activated by the hypoxanthine guanine phosphoribosyl transferase enzyme to the monophosphate nucleotide. The main effect of the drug is inhibition of de novo purine synthesis. It is mainly metabolized in the liver by the xanthine oxidase enzyme; hepatotoxicity of the drug is usually associated with daily dosing and it is common if the usual daily dose is over 2  mg/kg. The hepatotoxicity may present as cholestatic liver disease and or hepatocellular injury. Both of these effects are related with drug associated direct toxicity. Bland cholestasis with minimal hepatic necrosis, but with significant cytologic atypia, and disorganized hepatic cords of cholestatic pattern are seen at biopsy [38].

A.T. Sümbül and Ö. Özyilkan

In hepatocellular injury, most episodes of jaundice occur within 30 days of starting the therapy, and changing the administration route of the drug (oral to intravenous) does not affect the development of hepatotoxicity. In this picture, moderate elevations of aminotrasferases, alkaline phosphatase, and serum bilurubin levels are usually between 50 and 100 mmol/L. In both situations, abnormality in liver function tests usually resolves spontaneously after cessation of the causative drug. There is no recommendation about usage of this drug in patients with hepatic dysfunction but dose reduction should be considered in order to avoid drug accumulation.

Azathioprine Azathioprine is a nitroimidazole derivative of 6-mercaptopurine and commonly used as an immunosuppressive agent in renal transplant recipients and autoimmune diseases. In comparison to 6-MP, hepatotoxicity of the drug is less frequent, milder, and less dose dependent. Clinical patterns of hepatotoxicity associated with azathioprine are hypersensitivity reactions, idiosyncratic cholestatic reactions, presumed endothelial cell injury with raised portal hypertension, veno occlusive disease (VOD), or peliosis hepatitis [39]. Most of these patterns are reported in renal transplant recipients and in some of them progression of liver abnormalities after discontinuation of the drug is reported. There is no specific recommendation about dose modification in patients with hepatic dysfunction, but close monitoring of liver function tests and avoiding use in patients with severe hepatic dysfunction are reasonable.

6-Thioguanine Thioguanine is an antipurine drug and reported to be associated with hepatic VOD [40]. The drug is rapidly and extensively metabolized in the liver. Elevations of liver enzymes can be seen during the therapy with this drug, but serious hepatic injury is rarely reported. It is recommended to make a 50% dose reduction or avoid use in patients with severe hepatic dysfunction (ALT > 200 IU and/or serum bilirubin > 50 mmol/L).

Methotrexate Methotrexate (Mtx) is a folic acid analogue and commonly used in a variety of malignant and non-malignant diseases. It mainly binds dihydrofolate reductase and inhibits reduction

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of dihydrofolate to its active form tetrahydrofolic acid. This molecule is important for one-carbon transfer reactions that are required for synthesis of thymidylate which is an important precursor for DNA and RNA. At usual doses, Mtx is excreted in the urine without changing but in high doses the drug is partially metabolized to 7-hydroxymethotrexate by the liver [41]. Liver fibrosis and cirrhosis have been reported with maintenance therapy with Mtx in children with acute leukemia. The commonly seen clinical pattern with Mtx therapy is acute transient elevation of liver transaminases. This elevation can be 2–20fold especially in patients who received high dose Mtx despite leucovorin rescue. This pattern of injury usually resolves spontaneously within 1–2 weeks after discontinuation of the drug. The risk is higher in patients treated with a daily dose than in those treated on intermittent dosage schedules. In conclusion, chronic usage of this drug may cause acute elevations in liver function tests. Due to accumulation of the drug in body fluids, especially in third spaces of the body such as ascites or pleural effusions, where these fluids can act as a reservoir for slow distribution of the drug into the plasma, increased systemic exposure with the risk of toxicity can occur [42]. So draining third space fluids or dosage modification of the drug is recommended in patients with malignant effusions. There is no other recommended dose modification in patients with hepatic dysfunction.

Antitumor Antibiotics Members of this drug family are anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin), mitoxantrone, bleomycin, mitomycin, mithramycin (plicamycin), and dactinomycin.

Doxorubicin Doxorubicin is the most widely used member of the family. It acts through DNA intercalation, alteration of membrane function, and formation of free radicals [43]. The drug is mainly metabolized by the liver and nearly 80% of the total drug dose is excreted in the bile. There are a few case reports in the literature about doxorubicin related hepatic injury in patients with acute leukemia. As mentioned before, there are multiple factors which may contribute negatively to the effect of the drug on hepatic dysfunction in these patients. Cholestasis may cause delayed clearance of the drug and its metabolites. This delay can be associated with the development of greater systemic toxicity, such as myelosupression

and mucositis, even in standard doses. However, no increased toxicity has been reported in patients with cirrhosis or isolated elevations in liver transaminases. In conclusion, dosage recommendations for doxorubicin in the context of hepatic function are as follows: −− Bilirubin 20–50  mmol/L or ALT two to four times of upper limit → Administer 50% of the total dose −− Bilirubin >50  mmol/L or ALT more than four times of upper limit → Administer 25% of total dose.

Mitoxantrone Mitoxantrone is an anthraquinone antibiotic. Mitoxantrone has less toxicity than anthracyclines and usually presents itself with transient elevations in liver enzymes. Owing to interactions between mitoxantrone clearance and hepatic function (especially bilurubin levels), it is recommended to make a 50% dose reduction for mild to moderate dysfunction (bilirubin 25–50 mmol/L) and a 75% dose reduction in those with more severe dysfunction (bilirubin > 50 mmol/L).

Bleomycin Bleomycin is an anti-tumor antibiotic which is used in various types of cancers such as lymphomas, germ cell tumors, and various squamous carcinomas. The main mechanism for the drug’s action is through the breakage of double stranded DNA. Nearly 50% of each administered dose of bleomycin is excreted in the urine without change and the other part of the drug is inactivated by aminopeptidases present in many tissues including the liver. This enzyme does not exist in lung and skin, so these parts of the body are most susceptible to bleomycin associated injury. It is reported that bleomycin associated liver injury is a very rare condition, so there is no established recommendation for dosage modification in hepatic injury or dysfunction.

Mitomycin Mitomycin is an antitumor antibiotic that disrupts DNA synthesis like other alkylating agents. It is mainly metabolized in the liver and a small percent (app 10%) of drug is excreted unchanged in the urine. Our present understanding of hepatic function and mitomycin clearance is unclear. There is documented increased myelotoxicity in patients with concomitant hepatic dysfunction [44].

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There are no established dose modification recommendations for mitomycin in hepatic dysfunction but recommendations from reported studies are as follows: −− Fifty percent dose modification at bilirubin levels of 25–50 mmol/L −− Seventy-five percent dose modification at bilirubin levels of >50 mmol/L, hepatic enzymes more than three times of upper limit.

Plicamycin (Mithromycin) Plicamycin is the most hepatotoxic agent that is used in clinical practice. Nowadays it is only used in the treatment of malignant hypercalcemia in rare conditions, so hepatic injury seen with this drug is reported very rarely. Hepatotoxic effects mainly show themselves by elevations of aminotransferases and depression of the synthesis of the coagulation factors such as II, V, VII, and X. Because of alternative choices for this drug, it is recommended to avoid using it in patients with hepatic dysfunction.

Dactinomycin Transient elevations of liver enzymes can be seen during treatment, and this clinical picture appears to be related to the dose. Double doses on alternate days as compared to consecutive 5 day usage showed that hepatotoxicity is more common with consecutive usage. Also this drug is reported to be associated with hepatic VOD. Available data on dose modifications in hepatic dysfunction are limited but it is recommended that a 50% dose reduction be considered in patients with bilirubin levels more than 50 mmol/L.

Dacarbazine Dacarbazine (DTIC) is a potent antitumor antibiotic that is widely used in Hodgkin Lymphoma and Malignant Melanoma. It may cause VOD as a result of hepatic vascular toxicity, and another possible mechanism of hepatic injury associated with dacarbazine is idiosyncratic hypersensitivity reactions. The drug is mainly metabolized in the liver by the hepatic microsomal enzyme system, so clearance of the drug can be affected from hepatocellular damage, but there is no established recommendation about the usage of this drug in patients with hepatic dysfunction.

A.T. Sümbül and Ö. Özyilkan

Vinca Alkaloids Drugs in the vinca alkaloid family mainly act on tubulin and microtubules. Vincristine and vinblastine are members of this group. They are primarily metabolized by liver and excreted through the bile; therefore, in cases of hepatic dysfunction their metabolism will be affected and this may cause serious toxic effects. Mild transient elevation of liver enzymes can be seen during the course of therapy but these are temporary toxic effects. More severe hepatotoxicity can be seen in patients who receive vincristine with concomitant irradiation. Dose adjustments in hepatic dysfunction are as follows: −− Serum bilirubin 25–50 mmol/L or ALT 60–180 IU/L: 50% dose modification −− Serum bilirubin 50–85 mmol/L: 75% dose modification −− Serum bilirubin >85  mmol/L or ALT > 180  IU/L: avoid using

Etoposide Etoposide is a topoisomerase II inhibitor. It is extensively protein bound (nearly 97%) and primarily metabolized in the liver and excreted by the biliary system. It is not hepatotoxic at standard doses but higher doses of the drug may cause hyperbilirubinemia and elevation in liver enzymes. All of these effects are reversible. Clearance of the drug is correlated with serum bilirubin levels, so patients with high bilirubin levels are exposed to high levels of the unbound fraction of the drug and this is associated with subsequent hematologic and other toxic effects of the drug. Dose recommendations in patients with hepatic dysfunction are as follows: −− Bilirubin levels 25–50 mmol/L or ALT 60–180 IU/L: 50% dose modification −− Bilirubin levels 50–85 mmol/L or ALT > 180 IU/L: 75% dose modification −− Bilirubin levels >85 mmol/L: avoid using.

Taxanes Taxanes are also acting on tubules. However, they bind microtubules rather than tubulin dimers. Both paclitaxel and docetaxel are metabolized by the hepatic cytochrome p450 enzyme system and are excreted through the bile; therefore, both drugs clearances are affected by hepatic dysfunction [45].

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For paclitaxel the dose recommendations for three weekly regimens are as follows:

Platinum Derivatives

−− Total bilirubin levels <25 mmol/L and ALT more than two times upper limit of normal: total dose 135/mg m2 −− Total bilirubin levels 26–50 mmol/L: total dose <75 mg/m2 −− Total bilirubin levels≥51 mmol/L: total dose <50 mg/m2

Cisplatin, carboplatin, and oxaliplatin are platinum derivatives. All of them are excreted in the urine but mild transient elevations of the liver enzymes can be seen during therapy with them. In patients with colorectal cancer, combinations of oxaliplatin with 5-FU may cause steatosis, hepatic vascular injury, and nodular regenerative hyperplasia. There is no established dosage modification for platinum derivatives in patients with hepatic dysfunction.

For docetaxel, the dose recommendations are stricter than paclitaxel. Docetaxel should not be used in patients with serum bilirubin levels above the upper limit of normal or AST and ALT >1.5 times the upper limit, concomitant with alkaline phosphatase >2.5 times the upper limit of normal value (ULN).

Tyrosine Kinase Inhibitors Imatinib

Ixabepilone Ixabepilone is a microtubule inhibitor and is mainly used in patients with chemotherapy resistant metastatic breast cancer. It is metabolized in the liver and dosage adjustments in cases with hepatic dysfunction are as follows: −− ALT ≤2.5 times ULN or bilirubin levels ≤1 times ULN: 40 mg/m2 −− ALT ≤10 times ULN and bilirubin levels ≤1 times ULN: 32 mg/m2 −− ALT ≤10 times ULN and bilirubin levels >1.5–3 times ULN: 20 mg/m2

Irinotecan and Topotecan Irinotecan and Topotecan are topoisomerase I inhibitors. Irino­tecan is metabolized in different sites of body such as the intestine, plasma, and liver. The drug is metabolized into two metabolites that are either inactive or an active metabolite (SN-38). The active metabolite of the drug is inactivated by glucuronidation in the liver. In patients with colorectal cancer, the combination of irinotecan with 5-FU may cause steatosis and hepatic vascular injury. There is no dose reduction recommendation for topotecan in patients with hepatic dysfunction but for irinotecan the dosage should be reduced in case of hyperbilirubinemia. Dose recommendation is as follows: [46] −− Serum bilirubin levels 1.5–3 times ULN: reduction of the starting dosage from 350 mg/m2 to 200 mg/m2 for every 3 weeks −− Serum bilirubin levels >3 times ULN: avoid using.

Imatinib was the first commercially widely used tyrosine kinase inhibitor. It inhibits BCR-ABL kinase in chronic myleoid leukemia and gastrointestinal stromal tumors. It is metabolized by the cytochrome p450 enzyme system in the liver. Imatinib may cause mild to moderate elevations of liver enzymes during therapy, and severe and fatal acute hepatic necrosis also has been reported. There is no dosage recommendation for imatinib in patients with hepatic dysfunction.

Lapatinib Lapatinib is a widely used tyrosine kinase inhibitor mainly in HER neu (+) breast cancer. The drug is reported to be associated with severe potentially fatal hepatotoxicity, so it is recommended that liver enzymes be monitored monthly during the therapy. It is recommended to reduce the dose from 1,250  mg/day to 750  mg/day in patients with hepatic dysfunction and avoid using in patients with severe hepatic dysfunction.

Sorafenib Sorafenib is a potent inhibitor of multiple tyrosine kinases and is mainly used in renal cell carcinoma and hepatocellular carcinoma. It is also metabolized in the liver by the cytochrome p450 enzyme system and its use is contraindicated in patients with Child Pugh Class C cirrhosis. There is no recommendation for Child Pugh Class A and B, but results of a phase I study showed that a dose reduction to 200 mg twice daily is needed in patients with a bilirubin 1.5–3 times the upper limit of normal, and cessation of the drug is needed when bilirubin concentration is in excess of this level [47].

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Erlotinib Erlotinib is a tyrosine kinase inhibitor that inhibits epidermal growth factor receptor. It is mainly metabolized in the liver by the cytochrome p450 enzyme system. Clearance of the drug is affected by liver function so it is important to follow the liver function in patients with hepatic dysfunction. Hepatorenal syndrome and fatal hepatic failure can develop during treatment in patients with preexisting moderate to severe hepatic impairment or with multiple medication use in elderly patients [48]. The drug should be discontinued in patients with elevated bilirubin or transaminase levels.

A.T. Sümbül and Ö. Özyilkan

chemo preventive therapy and metabolized by the liver cytochrome p450 enzyme system. Tamoxifen associated liver injuries are non-alcoholic fatty liver disease, peliosis hepatitis, hepatic insufficiency, and rarely hepatocellular cancer. Non-alcoholic fatty liver disease is the most common form of these injuries. There is no recommendation for tamoxifen dosage modification in patients with hepatic dysfunction. Flutamide and megasterol acetate are other hormones commonly used in oncologic patients. Both of them are reported to be associated with cholestatic hepatitis. Their reactions are not dose dependent and usually resolve after cessation of the drug.

Biologic Response Modifiers Interferon

Hepatic Veno Occlusive Disease

Recombinant interferon alfa (IFNa) is used in various types of malignant or myeloproliferative diseases such as hairy cell leukemia, multiple myeloma, Aids related Kaposi’s sarcoma, and non-Hodgkin lymphoma. The drug is usually associated with reversible liver enzyme elevations [49]. Hepatotoxicity may be dose limiting at doses above ten million units daily [50]. The drug is mainly metabolized in the kidney and there is no dosage reduction in patients with hepatic dysfunction.

Hepatic VOD is defined as non thrombotic occlusion of small intrahepatic veins by subendothelial fibrin [52]. It is associated with congestion and potentially fatal necrosis of centrolobular hepatocytes. Bone marrow transplantation (BMT) is a risk factor for developing hepatic VOD. Symptoms of the disease are painful hepatomegaly, rapidly accumulating ascites, or unexplained weight gain and bilirubin >35 mmol/L within 20 days of BMT [53]. Progression is associated with fibrosis and atrophy of centrilobular hepatocytes [52]. Most cases are thought to be drug induced and most suspected drugs are alkylating agents, antimetabolites, high dose cyclophosphamide, busulfan, dacarbazine, dactinomycin, 6-thioguanine, and azothiopurine.

Interleukin 2 Interleukin 2 (IL-2) is another biologic response modifier that is used in the treatment of renal cell carcinoma and malignant melanoma. High dose intravenous IL-2 therapy is reported to be associated with elevations of serum bilirubin levels between 35 and 100 mmol/L. This clinical picture is thought to be associated with intrahepatic cholestasis [51]. Elevation of liver enzymes, hypoalbuminemia, and prolonged prothrombin time are other adverse effects of the drug. Impairment in sinusoidal perfusion and hypoxic damage due to activation of Kuppfer cells, and leukocyte and platelet adhesion to hepatic sinusoidal endothelium are mechanisms of hepatic damage. This toxicity is usually reversible and spontaneous resolution typically occurs within several days after discontinuation of the drug. There is no recommendation for IL-2 dosage adjustment in patients with hepatic dysfunction.

Tamoxifen and Other Hormones Tamoxifen is a nonsteroidal drug that has both anti-estrogenic and estrogenic effects. It is mainly used in breast cancer as

Combination Chemotherapy Regimens Combination chemotherapy is a therapeutic choice in the management of different types of cancers especially in the adjuvant setting. Every single agent has different effects on tumors and different toxicity profiles, so combinations of drugs increase both anti-tumour activity and toxic effects. It is important to follow liver function during therapy with some combinations. Possible hepatotoxic combination regimens are as follows: • • • • • •

Cyclophosphamide + methotrexate + 5-FU Cyclophosphamide + doxorubicin + 5-FU Doxorubicin + 6-Mercaptopurine Busulfan + 6-Thioguanine Carmustine + Etoposide 5-FU + Levamisole

28  Hepatotoxicity and Hepatic Dysfunction

Radiotherapy and Hepatotoxicity Radiotherapy is a hepatotoxic modality even when used in tolerable doses and also may potentiate or cause hepatotoxic effects when combined with normally non-hepatotoxic chemotherapeutic agents. Case report series consisting of 35 lymphoma patients showed that liver irradiation and concomitant vincristine usage may cause moderate to serious hepatotoxic effects. This situation was thought to be associated with delayed transportation of vincristine through the liver and its excretion into the bile [54]. A similar effect has been reported with radiation and doxorubicin [55]. It is important to be aware of hepatotoxicity during radiotherapy to the abdominal region, especially around the liver.

Conclusion As a single agent or combination with other drugs and radiotherapy, chemotherapeutic agents can be associated with mild to severe hepatotoxicity by idiosyncratic reactions or direct toxic effects. Also preexisting liver disease and hepatic dysfunction may alter drug metabolism and increase the risk of non-hepatotoxic toxicity. Many guidelines about dose modification in hepatic dysfunction seem to be empiric. It should be a good approach if a clinician is alert when using some possible hepatotoxic agents such as vinca alkaloids, taxanes, anthracyclines, and etoposide, deciding individually about dose modification on the basis of clinical and laboratory findings for optimal management of cancer patients.

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277 8. Wai CT, Tan BH, Chan CL et al. Drug-induced liver injury at an Asian center: a prospective study. Liver Int 2007; 27:465. 9. Norris W, Paredes AH, Lewis JH. Drug-induced liver injury in 2007. Curr Opin Gastroenterol 2008; 24:287. 10. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med 2006; 354:731. 11. Andrade RJ, Lucena MI, Fernandez MC et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the spanish registry over a 10-year period. Gastroenterology 2005; 129:512. 12. De Pree C, Giastro E, Galatto A et al. Hepatitis C virus acute exacerbation during chemotherapy and radiotherapy for oesaphageal carcinoma. Ann Oncology 1994; 5:861–862. 13. Santini D, Picardi A, Vincenci B et al. Severe liver dysfunction after ralitrexed administration in a HCV positive colorectal cancer patient. Cancer Invest 2003; 21:162–163. 14. Salt WB II. Nonalcoholic fatty liver disease (NAFLD) a comprehensive review. J Insur Med 2004; 36:27–41. 15. Zeiss J, Merrick HW, Savolaine ER, Woldenberg LS, Kim K, Schlembach PJ. Fatty liver change as a result of hepatic artery infusion chemotherapy. Am J Clin Oncol 1990; 13:156–160. 16. Zorzi D, Laurent A, Pawlik TM, Lauwers GY, Vauthey J-N, Abdalla EK. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br J Surg 2007; 94:274–286. 17. Watkins PB, Seeff LB. Drug-induced liver injury: summary of a single topic clinical research conference. Hepatology 2006; 43:618. 18. Lee WM. Drug-induced hepatotoxicity. N Engl J Med 1995; 333:1118. 19. Snyder LS, Heigh RI, Anderson ML. Cyclophosphamide-induced hepatotoxicity in a patient with Wegener’s granulomatosis. Mayo Clin Proc 1993; 68:1203. 20. Shaunak S, Munro JM, Weinbren K et  al. Cyclophosphamide induced liver necrosis: a possible interaction with azathioprine. Q J Med, New Series 1988;252:309–317. 21. King PD, Perry MC. Hepatotoxicity of chemotherapeutic agents. In: The Chemotherapy Source Book, Third Edition, Perry, MC (ed), Lippincott, Williams and Wilkins, Philadelphia, 2001. p. 487. 22. Paschke R, Worst P, Brust J, Queisser W. [Hepatotoxicity with etoposide-ifosfamide combination therapy]. Onkologie 1988; 11:273. 23. Ayash LJ, Elias A, Wheeler C et al. Double dose-intensive chemotherapy with autologous marrow and peripheral-blood progenitorcell support for metastatic breast cancer: a feasibility study. J Clin Oncol 1994; 12:37–44. 24. Amromin GD, Delman RM, Shanbran E. Liver damage after chemotherapy for leukemia and lymphoma. Gastroenterology 1962; 42:401–410. 25. Koler, RD, Forsgren, AL. Hepatotoxicity due to chlorambucil; report of a case. J Am Med Assoc 1958; 167:316. 26. Peters WP, Henner WD, Grochow LB et al. Clinical and pharmacological effects of high-dose single-agent busulfan with autologous bone marrow support in the treatment of solid tumors. Cancer Res 1987; 47:6402–6406. 27. Koren G, Beatty K, Seto A et al. The effects of impaired liver function on the elimination of antineoplastic agents. Ann Pharmacother 1992; 26:363. 28. Pizzuto J, Aviles A, Ramos E et al. Cytosine arabinoside induced liver damage: histopathologic demonstration. Med Pediatr Oncol 1983; 11:287. 29. George CB, Mansour RP, Redmond J 3rd, Gandara DR. Hepatic dysfunction and jaundice following high-dose cytosine arabinoside. Cancer 1984; 54:2360. 30. Donehower RC, Karp JE, Burke PJ. Pharmacology and toxicity of high-dose cytarabine by 72-hour continuous infusion. Cancer Treat Rep 1986; 70:1059. 31. Bateman JR, Pugh RP, Cassidy FR et al. 5-Fluorouracil given once weekly: comparison of intravenous and oral administration. Cancer 1971; 28:907.

278 32. Hohn D, Melnick J, Stagg R et  al. Biliary sclerosis in patients receiving hepatic arterial infusions of floxuridine. J Clin Oncol 1985; 3:98. 33. Zorzi D, Laurent A, Pawlik TM, Lauwers GY, Vauthey JN, Abdalla EK. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br J Surg 2007; 94:274–286. 34. Yildirim Y, Ozyilkan O, Akcali Z, Basturk B. Drug interaction between capecitabine and warfarin: a case report and review of the literature. Int J Clin Pharmacol Ther 2006; 44(2):80–82. 35. Aki Z, Kotilo lu G, Ozyilkan O. A patient with a prolonged prothrombin time due to an adverse interaction between 5-fluorouracil and warfarin. Am J Gastroenterol 2000; 95(4):1093–1094. 36. Robinson K, Lambiase L, Li J, Monteiro C, Schiff M. Fatal cholestatic liver failure associated with gemcitabine therapy. Dig Dis Sci 2003; 48:1804–1808. 37. Saif MW, Shahrokni A, Cornfeld D. Gemcitabine-induced liver fi brosis in a patient with pancreatic cancer. JOP 2007; 8:460–467. 38. McIlvanie SK, MacCarthy JD. Hepatitis in association with prolonged 6-mercaptopurine therapy. Blood 1959; 14:80–90. 39. Romagnuolo J, Sadowski DC, Lalor E et al. Cholestatic hepatocellular injury with azathioprine: a case report and review of the mechanisms of hepatotoxicity. Can J Gastroenterol 1998; 12:479. 40. Griner PF, Elbadawi A, Packman CH. Veno-occlusive disease of the liver after chemotherapy of acute leukemia. Report of two cases. Ann Intern Med 1976; 85:578. 41. Leme PR, Creaven PJ, Allen LM, Berman M. Kinetic model for the disposition and metabolism of moderate and high-dose methotrexate (NSC-740) in man. Cancer Chemother Rep 1975; 59:811. 42. Evans WE, Pratt CB. Effect of pleural effusion on high-dose methotrexate kinetics. Clin Pharmacol Ther 1978; 23:68. 43. Farrell GC. Drug-Induced Liver Disease. Churchill Livingstone, New York, 1994. 44. Buroker TR, Kim PN, Baker LH et  al. Mitomycin-C alone and in combination with infused 5-fluorouracil to the treatment of disseminated gastrointestinal carcinomas. Med Pediatr Oncol 1978; 4:35.

A.T. Sümbül and Ö. Özyilkan 45. Hirth J, Watkins PB, Strawderman M et al. The effect of an individual’s cytochrome CYP3A4 activity on docetaxel clearance. Clin Cancer Res 2000; 6:1255. 46. Mathijssen RH, van Alphen RJ, Verweij J et al. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res 2001; 7:2182. 47. Ramanathan RK, Egorin MJ, Takimoto CH et al. Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol 2008; 26:563. 48. Hirth J, Watkins PB, Strawderman M et al. The effect of an individual’s cytochrome CYP3A4 activity on docetaxel clearance. Clin Cancer Res 2000; 6:1255. 49. Alert letter available online at http://www.fda.gov/medwatch/ safety/2008/tarceva_dhcp.letter.pdf, accessed September 24, 2008). 50. Kim YH, Mio T, Mishima M. Gefitinib for non-small cell lung cancer patients with liver cirrhosis. Intern Med 2009; 48:1677. 51. Kirkwood JM, Ernstoff MS. Interferons in the treatment of human cancer. J Clin Oncol 1984; 2:336. 52. Rollins BJ. Hepatic veno-occlusive disease. Am J Med 1986; 81:297–306. 53. Carreras E. Veno-occlusive disease of the liver after hemopoietic cell transplantation. Eur J Haematol 2000; 64:281–291. 54. Wanless IR, Godwin TA, Allen F et al. Nodular regenerative hyperplasia of the liver in hematological disorders: a possible response to obliterative portal venopathy. A morphometric study of nine cases with a hypothesis on the pathogenesis. Medicine 1980; 59:367. 55. Fleming DR, Wolff SN, Fay JW et al. Protracted results of doseintensive therapy using cyclophosphamide, carmustine, and continuous infusion etoposide with autologous stem cell support in patients with relapse or refractory Hodgkin’s disease: a phase II study from the North American Marrow Transplant Group. Leuk Lymphoma 1999; 35:91.

Part X

Urogenital

Chapter 29

Urological Symptoms and Side Effects of Treatment Ehtesham Abdi

Introduction

leads to stretch receptors that trigger pelvic nerve fibres which, unless inhibited by higher centres, will lead to a paraUrological problems in patients with advanced cancer are sympathetic motor response and bladder contraction. infrequent [1]; however, they cause significant physical and Parasympathetic system activation causes the detrusor musmore importantly psycho-social problems. Many of urological­ cle to contract and bladder neck sphincter to relax, whereas complications and symptoms can be very serious, life threat- the sympathetic system has the opposite effect to that of the parasympathetic system. ening and can adversely affect a patient’s quality of life. Metastatic disease may involve the lower thoracic and The discussion focuses on symptom control in patients upper lumbar vertebrae and can cause spinal cord compreswith advanced cancer who have developed urinary tract dysfunction. In the palliative care setting, management decisions sion or nerve root injury. These neurological complications and discussions should focus on the appropriate option in the may interfere with normal voiding. Many drugs, frequently context of the patient’s overall situation. Biological, social used for palliation of symptoms in advanced cancer, can also and spiritual factors need to be taken into account and most affect bladder motility and neuromuscular function. Antiimportantly the patient’s and family’s wishes, the pre-morbid cholinergic drugs may cause relaxation of the detrusor mushealth of the patient and adequacy of existing symptom con- cle associated with contraction of the bladder neck sphincter. trol, rate of disease progression and the cost-benefit analysis Other drugs, such as haloperidol, phenothiazines and tricyof invasive investigation and intervention. Emphasis is placed clic antidepressant (TCA) have cholinergic properties. Antion less aggressive but effective interventions in keeping with cholinergic agents are particularly troublesome in the elderly the general physical health of these patients. However, in and in patients with pre-existing bladder dysfunction. A few some situations, more complex, invasive procedures are patients, upon first use of opioids, may develop temporary appropriate and should primarily be aimed at improving the urinary retention. Strong opioids, otherwise, do not affect bladder function unless there are other underlying problems quality of life and symptomatic improvement. such as faecal impaction. Acute urinary retention causes distension of the bladder wall, producing significant physical symptoms. Pain and disPhysiology of Voiding comfort from urinary tract obstruction, metabolic changes and impaired renal function may all cause mental confusion The normal act of voiding involves a functioning detrusor especially in the elderly. Cancers involving the retroperitoneum or the pelvis may muscle, an intact bladder wall and integrity of the nerves cause upper-urinary-tract obstruction whereas conditions of coordinating detrusor and vesical sphincter activities. The the bladder neck, prostate or urethra can cause lower tract bladder receives its principal nerve supply from one-paired obstruction. Pelvic tumours may locally infiltrate the bladder somatic nerves and two-paired autonomic nerves. The hypowall or other local organs causing fistulae. Haematuria may gastric nerves coordinate sympathetic activity, while the ­pelvic nerves contain parasympathetic fibres. The pudendal be caused by upper- or lower-urinary-tract pathology. The nerves provide non-autonomic fibres. Bladder wall distension­ possibility of spinal cord or nerve root damage, biochemical abnormalities such as hypercalcaemia, hyperglycaemia and diabetes insipidus presenting as urinary symptoms needs to E. Abdi (*) be kept in mind. Department of Medical Oncology, Cancer and Aged Care, Griffith The broad category of urological problems in advanced University, The Tweed Hospital, Tweed Heads, NSW, 2485, Australia cancer is as follows: e-mail: [email protected]

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_29, © Multinational Association for Supportive Care in Cancer Society 2011

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1 . Incontinence 2. Haematuria 3. Bladder outlet obstruction 4. Ureteric obstruction 5. Irritative voiding symptoms 6. Pain

Urinary Incontinence Urinary incontinence is defined as the involuntary leakage of urine. If not properly managed, urinary incontinence can lead to perineal rashes, pressure ulcers and urinary tract infections (UTIs) and may increase the risk of urosepsis, falls and fractures [2]. The commonest and the most significant type of urinary incontinence is urethral incontinence or extraurethral loss from urinary fistulae.

Total Urethral Incontinence Direct tumour invasion, surgical procedures or neurological damage from malignancy may cause urethral ­sphincter dysfunction. A careful history and physical examination, cystoscopic examination and, where appropriate, ­urodynamic studies confirm urethral sphincter abnormality. Spinal cord or nerve root damage is often associated with other motor or sensory nerve symptoms and signs. Most patients with urethral incontinence require an indwelling catheter; however, some men may manage condom ­drainage or a penile clamp. In patients with less advanced disease, artificial urethral sphincters may be a ­consideration [3].

Overflow Incontinence Bladder outlet or urethral obstruction may lead to overflow incontinence. Overflow incontinence is usually associated with acute pain and distress and urinary retention, and voiding occurs without control and in small amounts. The urinary bladder is usually palpable, distended and tender. Following placement of an indwelling urethral catheter definitive treatment involves surgical or other means to decompress the bladder. Treatment needs to be individualised but may consist of long-term suprapubic or urethral catheter, intermittent self-catheterisation or an intraurethral stent.

E. Abdi

Urge Incontinence Intrinsic or extrinsic bladder tumours, inflammation from radiation or chemotherapy or active UTI may irritate the trigone or bladder neck causing pain and sudden the urge to urinate. The presence of other physical disabilities and immobility may further aggravate urge incontinence. Treatment of urge incontinence includes the use of anti-cholinergic drugs, such as oxybutynin to reduce detrusor overactivity.

Stress Incontinence A socially embarrassing problem is that of urinary incontinence with coughing, sneezing or laughing. These physiological acts cause an increase in intra-abdominal pressure with consequent involuntary urinary incontinence. Physiologically, stress incontinence is due to abnormal urethral support. The usual treatment for this condition is surgery; however, in patients with advanced cancer, non-surgical measures need to be considered. The medical treatment is either a TCA or an alpha-adrenergic agonist such as phenylpropandamine [4]. If medical therapy is ineffective, longterm urethral catheterisation may be necessary.

Haematuria Gross haematuria can be a very frightening symptom; however, the degree of urinary bleeding does not always correlate with the extent or the seriousness of the underlying aetiology [5]. Some patients with bladder or kidney abnormalities present with frank haematuria. However, many patients only have biochemical or microscopic haematuria. A positive dipstick test will require microscopic confirmation of the presence of red blood cells in the urine. In most cases, a careful history, including the type and timing of bleeding, presence of clots and association of pain with urination can point to the site of urinary tract bleeding. The presence of bright red blood suggests bleeding from the prostate or the urinary bladder whereas darker blood often originates from the upper urinary tracts and kidney. Urethral bleeding usually presents with initial haematuria followed by clear urine. If blood is present throughout the urinary stream then bleeding may be from the kidney, ureter or bladder, whereas terminal haematuria is likely to be from the bladder neck or prostatic urethra. If haematuria is associated with symptoms of dysuria, urinary frequency and urgency, then UTI needs to be excluded. Anticoagulants, non-steroidal anti-inflammatory (NSAID)

29  Urological Symptoms and Side Effects of Treatment

and anti-platelet drugs may lead to platelet dysfunction and cause microhaematuria. For proper and adequate assessment of the bladder, a complete cystourethroscopy is required when upper-tract imaging studies do not establish the cause of haematuria. Treatment needs to be individualised, based on the underlying aetiology.

Haematuria of the Upper Renal Tract Investigations for haematuria [6] include microscopy and urine culture, urine cytology and radiological examination of the kidneys, ureters and the bladder and, if appropriate, cystoscopy. Bleeding from the upper urinary tract is often confused with renal colic or acute ureteric obstruction causing acute flank pain. A clot causing complete ureteric obstruction can present without clinical haematuria. Although uncommon, gross haematuria due to upper renal tract pathology can occur. A careful history and selective radiological studies are able to differentiate between renal colic and complete ureteric obstruction from a clot or a tumour. In a patient with upper urinary tract obstruction, acute onset flank pain and no previous history of renal stones, the problem is more likely caused by clot or tumour than a stone. Initial radiological studies to investigate haematuria include standard intravenous pyelogram (IVP) and renal ultrasound. Cystoscopy and retrograde pyelogram may be required to identify upper urinary tract pathology. Spiral CT scans can also locate ureteric obstruction, and possibly the aetiology of haematuria. A renal arteriogram may be necessary to exclude an arteriovenous fistula. In patients with painless haematuria, cystoscopy and retrograde studies may identify the site and source of bleeding if it is performed at the time of active bleeding. However, further diagnostic procedures including selective ureteric catheterisation for cytology, or ureteroscopy, may be required for definitive therapy for the underlying cause [7]. Renal cell carcinoma of the kidney or transitional cell carcinoma of the renal pelvis, or ureter, or a calculus are the most likely causes of upper renal tract bleeding. If a renal tumour is identified, and staging imaging studies show no metastatic disease, a radical nephrectomy is the definitive therapy. For transitional cell carcinoma of the upper tract, radical nephroureterectomy can be performed. In the presence of extensive metastatic disease or if other co-morbid conditions exist, radical surgery would usually be contraindicated. Many patients, however, may tolerate a laparoscopic nephrectomy or nephroureterectomy that cause much less morbidity and seem to achieve as good an outcome as open surgery in some centres [8, 9]. When surgical

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measures are inappropriate, bleeding from a renal cell ­carcinoma can be controlled by chemoembolisation of the renal artery [10]. If bleeding persists, palliative nephrectomy may be required despite the presence of metastases [11]. For patients who have indwelling ureteric stents and develop frank haematuria, arteriography is needed to exclude a potential iliac vessel fistula in the ureter. An elective embolisation or vascular stenting may be possible in this situation. Medical management of controlling haemorrhage from upper urinary tracts may be necessary under certain situations when surgical means are inappropriate. Forced diuresis by increasing oral and intravenous fluids may help dilute the blood and prevent clot formation. Anti-fibrinolytics, such as e-aminocaproic acid (EACA) and tranexamic acid are used as inhibitors of fibrinolysis. These lysine-like drugs interfere with the formation of the fibrinolytic enzyme plasmin from its precursor plasminogen, by plasminogen activators, which take place mainly in lysine-rich areas on the surface of fibrin. These drugs block the binding sites of the enzymes or plasminogen, respectively and thus stop plasmin formation. Tranexamic acid is an anti-fibrinolytic that competitively inhibits the activation of plasminogen to plasmin, a molecule responsible for the degradation of fibrin. It has roughly eight times the anti-fibrinolytic activity of the older analogue, EACA. Systemic EACA administration can, in rare situations, be considered for upper renal tract haemorrhage; however, this approach needs very careful consideration. EACA administration may lead to the formation of large tenacious clots that can produce ureteric obstruction. If no obvious cause or location of upper renal tract haemorrhage is identified in a patient who is very symptomatic from the bleeding, and when all other conservative measures have failed, nephrectomy or ureterectomy is an option. Patients with advanced renal cell carcinoma may develop bleeding and clot formation. Palliative measures in this situation include radiation therapy or newer targeted systemic therapies [12, 13]. With laparoscopic and partial nephrectomy being used more frequently and successfully, surgical means to deal with bleeding from renal cell carcinoma remain a viable option [14].

Haematuria from Lower Renal Tract A majority of patients who present with microscopic haematuria are clinically asymptomatic. The source of this microscopic bleeding is usually the lower urinary tract. Microscopic haematuria rarely leads to anaemia. Non-invasive procedures such as IVP, renal ultrasound and CT scans may detect pathologies that may obviate the need for invasive procedures such as a cystoscopy. However, ureterocystoscopy may

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detect a malignancy such as transitional cell carcinoma (TCC) of the ureter that radiological studies may not identify. Flexible cystoscopy is now widely available and is a much better tolerated procedure [15] in frail patients and it may not be any more uncomfortable than simple urethral catheterisation.

Symptomatic Lower Tract Haematuria Macroscopic haematuria may occur without a change in the voiding pattern. Clot retention causes painful and tender bladder distension due to accumulation of blood clots and urine. If prolonged and untreated, clot retention may lead to renal failure. Pain and discomfort causes patients to become restless. In general, most patients do not lose much blood in their urine, although it might be a frightening experience; however, in a number of patients bleeding may be severe enough to cause hypotension and shock. Physical examination should include rectal examination in men for prostatic abnormalities and of the pelvis in women for gynaecological causes. Patients with frank haematuria need increased fluid intake to dilute the blood in the bladder and reduce clot formation. All anticoagulants should be ceased to minimise ongoing bleeding. A large-bore multi-eyed urethral catheter (24F or 26F) is required to completely evacuate the clots from the bladder and for subsequent vigorous bladder irrigation with water or saline to keep the bladder free of clots. After satisfactory manual irrigation, a 22F or 24F three-way indwelling catheter is inserted for cold water or saline continuous bladder irrigation (CBI). Suprapubic catheters are not large enough to provide adequate irrigation for evacuation of clots. A small number of patients, however, may continue to bleed or have obstruction of the irrigating catheter from clots and require evacuation of clots by cystoscopy or cautery. Apart from malignancies of urological tract, lower urinary tract haematuria can occur due to other causes. Haemorrhagic cystitis often occurs following treatment for cancer. Haematuria caused by cytotoxic drugs does not usually cause irritative voiding symptoms. Cyclophosphamide and ifosphamide are the agents most likely to cause haemorrhagic cystitis. The risk of haemorrhagic cystitis after cyclophosphamide is reported to be up to 40% [16]; however, with most standard doses the expected risk is about 5%. The active metabolite of cyclophosphamide is acrolein, and this agent is believed responsible for causing mucosal damage [17, 18]. 2-Mercaptoethane sulphonate (Mesna) is a sulphydryl compound that reacts with the metabolites of cyclophosphamide that may produce bladder wall irritation. Mesna is converted in the blood to a biochemically inactive compound that is reduced back to mesna in the kidneys. In vivo mesna is a chelating agent that binds acrolein, hence it protects the blad-

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der mucosa without interfering with the cytotoxic effect of cyclophosphamide or iphosphamide [19, 20]. For bleeding refractory to conservative measures, topical agents can be used with varying degrees of success. Intravesical administration of formalin is one of the most effective but also the most toxic treatment for haemorrhagic cystitis. Formalin stops bleeding by fixing the bladder mucosa by cross-linking proteins, thereby preventing necrosis, sloughing and blood loss. Formalin instillation carries greater risk, including perforation and bladder fibrosis [21]. Formalin at a 2.5–4% concentration is instilled passively into the bladder using low-pressure gravity feed over 20–30 min. The bladder is then irrigated continuously with normal saline. Intravesical formalin requires general or regional anaesthesia because the procedure can be quite painful [22, 23]. Reflux of formalin to the ureters and kidneys can lead to fibrosis, obstruction, hydronephrosis and renal papillary necrosis. The presence of vesicoureteral reflux requires prophylactic ureteric balloon catheters to prevent retrograde flow of formalin. Case reports and non-randomised studies report up to 80% efficacy of formalin in controlling haemorrhage from the bladder [24–26]. As intravesical formalin can lead to fibrosis of bladder mucosa and a scarred and contracted bladder, this therapy must be reserved for haemorrhagic cystitis that is truly refractory to all other treatments. For acute vesical haemorrhage a 10–20  min intravesical instillation of 0.5–1.0% silver nitrate in sterile water has also been reported. In refractory cases, multiple instillations of silver nitrate may be required [27]. No controlled randomised trials of silver nitrate have been done. EACA works as an anti-fibrinolytic or anti-proteolytic agent and can be used to treat bladder mucosal haemorrhage. EACA can be given either orally, parenterally or intravesically [28–30]. Although there has been widespread use of EACA, most of the studies have been uncontrolled; however, clinical experience of many years’ duration may justify its use for severe haemorrhagic cystitis. A loading dose of 5 g is given followed by hourly doses of 1.00–1.25 g. Bleeding should stop within 8–12 h. If bleeding is successfully controlled, maintenance EACA therapy with total oral daily dosage of 6–8 g divided into four doses is given. If administered intravesically, EACA is given as continuous irrigation. To each litre of normal saline 200  mg EACA is added and the irrigant is administered as CBI. However, EACA causes thick clots, which are very difficult to irrigate in patients with normal urethral catheters. To control haemorrhage from upper renal tracts, EACA is therefore contraindicated as the thick clots cause upper renal tract obstruction, clot colic and, potentially, renal failure. Another topical agent, ammonium salt of aluminium, 1% solution of alum, administered intravesically and CBI, also has shown modest efficacy in stopping bleeding from the urinary tract [31]. Alum administration is relatively safe, nontoxic and does not require general anaesthesia. Intravesical

29  Urological Symptoms and Side Effects of Treatment

administration of carboprost tromethane, an F2-a prostaglandin has been used to treat cyclophosphamide haemorrhagic cystitis. Carboprost tromethamine is administered as intravesical solution at a concentration of 0.4–1.0 mg/dL for 2  h, four times per day, alternating with continuous saline bladder irrigation for 2 h, during 4–5 days [31]. Both external beam radiation and brachytherapy for cancers of genitourinary tract, cervix, rectum or other pelvic cancers may cause haemorrhagic cystitis. Haemorrhagic cystitis can occur 6 months to 10 years after pelvic radiation therapy with moderate to severe rates of haematuria at 3–5% after radiotherapy for pelvic malignancies [32]. Radiation cystitis usually presents with haematuria, dysuria, urinary frequency and urgency. Late effects of radiation therapy generally result from a combination of vascular damage through radiation endarteritis in combination with a loss of parenchymal cells. Radiation endarteritis leads to significant vascular changes with consequent hypoxia, telengiectasiae, hypovascularity and hypocellularity several years after initial therapy. Radiation therapy may also cause depletion of the stem-cell population below levels needed for tissue repair [33]. Such loss of stem cells leads to an inability to replace normal collagen and cellular losses leading to tissue breakdown and healing. If severe, these changes may eventually result in tissue fibrosis. Unlike chemotherapy-induced haemorrhagic cystitis, there are no preventative agents or measures in common use. For radiationinduced haemorrhagic cystitis, aggressive symptomatic therapy is needed and further radiation exposure is to be avoided. Radiation-induced haemorrhagic cystitis has been treated with hyperbaric oxygen with significant success [32]. Obliterative endarteritis secondary to ionising radiation leads to tissue hypoxia and poor healing. Hyperbaric oxygen therapy has been demonstrated to improve angiogenesis and promote healing in radiation injured tissue by formation of healthy granulation tissue, including the bladder [34]. Hyperbaric oxygen given at the time of initial radiation therapy may also prevent the long-term risk of haemorrhagic cystitis [34]. Hyperbaric oxygen can reverse some of the ischaemic changes caused by radiation therapy. Furthermore, hyperbaric oxygen induces vasoconstriction with direct effects on bleeding from the bladder mucosa. Hyperbaric oxygen therapy is effective in up to 75–80% of treated patients especially if commenced within 6  months of the development of radiation-induced haemorrhagic cystitis. Treatment efficacy seems to be independent of prior intravesical therapy and the timing of radiotherapy [35, 36]. Conjugated oestrogens have also been used for the treatment of cancer therapy-induced haemorrhagic cystitis [16, 37]. The recommended starting dose of conjugated oestrogens is 2.5 mg twice daily followed by a maintenance dose of 0.625–1.25 mg daily. Due to the cardiovascular toxicities of conjugated oestrogens, the lowest effective dose of oestrogen should be used. However, in a patient with poor perfor-

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mance status and uncontrolled urinary tract haemorrhage, conjugated oestrogen therapy may be a consideration. Recurrent haemorrhagic cystitis due to locally advanced unresectable cancer may respond to oral pentosan polysulphate [34]. Rarely oral tranexamic acid could be used as this drug can cause clot formation [25]. Rarely hypogastric artery ligation or embolisation, or proximal urinary diversion with or without cystectomy may be the procedures of last resort. If the bleeding is coming from the prostate or bladder neck, a TURP is required to resect the abnormal prostatic tissue. The friable area is electrocoagulated to prevent further bleeding. A urethral catheter on traction may further compress the bleeding vessels in the prostate and bladder neck. However, despite TURP or TURBT, chronic haematuria secondary to abnormal prostatic pathology may recur. Finasteride, a synthetic anti-androgen inhibits type II 5-alpha reductase, the enzyme that converts testosterone to dihydrotestosterone (DHT). Finasteride is used in treating benign prostatic hyperplasia for decreasing the risk of urinary retention and haematuria as well as for the treatment of hair loss. Finasteride decreases suburethral prostatic microvessel density, and significantly lowers VEGF expression at the suburethral but not at the hyperplastic prostate level. Bleeding observed in patients with BPH and obstructive voiding symptoms may be due to increased neovascularity within the prostatic urethra rather than the hyperplastic prostate zone [38]. Finasteride induces a reduction in the density of prostatic microvessels, thereby helping to reduce bleeding [38]. A few non-randomised clinical studies confirm that finasteride reduces the severity and frequency of recurrent haematuria due to bleeding from the prostate [39, 40]. However, most of the clinical trials of finasteride have been in benign prostatic hyperplasia and its role and effectiveness in haematuria caused by prostate cancer has not been confirmed. As finasteride has relatively few side effects, in recurrent prostatic bleeding it could be used empirically (Fig. 29.1). Patients, who fail conservative measures, may require total cystectomy and urinary diversion to control refractory haemorrhagic cystitis. However, the outlook of these patients is extremely poor and most of these patients are poor surgical candidates because of ongoing haemorrhage and coagulopathy. In seriously ill patients, who are not suitable for major surgical intervention, selective embolisation of branches of the hypogastric arteries may be successful in stopping bleeding. Selective embolisation works best when arteriography demonstrates a discreet vessel responsible for the bleeding; however, in most patients such discreet sources of bleeding cannot be identified as the entire bladder urothelium is usually involved in bleeding. Permanent embolotherapy is now carried out with new, more thrombogenic coils made of either platinum or titanium [41]. Complications of arterial embolisation include claudication of the gluteal muscles, temporary

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Fig. 29.1  Algorithm for management of haematuria

lower extremity paralysis and even necrosis of the bladder [41–44].

Urinary Outlet Obstruction Urinary tract obstruction can occur throughout the urinary tract, from the kidneys to the urethral meatus. Causes of unilateral or bilateral obstruction include calculi, tumours,

strictures and anatomical abnormalities. Anatomically, ­certain parts of the urinary tract are more susceptible to obstruction. Narrowing of the ureters can occur at the pelviureteric junction, the pelvic brim and the ureterovesical junction. In women, the distal ureter, as it crosses posterior to the pelvic blood vessels and the broad ligament in the posterior pelvis is another potential site of obstruction. Furthermore, urinary tract obstruction can also occur due to the external compression of the ureters by gynaecologic malignancies.

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29  Urological Symptoms and Side Effects of Treatment

Bladder Neck and Lower Urinary Tract Obstruction In men, common causes of lower urinary tract obstruction include malignancies of the prostate gland as well as local invasion of tumours of the rectum or urethra. Bladder neck obstruction occurs much less frequently in women than in men. In women, locally advanced cancers of the ovary, cervix or the uterus can also cause bladder neck obstruction. Prolonged complete bladder neck obstruction may lead to renal failure due to chronic urinary retention and especially if sepsis is superimposed. In the presence of bladder neck obstruction, detrusor muscles may not be able to overcome urethral resistance; hence, the bladder is unable to be emptied. Neuropathic causes may lead to primary failure of detrusor muscles. Patients with symptoms of urinary frequency, urgency, nocturia and a poor urinary stream, with or without haematuria, frequently have mechanical lower urinary tract obstruction. Patients with a poor urinary stream, abnormal voiding urgency or sensation and decreased urinary frequency have primary detrusor failure. As the management of these disorders differs significantly, it is critical to make an appropriate diagnosis before initiating therapy (Table 29.1). A comprehensive history of presentation, use of medication (e.g. anti-cholinergics, opioids), past medical history (diabetes, calculi, tumours, radiation therapy, retroperitoneal fibrosis and neurologic disorders) and past surgical history are helpful in identifying potential causes of obstruction. Complete urinary retention is usually preceded by gradually progressive symptoms of urinary obstruction including urinary hesitancy, frequency, nocturia, incontinence, UTI, poor urinary stream and incomplete bladder emptying. Urethral stricture may occur due to previous urethral trauma, surgery or infection. Furthermore, anti-cholinergic or a-adrenergic drug use may also cause urinary bladder obstruction. Usually, the bladder is palpable and painfully distended. Cystoscopic studies are required to diagnose meatal stenosis, urethral fibrosis, induration or tumourrelated stricture. A urethral or, more frequently, a suprapubic catheter will decompress the bladder. If the bladder obstruction has been present for some time, the sudden relief of obstruction may lead to a significant post-obstructive diuresis. In the event of prostatic enlargement causing urinary obstruction, a limited transurethral prostatectomy (‘channel TURP’) may achieve good palliation; however, surgical procedures in these patients may be associated with increased risk of bleeding, clot retention, infection and persistent failure to void.

Table 29.1  Pharmacological management of urological disorders Problem Drug therapy Usual dose Haematuria from prostate Haematuria from prostate Painful bladder/ interstitial cystitis Irritative symptoms Urge incontinence Irritative symptoms Bladder antispasmodic Bladder antispasmodic Bladder antispasmodic Irritative symptoms Detrusor instability Extrinsic bladder compression; irritation Detrusor overactivity Eosinophilic cystitis Detrusor overactivity Interstitial cystitis Intravesical foreign body/ calculus Atrophic vaginitis Detrusor instability Detrusor instability Irritative symptoms

Finasteride

5 mg daily

Dutasteride

0.5 mg daily

Pentosan polysulphate

100 mg tds

Oxybutynin

2.5–5 mg qid

Oxybutynin ER

5–15 mg daily

Oxybutynin transdermal patch Tolterodine

Twice per week

Tolterodine ER

4–8 mg daily

Tolterodine transdermal patch

Twice per week

Trospium XR

20 mg daily

Solifenacin

5–10 mg daily

Darifenacin

7.5–15 mg daily

Flavoxate

100–200 mg PO qid

Hyoscyamine

0.125–0.5 mg oral or sl

Dicyclomine SR

10–20 mg PO qid

Belladonna and opium Suppository Phenazopyridine

3–4 h prn

2–4 mg bd

200 mg orally tds

Oral anti-cholinergics Propantheline bromide Imipramine chlorhydrate Intravesical botulinum toxin A

7.5–15 mg qid 10–25 mg bd Not yet established

Symptomatic Treatment Bladder neck obstruction due to prostatic enlargement requires urethral catheterisation for symptom relief. In addition, medical therapy using one of the selective a-1 antagonists may be required. These drugs work by blocking the action of adrenaline on the smooth muscle of the bladder and

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the blood vessel wall. Drugs of this family include terazosin, doxazosin, alfuzosin or tamsulosin. These drugs are known to be effective in benign prostatic hyperplasia but their benefit in advanced prostate cancer or in patients with other comorbidities, debility and poor performance status is less well known but the likelihood of recovery of adequate bladder detrusor function is small. If conservative measures fail to decompress the obstruction, more-invasive measures including long-term urethral or suprapubic catheterisation, intermittent self-catheterisation, urethral stenting, urinary diversion or resection of the obstructing lesion may be needed. In patients with malignant tumours, definitive measures should be considered much earlier as recovery of bladder function in this setting is much slower and often incomplete.

Androgen Suppression Therapies A majority of patients with newly diagnosed and locally advanced prostate cancer respond to androgen suppression therapy and this treatment may be preferable to surgery [45, 46]. Luteinising hormone stimulates Leydig cells in the testes to produce testosterone, which is converted to dihydrotesterone (DHT) by the action of 5a-reductase [47]. DHT binds to intracellular androgen receptors. Androgen suppression therapy for prostate cancer is aimed at reducing circulating testosterone to levels seen in castrate men. Low testosterone levels cause apoptosis in neoplastic prostate cells, with little or no acute effect on non-androgen target tissues. Although androgen deprivation therapy (ADT) can be achieved by bilateral orchidectomy, medical castration with luteinising hormone-releasing hormone (LHRH or GnRH) analogues with or without an anti-androgen therapy is nowadays the preferred approach. Immediately after commencement of LHRH analogue therapy, there is a surge in testosterone levels, which may cause spinal cord compression from vertebral metastases as well as aggravate bone pain. Concomitant administration of an anti-androgen agent, 1–2 weeks prior to the start of GnRH therapy, avoids the flare phenomenon. If satisfactory voiding does not occur within 2–3  weeks, a TURP, other surgical treatments or long-term catheterisation will be required. Patients with advanced prostate cancer, who either develop obstructive uropathy while on ADT or whose obstructive uropathy fails to adequately respond to ADT, have very poor survival [48].

Self-Catheterisation For patients with mechanical bladder outlet obstruction ­self-catheterisation or a chronic indwelling catheter is not

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appropriate and is best for those with urinary retention due to detrusor failure. Patients with urinary retention who are physically capable and motivated may be suitable for clean intermittent self-catheterisation. This approach causes less urinary tract infection than either urinary retention or an indwelling catheter and allows the patient to spend most of the day without a urethral catheter [49]. Chronic indwelling urethral catheters can be associated with infection, urethral stricture, epididymitis and symptoms associated with a defunctional bladder. These methods are suitable for patients who are unfit for surgery or those who choose not to undergo a surgical procedure to decompress the bladder. The amount of residual urine in the bladder must be monitored to prevent upper urinary tract complications due to residual urine at high pressures. Despite clean intermittent catheterisation, most patients develop asymptomatic pyuria and bacteriuria. Empirical broad-spectrum antibiotic therapy should be avoided unless there is systemic evidence of urinary infection. Chronic low-dose antibiotics may be justified in patients with recurrent symptomatic urosepsis.

Long-Term Intravesical Catheters For patients with acute urinary retention, regardless of the underlying cause, short-term indwelling catheters are necessary for immediate decompression of a distended and tender bladder. For sick and medically unfit patients with poor performance status a long-term permanent catheter may be the best palliative choice. Modern long-term urethral catheters need to be replaced infrequently and therefore may be the best choice for patients who are technically difficult to catheterise. However, encrustation and the subsequent blockage of indwelling urinary catheters is a common problem affecting up to 50% of long-term catheterised patients [50]. Patients who develop catheter blockage due to encrustation are classified as ‘blockers’. ‘Blockers’ have a high urinary pH and ammonium concentration, and are often women with poor mobility and often have urinary leakage or urinary retention. Urethral catheters cause significant discomfort in patients with bladder spasms. In this group of patients, urine may leak around the urethral catheter and they may experience severe suprapubic pain or discomfort. A combination of oral anti-cholinergic, analgesic and antispasmodic drugs may be effective in pain control. Belladonna and opium suppositories have been used effectively in this setting. Long-term indwelling catheters may become calcified paradoxically causing urinary obstruction, urethral stricture and calcification of the catheter balloon, urethritis, epididymitis, urosepsis and urethral erosion. Suprapubic catheters avoid some of the complications of a urethral catheter; however, long-term catheters are still associated with many other complications.

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29  Urological Symptoms and Side Effects of Treatment

Surgery for Urinary Obstruction Transurethral Resection of the Prostate TURP is a surprisingly challenging procedure, technically. The procedure is usually required in older, less healthy men. However, continuing improvements in surgical technique and instruments allow this procedure to be done more safely and easily. Approximately 25% of all candidates for TURP present with urinary retention and require preoperative catheter drainage. Some of these men may develop post-obstructive diuresis and other electrolyte disturbances. Abnormal electrolyte and elevated BUN and creatinine levels should be corrected. The use of preoperative finasteride may reduce bleeding during and after TURP surgery, although the optimal timing is unclear. Significant amounts of fluid may be absorbed during a TURP, especially if venous sinuses are opened early or when the operation is prolonged. On an average, during a TURP, approximately 1.0–1.2 L fluid is absorbed in the first hour. One third of this fluid is absorbed directly into the venous system. This may lead to dilutional hyponatraemia (TUR syndrome), which causes mental confusion, nausea, vomiting, visual disturbances, haemolysis, haemoglobin nephropathy, coma, cardiac failure and shock. Haemodynamically, this is characterised initially by increased central venous pressures, hypertension, bradycardia and other signs of early vascular overload, including restlessness, tachypnoea and, sometimes, dusky skin changes of the conjunctivae, mucous membranes or fingernails. Symptoms of TUR syndrome generally do not occur until the serum sodium level has decreased to 125 mmol/L or less. Therefore, a TURP is recommended only when procedure is expected to last no longer than 90  min [51, 52]. Other expected and mostly manageable complications following TURP include bladder perforation and urinary tract infection.

Palliative Resection of the Prostate In patients with prostate cancer, particularly those with locally advanced disease, obstructive voiding symptoms are common. In newly diagnosed prostate cancer up to 82% of men present with obstructive symptoms. Approximately one-third of patients with prostate cancer, on an observation treatment plan, develop bladder neck obstruction and require TURP [53]. Even after radiotherapy for stage C prostate cancer, many patients subsequently require TURP for symptomatic local progression. When assessing the role of TURP three aspects need to be considered: (a) the safety of the procedure; (b) the functional outcome; and (c) oncological aspects [54]. For many patients, with symptomatic locally advanced prostate cancer, a channel TURP is a very good

option. Channel TURP removes only the obstructing ­prostatic tissue and does not resect all of the malignant prostatic tissue. A channel TURP procedure has less operative morbidity but this technique is suitable only for a proportion of patients due to the increased risk of bleeding, clot retention, infection and persistent failure to void [55]. Other complications of channel TURP include urinary incontinence due to the procedure cutting through malignant prostatic tissue and the normal anatomic structures being disturbed. Tumour may also directly invade the external urethral sphincter. In carefully selected patients, channel TURP for prostate cancer results in satisfactory voiding; however, about one in five patients will require other procedures several months later [53, 56, 57]. However, patients whose tumour directly invades the external sphincter need resection of the sphincter; therefore, incontinence is an expected outcome. Channel TURP therefore is a suitable option for symptomatic relief of bladder outlet obstruction from locally advanced prostate cancer. A risk of tumour dissemination through prostatic venous channels exists when TURP is performed through malignant tissue. Nevertheless, there is no evidence that patients undergoing palliative TURP have worse survival than those who do not. Alternatives to surgical prostatectomy include intraurethral stent, transurethral microwave therapy, transurethral needle ablation and holmium laser enucleation. Medical therapy, such as the use of a-blockers and 5a-reductase inhibitors, may be used for symptomatic benign prostatic hyperplasia but is not indicated in men with refractory urinary retention from prostate cancer. A TURP is occasionally indicated after brachytherapy, as monotherapy for the treatment of localised prostate cancer. The indications for TURP are acute urinary retention and failure to resume micturition after catheter removal or bothersome urinary symptoms refractory to medical treatment. Urinary retention has been reported in 1.5–22% of patients after brachytherapy implant, and post-implant TURP rates range from 0–8.7% [58]. If possible, TURP should be deferred for at least 6  months following brachytherapy to allow delivery of over 90% of the intended radiation dose. If TURP is performed after brachytherapy, the postoperative urinary incontinence rates are between 0% and 18% [57, 58].

Newer Treatments for Urinary Obstructions Newer treatment modalities are being developed to minimise the complications of bladder and prostatic surgery. These minimally invasive procedures can resect, evaporate or coagulate the prostatic lesions and include electrosurgical vapourisation of the prostate, transurethral needle ablation,

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microwave therapy and high-frequency radio wave ablation. Two outpatient-based treatments are Transurethral Microwave Thermotherapy (TUMT) and Trans Urethral Needle Ablation (TUNA). Both procedures deliver high energy to the prostate to create heat and cause tissue necrosis. When the necrotic tissue is reabsorbed, the prostate gland shrinks, relieving urethral obstruction [59]. Other minimally invasive techniques for prostatic resection utilise lasers. The Visual Laser Ablation of the Prostate (VLAP) technique involves the use of Nd:YAG lasers for treatment of benign prostatomegaly [60]. Another technique involves the use of potassium-titanyl-phosphate (KTP) and holmium lasers that vapourise benign prostatic tissue rather than resect it. A technology called Photoselective Vapourisation of the Prostate (PVP) with the GreenLight (KTP) laser involves a high-power 80 W laser. A 550 mm KTP laser fibre is inserted into the prostate to vapourise most of the prostatic tissue [61, 62]. KTP lasers typically have a penetration depth of 2.0  mm. Holmium Laser Ablation of the Prostate (HoLAP) is a similar procedure [63]. The delivery device for HoLAP procedures is also a 550 mm side-firing fibre that directs the beam from a highpower 100 W laser at a 70° angle. The holmium wavelength is invisible to the naked eye. Whereas KTP relies on haemoglobin as a chromophore, for Holmium lasers, water within the target tissue is the chromophore. The penetration depth of Holmium lasers is <0.5 mm, avoiding complications associated with tissue necrosis often found with the deeper penetration and lower peak powers of KTP. These less-invasive techniques therefore reduce the risks of surgical complications and decrease post-operative catheter times when compared to standard TURP. These newer techniques, although developed for the treatment of benign disease, may have a role in the management of prostate cancer that remains undefined and experimental [64]. Overall, these alternative methods seem promising in providing a quick relief of symptoms from urinary outlet obstruction, with relatively low morbidity. However, long-term results of the benefits and limitations of these techniques require further follow-up.

Urethral Stents Self-expanding metal stents are now widely used for the palliation of obstructed organs and viscera in multiple organ systems, including the urinary tract [65]. These devices are relatively easily inserted under local anaesthetic with minimal sedation [66, 67]. These stents are particularly useful for patients with poor performance status and with a limited life expectancy. These self-expanding stents may obviate the need for placement of long-term indwelling urethral or suprapubic catheters and external urine collection. However,

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stent migration has been reported in a number of patients [67]. Almost all the patients initially achieve successful voiding with insertion of a urethral stent however, about 25% patients subsequently re-obstruct due to stent migration. In benign prostatic hyperplasia, 23% of the stents need removal, as do 5% of those implanted in patients with bulbar urethral stricture and 22% of those in patients with detrusor-sphincter dyssynergia. Of the explantations, about 44% need to be done during the first year. Migration and/or inappropriate placement are the cause for explantation in 38.4% of cases [68]. These stents seem to be more durable and more successful in benign than in malignant prostatic enlargement [68–71]. Patients, who have intrinsic obstruction as well as detrusor muscle dysfunction, only have a modest improvement in their voiding. The procedure is safe and has minimal long-term complications. The stent also provides a sustained, good quality of life for patients and avoids the necessity of long-term catheterisation. Intra-prostatic stents therefore are very promising for the management of urinary outflow obstruction in the medically ill patient who has bladder neck obstruction, as long as the technique of stent insertion is correct and the chosen stent is of the right length.

Ureteric and PUJ Obstruction Acute renal failure secondary to bilateral ureteric obstruction is a common problem in palliative care. Obstruction may be secondary to pelvic tumour invasion, compression of both ureters by retroperitoneal tumour or metastatic pelvic lymph nodes, or rarely, by direct metastases to the ureters. In the majority of patients, an underlying malignancy will be diagnosed [72]. In almost one half, the development of bilateral ureteric obstruction is the initial manifestation of the underlying cancer. The commonest cancer in women is carcinoma of the cervix, and in men, carcinoma of the prostate. Pelviureteric junction (PUJ) obstruction is defined as an obstruction of the flow of urine from the renal pelvis to the proximal ureter. The critical decision to be made in dealing with suspected PUJ obstruction is whether the radiologic findings correlate with the physiologic picture. The role of the medical treatment of hydronephrosis and hydroureter is limited to pain control and treatment or prevention of infection. Most conditions require either minimally invasive or rarely surgical treatment. Surgical procedures to treat PUJ obstruction include laparoscopic pyeloplasty, open pyeloplasty, endopyelotomy, endopyeloplasty and robotic-assisted laparoscopic pyeloplasty. In patients with advanced cancer, suitable for surgical intervention, laparoscopic pyeloplasty is the treatment of choice. Bulky tumour in the pelvis or in the retroperitoneum may present with unilateral or bilateral extrinsic ureteric

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obstruction. Conservative therapy is the preferred approach for a patient with limited life expectancy, poor performance status, other co-morbidities and a poor quality of life. Surgical urinary diversion for symptomatic progressive upper urinary tract obstruction is of minimal or no benefit for patients who have no further anti-cancer therapy options and who have a limited life expectancy. Conservative measures may allow a comfortable, peaceful and predictable death. Patients with tumour-related urinary tract obstruction have severe pain and surgical urinary diversion does not improve pain control. Untreated bilateral ureteric obstruction will lead to anuria, uraemia and renal failure, anorexia, fatigue, nausea and vomiting and, eventually, death. The potential for durable benefits after surgical treatment for ureteric obstruction depends mainly on the type and severity of the underlying disease process and whether there are any further therapeutic options.

Internal Ureteric Stents In patients with intrinsic and extrinsic causes of hydronephrosis, ureteral stent placement is standard practice. The procedure requires cystoscopy and retrograde pyelography. For obstructed ureters, endoscopic insertion of a ureteric stent can achieve internal urinary diversion. However, internal ureteral stents (IUS) need to be changed every 3–6 months to prevent encrustation. Internal urinary diversion for malignant ureteric obstruction can be a difficult procedure, failures are frequent and often the obstruction is only partially relieved, with a success rate of approximately 40% for extrinsic ureteric obstruction [73]. Morbidities after internal or external diversion are minimal in cases of malignant obstruction. However, ongoing obstruction following IUS is more frequent than for percutaneous nephrostomy tube placement.

Self-Expanding Ureteric Stents Recently, self-expanding metallic ureteric stents have become available for external ureteric obstruction. These devices are appropriate for a patient who does not want a urethral catheter, external urine-collecting devices and has a limited life expectancy. Insertion of the stent itself is a relatively simple procedure and can usually be performed with local anaesthesia and a minimal amount of sedation. In a study of 28 patients, insertion of a self-expanding ureteric stent was successful in almost all of the patients. At almost 19 months follow-up, the stent remained patent and functional in over 80% of patients [74]. Self-expanding ureteric stents are therefore another option for treating obstructed ureters once these stents become more widely available [74, 75].

Unilateral Ureteric Obstruction Unilateral ureteric obstruction by primary or secondary ­cancers is slowly progressive and usually asymptomatic. However, occasionally unilateral ureteric obstruction is sudden and causes pain similar to renal colic. Imaging studies such as an IVP, renal ultrasound or helical CT of the abdomen may demonstrate ureteric obstruction as well as the underlying cause. If imaging studies do not demonstrate the site of obstruction, cystourethroscopy with a retrograde study is required. In the presence of symptomatic obstruction, or if the contra-lateral side is non-functioning, an internal ureteric stent can be inserted for the relief of obstruction. In many patients, advanced underlying malignancy precludes major surgical procedures to divert the urine or to lyse the ureters. If the contra-lateral kidney is functioning well, and if internal or external drainage of the obstructed kidney has failed, removal of the involved kidney and ureter may need to be considered. If the obstructed kidney is completely asymptomatic and the contra-lateral kidney is functioning well, intervention may not be required.

Urinary Diversion The traditional treatment for patients with bilateral ureteric obstruction with renal failure, or those with symptomatic unilateral obstruction is open nephrostomy. However, the median survival following urinary diversion by open procedures is about 6 months, morbidity is about 50%, and there is a 3–8% mortality rate and about 30% satisfactory outcome from surgery [76]. A study of 47 patients undergoing palliative urinary diversion for ureteral obstruction due to pelvic cancers reported the average survival time at 5.3  months, with only half of the patients alive at 3  months and only about 20% alive at 6 months. After urinary diversion, about two-thirds of the survival time was spent in the hospital [77]. Therefore, open nephrostomy is associated with significant operative and peri-operative risks, without durable benefits. Recent advances in percutaneous nephrostomy, retrograde and antegrade stenting, and stenting biomaterial itself have dramatically changed the indications for and the results of urinary diversion in the management of malignant ureteric obstruction. In cases of advanced urologic malignancies with impairment of renal function secondary to tumour infiltration in high-risk patients, the possibility of performing a laparoscopic instead of an open cutaneous ureterostomy should be considered [78]. Percutaneous external urinary drainage using a nephrostomy tube for obstructed ureters is now common ­practice and is an alternative to endoscopic ureteric stenting. Modern percutaneous external urinary diversion

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t­ echniques for malignant ureteric obstruction can be ­performed with ­minimal procedural morbidity and it does improve renal function, and provide significant clinical and quality-of-life improvement with minimal morbidity; however, there is no improvement in overall survival. Compared to internal stenting, percutaneous nephrostomy is more invasive, with an associated risk of tube dislodgement; and the diverted urine needs to be collected externally [79]. A large proportion of patients will achieve improvement of renal function. Nevertheless, the median survival of patients undergoing nephrostomy is still very short and post-procedure hospitalisation rates are substantial [80]. Patients with prostate cancer or gynaecologic malignancy seem to have better survival than those with bladder cancer [81, 82]. Also, patients with earlier stage disease or those with newly diagnosed advanced disease have better outcomes [83]. Patients without prior systemic therapy also have better survival and the peri-operative cardiac, pulmonary or haemorrhagic complications are low. The risk of post-procedure complications, fever or acute pyelonephritis following an endoscopic stent insertion or percutaneous catheter insertion seems similar [73]. However, internal stents have a higher failure rate (11%) than percutaneous nephrostomy (1.3%). For longer-term survivors of percutaneous nephrostomy tubes, internalisation of the nephrostomy tube is another option. The technique involves antegrade placement of a stent into the ureter through the existing nephrostomy tract. A nephroureteral stent can also be placed through the percutaneous approach into the bladder. This technique allows antegrade flow of urine from the kidney into the bladder obviating the need for an external collection bag.

Irritative Voiding Symptoms Irritative voiding symptoms such as dysuria, nocturia, urgency or urge incontinence have many causes. Most of the patients presenting with irritative voiding symptoms do not have a serious underlying condition. The management of such cases must focus on identifying and treating the underlying disorder. Tumour in the lower urinary tract, including carcinoma in situ of bladder, can cause irritative symptoms. Chemotherapeutic and biological agents can cause similar difficulties, as can neurological involvement. Neurological involvement, more typically, causes an atonic bladder. Inflammation of the bladder is most often due to infection and symptoms consist of excessive urinary frequency, dysuria and urge incontinence. Dysuria at the end of voiding suggests prostatic problems in the male and trigone in the female.

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Urinary Tract Infection The diagnosis of symptomatic urinary tract infection (UTI) may be complicated by the high prevalence of asymptomatic bacteriuria which does not require any treatment, and the difficulty in interpreting the signs and symptoms of UTI in a population in which significant co-morbidities exist. For a patient presenting with symptoms of acute irritative voiding symptoms, urinary tract infection should be among the first diagnoses to be considered. Classic symptoms and signs for UTI include dysuria, incontinence, increased frequency, urgency, haematuria and suprapubic pain; when pyelonephritis is present, flank tenderness and fever are usually encountered [84]. A diagnosis of UTI should be based on a thorough clinical evaluation, the exclusion of other possible diagnoses and the presence of new signs and symptoms localised to the genitourinary tract. A new onset of urinary tract symptoms can indicate the presence of a UTI, although attention should be given to differentiating these symptoms from chronic symptoms. In general, a biochemical and microscopic urine examination is necessary before starting any antibiotic therapy. Patients who have recurrent urinary tract symptoms or those who have been recently hospitalised should also have a urine culture and sensitivity performed. In the aged and patients with disabilities, however, the cause of urinary tract infection is often iatrogenic, secondary to long-term indwelling urinary bladder catheters. The incidence of urinary tract infections in patients with indwelling urinary catheters is related to the duration of catheterisation [85]. This acquired bacteriuria occurs at a rate of about 5–10% per day of catheterisation, with more than one half of patients with indwelling catheter developing bacteriuria within 10–14 days, and virtually all by 6  weeks. Since it is impossible to eliminate catheter-associated infections, and the bacterial flora changes rapidly in patients with chronic indwelling urethral catheters, treatment of asymptomatic bladder bacteriuria or funguria is not recommended [86]. Antibiotic prophylaxis simply promotes the emergence of antibiotic-resistant microbes. For antibiotic therapy to be effective, proper collection of the urine specimen is very important. Clean-catch specimens are not easily obtained from patients who have physical or other functional impairments. Under certain circumstances, therefore, a clean catheterised specimen may be required to obtain proper bacteriological information. The urine of many patients, who have an indwelling catheter or condom catheter, is almost always colonised with bacteria and, therefore bacteriuria alone, in the absence of other features of urinary tract infection, does not require active treatment. However, a negative urine culture is often considered adequate to rule out infection. Pathogenic bacteria

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readily proliferate in the presence of urinary stasis at any level of the urinary tract. Anatomic abnormalities of the urinary tract, obstructing stone or neoplasm, benign or malignant bladder outlet obstruction may all predispose to urinary stasis or even obstruction. Immuno-suppression, due to cancer or its therapies, other acquired or inherited immune deficiency syndromes, chronic steroid administration and diabetes mellitus may also increase the risk of urinary tract infection. Patients with recurrent urinary tract infections require further investigations to rule out anatomical or other structural abnormalities of the urinary tract. A post-voiding residual urine volume exceeding approximately 150–200 mL requires further evaluation. Imaging studies include renal ultrasound, IVP or non-contrast CT scan for evaluation of calculi, hydronephrosis or bladder diverticulae. Irritative voiding symptoms or symptoms in patients without infection are treated symptomatically with agents such as phenazopyridine, 200 mg orally three times a day, or flavoxate, one tablet daily. Symptomatic and conservative treatments of irritative voiding symptoms include anticholinergics such as oxybutynin, flavoxate and solifenacin; and antimuscarinics such as tolterodine, darifenacin and trospium. Bladder anti-cholinergic agents block the binding of acetylcholine at bladder muscarinic receptors. Acetylcholine stimulates muscarinic receptors, resulting in contraction of the bladder detrusor muscle and an urge to urinate [87]. Anti-cholinergic drugs cause contraction of the bladder neck sphincter and relaxation of the detrusor muscle. Long-term use of anti-cholinergics can cause a decline in cognitive function. Patients with advanced cancer may also be on a number of other drugs with anti-cholinergic properties that may potentially aggravate the anti-cholinergic symptoms. These drugs include benzodiazepines, antipsychotics, hypnotics, TCAs, skeletal muscle relaxants, antihistamines and anticonvulsants. The cholinesterase inhibitors often used to treat dementia can also worsen incontinence [88]. New anti-cholinergics, solifenacin, darifenacin and trospium, appear to have different side effects and may be safer alternatives to tolterodine and oxybutynin [89]. The M3 receptor-specific agents, darifenacin and solifenacin, may have the least effect on cognitive function; however, dry mouth and constipation remain side effects. Paradoxically in patients with severe and disabling irritative voiding symptoms, anti-cholinergic drugs can be used to induce urinary retention, so to allow the patient to manage intermittent catheterisation. Urinary analgesic drugs such as flavoxate or phenazopyridine may partially relieve irritative voiding symptoms. Flavoxate seems to be a more effective agent with less toxicity than phenazopyridine [90]. A combination of urinary analgesics and an anti-cholinergic agent

may be quite effective in managing these symptoms (Table 29.1).

Tumour-Related Irritating Symptoms Intravesical or extravesical tumours may produce irritative bladder symptoms and, along with other agents, may be responsible for the development of painful bladder spasms. Carcinoma in situ of the bladder commonly presents with irritative voiding symptoms and haematuria. Low-grade TCC of the bladder, on the other hand, is often asymptomatic. Locally invasive tumour in the pelvis, e.g. cancers of the ovary, cervix, uterus, rectum, prostate and colon may involve the serosa or even the mucosa of the urinary bladder. It is important to differentiate between tumour infiltration and urinary tract infection from the history, examination and additional investigations. Although some of the urinary symptoms may be quite similar, direct tumour invasion often causes painless haematuria. Patients with irritative voiding symptoms, haematuria and sterile urine cultures require investigation for upper and lower urinary tract pathology. Investigations include urine cytology, IVP and cystoscopy. Urine cytology sensitivities vary between 4% and 69% depending on the grade of the tumour. However, the specificity of urine cytology in bladder cancer is 99% [91]. A negative cytology does not exclude malignancy. Lessinvasive procedures may be needed for patients with poor performance status or those with advanced disease. Fibreoptic and flexible cystoscopes cause minimal discomfort and do not require full anaesthesia. Renal and bladder ultrasound and spiral CT scans are also minimally invasive, and can define the entire urinary system with minimal inconvenience. If a tumour invading the bladder wall is identified and is causing irritative voiding symptoms then transurethral resection of the bladder tumour (TURBT) is required. Full thickness resection of the tumour will also provide additional histological and prognostic information. One of the distinctive features of TCC is that multiple metachronous or synchronous cancers frequently develop. These arise from either polyclonal origin or metastasis from a single clone. Patients with bladder cancer, therefore, need to have a longterm follow-up with repeated urine cytology and cystoscopy for monitoring. More sensitive and non-invasive methods for bladder cancer detection are required. A number of urinary markers are under investigation for the early diagnosis of carcinoma in situ, including nuclear matrix protein-22 [92], hyaluronic acid-hyaluronidase, BTA-Stat [93], urinary bladder cancer antigen [94] and multi-target fluorescence in situ hybridisation (FISH) probe [95].

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Post-Radiation Cystitis

Non-bacterial Cystitis

Acute genitourinary effects of RT to the bladder and ­urethra occur in approximately 20% of patients. The acute and subacute phases of radiation cystitis generally occur within 3–6 months after therapy. Symptoms during this time may include urinary frequency, urgency and dysuria. Gross haematuria occurs in up to 7.7% of patients and although it is more common in the first 6 weeks after therapy, it has been reported as long as 14  years later [96]. These effects are exacerbated when chemotherapy is used concomitantly. Late genitourinary complications of RT include persistent irritative voiding symptoms. Urinary incontinence may be precipitated or exacerbated, particularly in men with prior prostatectomy. Severe late radiation cystitis and haematuria may occur in 3–5% of patients [97]. However, many of the symptoms may also be caused by residual tumour. The incidence and severity of acute radiation cystitis is dose-related with most cases occurring with RT doses of 60.00–65.00 Gy [98–100]. Newer radiation techniques, such as 3-D conformal RT or intensity modulated radiation therapy (IMRT), may deliver high radiation doses without increasing the side effects. The radiation dose intensity is increased near the tumour while the surrounding normal tissue is relatively spared. This may result in better tumour targeting, reduced side effects and improved treatment outcomes [101]. Treatment of symptomatic acute radiation cystitis requires analgesics such as phenazopyridine in combination with an anti-cholinergic. Phenazopyridine is a compound which, when secreted into the urine, has a local analgesic effect. Some patients do not adequately respond to these therapies. Some of the patients can become quite debilitated due to severe urinary frequency, urgency, dysuria, nocturia and at times, urge incontinence. Occasionally, urinary diversion with a urethral catheter improves symptoms temporarily, although frequently the bladder pain is aggravated by catheter itself. Small suprapubic catheters and bilateral percutaneous nephrostomy diversions have been used. More definitive but also more-invasive procedures involve diverting the urine or enlarging the bladder. These are major procedures and require open abdominal surgery. Any urological surgery following radiation therapy is relatively difficult and potentially has more peri- or post-operative complications. For augmentation, cystoplasty or urinary diversion peri- or post-operative complications are dramatically increased in patients with irradiated bowel or bladder due to underlying radiation-induced vasculitis. In practice, however, very few patients are likely candidates for these interventions because of the associated surgical morbidity and mortality.

Non-bacterial cystitis is a term that comprises various ­medical disorders, including non-bacterial infectious (viral, mycobacterial, chlamydial, fungal) and non-infectious (radiation, chemical, autoimmune, hypersensitivity) cystitis, as well as interstitial cystitis. This term also includes painful bladder syndrome/interstitial cystitis (PBS/IC), a syndrome of genitourinary symptoms, such as frequency, urgency, pain, dysuria, nocturia, dyspareunia, abdominal cramps and/or bladder pain and spasms for which no aetiology can be found. Establishing a specific diagnosis often requires urine cultures and various urologic procedures, including cystoscopy and tests of immunological function. Intravesically administered biological or cytotoxic drugs to treat superficial or multi-focal transitional cell carcinoma of the bladder or carcinoma in situ can be potentially quite irritating, inducing varying degrees of chemical cystitis. Intravesical bacillus Calmette-Guerin (BCG) is the most common and the most effective agent for the treatment of superficial and in situ bladder carcinoma. Since the late 1980s, evidence has become available that instillation of BCG into the bladder is an effective form of immunotherapy in this disease [102]. While the mechanism is unclear, it appears that a local immune reaction is mounted against the tumour. Immunotherapy with BCG prevents recurrence in up to 67% of cases of superficial bladder cancer. In addition to the usual weekly intravesical instillations, maintenance therapy may continue after the initial 6-week regimen. Symptoms of urinary frequency, dysuria and haematuria may develop after two or three instillations and last for approximately 2 days after each treatment. These symptoms are expected as BCG therapy elicits an immune stimulatory and inflammatory reaction. Following intravesical BCG therapy, dysuria may occur in up to 91% of patients, urinary frequency in 90% and haematuria in 43% [103]. A combination of phenazopyridine and anti-cholinergic drugs, seem to be quite effective in controlling these symptoms for the initial 6-week course of therapy. Although there have been no randomised controlled trials of these drugs, either singly or in combination, empiric treatment supports their routine use. For patients not responding to this regimen, treatment with isoniazid, paracetamol, diphenhydramine and non-steroidal anti-inflammatory agents may be helpful. Intravesical chemotherapy drugs, such as mitomycin C, doxorubicin, ethoglucid, epirubicin or thiotepa, may reduce tumour recurrence but have no effect on disease progression to muscle-invasion [104, 105]. The most commonly used intravesical chemotherapy drug is mitomycin and because of its high molecular weight and minimal systemic absorption, it has few local or systemic side effects. Increasing the drug concentration, decreasing urine volume and alkalinising the

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urine to stabilise the drug may improve the therapeutic ­effectiveness of mitomycin [106]. Cytotoxic agents used as topical therapy are ineffective when administered as systemic therapy and agents effective as systemic therapy are ineffective as intravesical treatments. Unlike BCG, intravesical cytotoxic drugs are usually better tolerated. Mitomycin C may cause chemical cystitis in only 10–15% of patients and rarely leads to a contracted bladder. Doxorubicin has also been associated with chemical cystitis. Treatment of cystitis due to these agents is similar to that for BCG, except that isoniazid is not required. Systemic administration of cyclophosphamide and ifosphamide, busulphan and methenamine mandelate may cause irritative symptoms. Concomitant administration of mesna during cyclophosphamide and ifosphamide seems quite effective in preventing these complications. Mesna is a chelating agent that binds acrolein, a toxic by-product of phosphamides, thereby decreasing its toxic effects [107]. In rare cases, irritative voiding symptoms can be refractory to conservative management and urinary diversion may need to be considered. The standard form of urinary diversion with the lowest risk of short-term morbidity is the ileal conduit. Many oral agents have been used for the treatment of PBS/IC, with varying success. Medications often used as first-line therapy include TCAs such as amitriptyline and imipramine, which have bladder-relaxing and analgesic properties. In the bladder wall of patients with PBS/IC, often there are increased numbers of mast cells. Whether these mast cells have any pathological basis to PBS/IC is unclear; however, these mast cells contain large amounts of histamine, a vasoactive substance that causes itching and swelling while promoting inflammatory cell infiltration. Antihistamines could therefore be as used first- or secondline therapy. Hydroxyzine, a first-generation antihistamine, blocks mast cell activation and, in uncontrolled studies, was reported effective in interstitial cystitis. However, randomised controlled trials subsequently failed to demonstrate hydroxyzine to be superior to placebo [108]. Another firstor second-line therapy is pentosan polysulphate, an oral restorative for the bladder lining’s damaged, attenuated or missing glycosaminoglycans barrier. The usual dose of pentosan polysulphate is 100–200 mg bd [108]. Approximately 20–30% of patients experience pain and symptom relief with pentosan, although it may take as long as 6 months for adequate relief of symptoms. Several recent randomised double-blind trials of pentosan polysulphate have been published. A dose-finding study did not show any difference in symptom control between 300, 600 or 900 mg of pentosan polysulphate. After 7 months, symptom scores decreased by similar amounts in about 20% of patients, improvement usually occurred within the first 4  weeks. A small trial of oral pentosan polysulphate, with or without hydroxyzine, showed a low response rate and non-significant differences

between the groups [109]. Calcium channel blockers inhibit detrusor muscle contraction and down-regulate lymphocyte production of interleukin (IL)-2. In a small trial using the calcium channel blocker nifedipine, eight out of nine patients reported improvement of symptoms for at least 4  months, but only about half reported longer-term improvement [110, 111]. In many patients, especially those who are normotensive, the drug is better-tolerated in the extended-release form. Apart from orally administered agents, a number of topical agents have also been used for symptomatic relief of PBS/IC. One such agent is RIMSO-50, a purified form of the industrial solvent DMSO. In approximately 50–70% of cases, DMSO has been shown to have therapeutic benefit [112]. Its presumed mechanism of action is multi-factorial; the agent has anti-inflammatory, analgesic, muscle-relaxant, collagen-degrading and bacteriostatic properties and causes mucosal injury [113]. For treatment of PBS/IC, 50  mL DMSO is instilled into the bladder. It needs to be retained for 15  min, and then excreted. This procedure is repeated for 6–8  weeks, followed by a maintenance regimen of 50  mL every 1–2  week for 3–12  months. The addition of sodium bicarbonate, a steroid such as triamcinolone and heparin to the DMSO solution may improve its effectiveness. About half the patients treated with this combination regimen obtain significant pain relief. However, treatments generally become less effective over time. Adverse effects include transient worsening of bladder symptoms probably due to histamine release, and minor haematologic, renal and hepatic dysfunction. Intravesical heparin added to RIMSO-50 may be even more effective in reducing relapse rates. Heparin is a polyanionic compound that is thought to mimic the anti-adherence characteristics of the glycosaminoglycans of the bladder mucosal lining. Intravesical instillation of 20,000 units of heparin in 10–20  mL of sterile water is used as initial therapy while waiting for other treatments to take effect. While this treatment helps some patients immediately, it usually takes 2–3 weeks before definitive response is seen. Corticosteroids and/or lignocaine have also been used to improve the antiinflammatory and analgesic response of RIMSO-50.

Urinary Fistulae Malignancy-associated urinary tract fistulae in patients with advanced cancer can be very difficult to manage both physically and psychologically. These fistulae can cause patients, their families and their caregivers significant distress and a sense of hopelessness. From the urinary tract, locally invasive cancer may cause rectourethral, urethrocutaneous, vesicovaginal and vesicoenteric fistulae.

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One of the uncommon complications of radical prostatectomy is the development of a rectourethral fistula; however, occasionally these may also develop due to locally invasive prostate or rectal cancer. Symptoms of a rectourethral fistula include passage of urine per rectum, faeces per urethra and pneumaturia. Cystoscopy or proctoscopy is required to confirm the diagnosis. A small fistula may close spontaneously following a diverting colostomy and bladder catheterisation; however, in most patients, surgical repair may be needed if there is no underlying active malignancy. For an active malignant fistula the underlying malignancy may require appropriate therapy, otherwise urinary and/or faecal diversion may be necessary.

Urethrocutaneous Fistulae In the rare cases of primary or secondary urethral or penile malignancies, urethrocutaneous fistulae may develop. There may be a localised penile mass and the urine may drain through the urethrocutaneous tract. Surgical treatment depends on the location of the fistula but includes proximal, total or partial penectomy followed by other local or pharmacological treatment, depending on the underlying cause. If the definitive surgical option is not appropriate, urinary diversion through a percutaneous suprapubic cystostomy may be an option.

Vesicovaginal Fistulae A fistulous tract between the urinary bladder and the vagina is often a consequence of gynaecological surgery or puerperal trauma [114]. Presenting symptoms include the passage of urine from the bladder into the vagina through the fistulous tract. Pelvic examination is usually non-contributory as no specific abnormalities are seen unless there is a large fungating tumour. Contrast imaging of the renal tract will exclude the presence of ureteric abnormalities. Cystoscopy can assess the size, site and number of fistulous tracts. More often than not, these fistulae are seen on the posterior bladder wall. However, for planning corrective surgery, information regarding the extent of the tumour including its proximity to a ureteric orifice is required. If the irrigating fluid escapes from the vagina during the cystoscopy, the diagnosis of a vesicovaginal fistula can be confirmed. A speculum examination of the vagina may be useful. Methylene blue dye can also be injected into the bladder to see if it escapes into the vagina through a fistulous tract. During cystoscopy, biopsies of any suspicious areas may also confirm a specific diagnosis.

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For small benign fistulae, 4–6 weeks of urethral or suprapubic catheter drainage may be sufficient for spontaneous closure of the tract. In most patients, however, trans-vaginal or trans-abdominal surgical repair is necessary with interposition of an omental pedicle graft. Surgery for repair of a vesicovaginal fistula needs careful and selective tissue handling, layered closure of the wound, low tension along suture lines, use of absorbable sutures, post-operative suprapubic catheter drainage and peri-operative use of antibiotics [115]. However, most patients with symptomatic vesicovaginal fistula have extensive pelvic disease. In most people, urinary diversion rather than surgical procedures is the best palliative option. In patients with widespread local disease or disseminated metastases or those who are not candidates for major surgery, bilateral nephrostomy tubes with subcutaneous tunnelling will provide good palliation and quality of life.

Vesicoenteric Fistulae Fistulae can form between the bladder and any part of the GI tract. Both benign and malignant large bowel and inflammatory small bowel conditions may lead to vesicoenteric fistula. Most patients complain of dysuria followed by pneumaturia [116]. Vesicoenteric fistulae lead to the risk of recurrent urinary tract infections, especially for fistulae between the GI tract and the bladder. Vesicocolic fistula may also present with the passage of faecal matter in the urine. Cystoscopy may visualise the fistulous tract in up to two thirds of the patients [117]. These, fistulae are usually present high on the posterior wall of the bladder as an area of erythema and small amounts of faecal matter may be seen extruding from the tract. There may be only local or generalised inflammation of the bladder mucosa. If the fistula cannot be seen on cystoscopy, other diagnostic procedures including imaging and dye studies may be required. Spiral CT scans and MRI are the most sensitive methods used to detect enterovesical fistulae. In general, CT scans with oral and rectal contrast, together with cystoscopy, are able to identify most enterovesical fistulae. Occasionally however, the fistulous site is very small when other contrast-imaging studies may be needed to identify the location of the tract. These studies include cystography, upper and lower GI barium studies, 51Cr-labelled sodium chromate [118]. The treatment of symptomatic enterovesical fistulae is dependent on the abnormality of the GI tract and the general condition of the patient. If possible, en bloc surgical excision of the segment of bowel and bladder is the ideal therapy. This will allow normal bowel and bladder function to return. If the poor general physical health or the extent of local disease prevents this procedure, intestinal diversion may be required to redirect the faecal matter and hence reduce the urinary symptoms. Very rarely a total

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29  Urological Symptoms and Side Effects of Treatment

c­ ystectomy with ileal conduit urinary diversion may be ­performed. This type of procedure, however, may need to be accompanied by complete pelvic exenteration. A simpler option may therefore be the placement of bilateral nephrostomy tubes, with subcutaneous tunnelling and external urinary diversion.

Pain Pain is a major problem in advanced malignancy. Prostate, kidney and urinary bladder cancer all have a high probability of painful bony metastases. Management of pain from bone metastases as well as other obstructive visceral pain requires treatment as per standard WHO analgesic guidelines. In recent times, for patients who have developed hormone refractory prostate cancer with bone metastases, bisphosphonate therapy, especially zoledronic acid, has been demonstrated to be effective in reducing the risk of skeletal-related events and mean skeletal morbidity rate, hence, aid in pain control from bone metastases from prostate cancer. It is noteworthy that pamidronate sodium was not shown to be superior to placebo in the same setting [119]. In addition, radiation therapy for pain from bony metastases is extremely effective. Also pain from spinal cord compression requires therapy with steroids and either surgical spinal decompression or radiation therapy.

Renal Colic Renal colic is one of the most painful conditions experienced by patients. Ureteric obstruction, caused by a calculus, blood clot or rarely a tumour, causes capsular distension resulting in severe pain in renal distribution. The pain is colicky in nature due to ureteric muscle spasm, and extends from the flank radiating to the testis or the perineum. The pain is severe enough to generate an autonomic response with severe restlessness, pallor and diaphoresis. Relief from this pain requires parenteral administration of an opioid, such as morphine or a non-steroidal anti-inflammatory drug such as ketorolac or diclofenac [119, 120].

Obstructive Bladder Pain Acute urinary retention causes severe lower abdominal pain, restlessness and a constant and compelling urge to void. Uncommonly, the obstruction is relieved spontaneously; however, in most instances a urethral catheter needs to be inserted to relieve this pain. If the obstruction is not relieved,

the acute urge will gradually subside but bladder distension will persist. The elderly patients as well as those on opioids may not present with these symptoms but instead may have confusion as the main or only presenting symptom. Chronic urinary obstruction, causing gradual bladder distension over time may present with just a sense of fullness, symptoms of chronic urinary retention, and overflow incontinence.

Conclusions Like most palliative approaches, the aim of managing urologic complications in patients with progressive and incurable diseases is to maintain and possibly improve the quality of life of a patient while maintaining the quantity of life. Urological symptoms and complications may develop due to the underlying benign or malignant disease or due to the treatments required for the urological or other malignancy. With significant improvement in imaging modalities, newer devices and medications, and surgical interventions, patients with advanced disease now can enjoy a better quality of life and the morbidities associated with underlying illness and previous treatments can be minimised.

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Chapter 30

Gynecological Symptoms Stefan Starup Jeppesen and Jørn Herrstedt

Introduction Gynecologic cancer comprises cervical cancer, ovarian cancer, and Fallopian tube cancer, cancer of the uterus, and cancers of the vagina and vulva. Furthermore, a number of small disease groups such as gestational trophoblastic disease are included. The incidence of gynecological cancers differs around the world. In high-economic countries, the incidence of cervical cancer is decreasing, whereas in many low-economic countries, cervical cancer is among the most common of all cancer types and accounts for the highest number of cancer deaths in women. Due to the development of a human papilloma virus vaccine, it is expected that the incidence of cervical cancer will decrease further in countries with access to a vaccination program. Cervical cancer is diagnosed in women aged 25–70 years, and is more prevalent in lower socioeconomic groups and in women with multiple sexual partners. The most frequent symptom at the time of diagnoses is postcoital vaginal bleeding [1]. Ovarian cancer is most common in high-economic countries and is worldwide the sixth most common cancer in women. The incidence has been slowly increasing. Because of the lack of symptoms in early-stage disease, ovarian cancer has been called the “silent killer.” Several studies have shown that women with newly diagnosed ovarian cancer can report uncharacteristic symptoms up to 2 years prior to diagnosis. These symptoms include unusual abdominal or lower back pain, distended abdomen, bloating, gastrointestinal problems, urinary symptoms, and vaginal bleeding [1–3]. Age distribution is typically 35–75 years with epithelial cancers primarily diagnosed in women older than 50 years and germ cell tumors primarily diagnosed in younger women. The incidence of carcinoma of the uterus almost displays the same geographical distribution as ovarian cancer, and is most commonly diagnosed in women between 40 and J. Herrstedt (*) Department of Oncology, Odense University Hospital, DK-5000 Odense C, Denmark e-mail: [email protected]

70 years of age. Due to early onset of symptoms (often postmenopausal bleeding) and a much lower tendency to distant metastases, survival is significantly superior as compared to women diagnosed with ovarian cancer [1]. This chapter will focus on symptoms and supportive care in patients with cervical cancer, ovarian cancer, and cancer of the uterus. Prophylaxis and management of complications due to the cancer and of side effects from cancer therapies will be described. Patients suffer from different problems at the time of diagnosis, after surgery, during chemotherapy and/or radiotherapy, and in the phase of survivorship. Furthermore, a variety of symptoms occur in gynecologic cancer patients at the end of life.

Specific Symptoms and Complications in Gynecologic Cancer In general, patients with gynecologic cancer experience a high number of different symptoms, and the need for supportive care is significant. The most common disease-specific symptoms in gynecologic cancer patients are lymphedema of the lower extremities, vaginal bleeding, bowel obstruction, and fistulas. Lymph node dissection, in particular, in women who have had inguinal (cancer of the vagina or vulva) or deep pelvic node dissection with or without postoperative radiotherapy (cancer of the vulva or cervical cancer), often result in subsequent lymphedema of one or both of the lower extremities. Lymphedema may have a huge impact on daily activities and quality of life and typically develops within the first 12 months posttreatment. The risk varies substantially in the literature. It has been reported in 36–69% of women with cancer of the vulva [4, 5], in 8–12% of those with cervical cancer or cancer of the uterus and in 5–7% of women undergoing surgery for ovarian cancer [4]. Postoperative radiotherapy increases the risk 3.5-fold in women with cancer of the vulva or cervical cancer and the more frequent use of extensive surgery in ovarian cancer will undoubtedly increase the risk of lymphedema as well. Fortunately, the more frequent use of the sentinel

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node technique (e.g., in cancer of the vulva) is a landmark and will significantly reduce the risk of surgery-induced lympedema. Treatment results are poor [4, 5] and are described in detail in Chapter 19. Malignant intestinal obstruction is a particular problem in advanced ovarian cancer [6, 7]. Both direct obstruction (due to invasive tumor) and peritoneal carcinomatosis are frequent causes. Symptoms are nausea and vomiting, constipation or partial-overflow diarrhea, and pain. The management is challenging because of the impact on quality of life and the often short life expectancy. Surgical intervention is often indicated if symptoms occur at the time of diagnosis, but in advanced ovarian cancer, surgery should be reserved for patients with a good performance status, a single well-defined obstruction, and with no prior surgery due to intestinal obstruction. In patients with a single obstruction, available for endoscopic intervention, self-expanding metallic stents (SEMS) can be used as an alternative to surgery or in cases where surgery is not indicated [7]. Due to the high frequency of peritoneal carcinomatosis as the cause of obstruction in advanced ovarian cancer, the first choice of treatment will often be conservative limited to medical management and/or a percutaneous endoscopically placed gastrostomy. As described above, vaginal bleeding is a common presenting symptom in women with cervical cancer or cancer of the uterus. In rare cases, bleeding could be severe due to cervical cancer eroding into a small artery, but most commonly the bleeding is slow and patients suffer the symptoms of chronic anemia. Bleeding complications can also occur after diagnosis. Control of bleeding can in most cases be obtained with a vaginal pack stuffing the entire vagina. If this is not successful, surgery should be considered. Palliative radiotherapy to the pelvis given as 15  Gy in three fractions or 30  Gy in ten fractions is effective in most cases. Selective embolization of the hypogastric or uterine arteries can be helpful in patients not suitable for surgery or radiotherapy or in patients with persistent bleeding. In mild cases, e.g., in patients undergoing radiotherapy, treatment with oral or intravenous tranexamic acid is often useful. In case of massive intractable bleeding in patients with incurable cancer, best supportive care is sedation with midazolam [8, 9]. Management of patients with fistulas is reviewed in the section of radiotherapy-induced side effects.

Complications Following Surgery The therapeutic approach in gynecologic cancer has changed markedly during the past years. In ovarian cancer, almost all patients previously had upfront debulking surgery performed, and staging was determined according to surgery and pathology outcome. Today, patients undergo extensive preoperative radiologic evaluation and neo-adjuvant chemotherapy is

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given to many of those who cannot be optimally debulked at the time of diagnosis. A number of patients with advancedstage disease are offered extensive surgery resulting in a macroscopically radical operation. In these patients, postoperative complications can be significant and the magnitude of survivorship problems is unknown. In cervical cancer and cancer of the uterus, clinical staging (not involving radiology) was previously done prior to surgery. Low-stage disease patients were offered surgery and high stage-disease patients were offered radiotherapy. Staging in cervical cancer is still clinical, but today, the majority of patients with endometrial cancer have surgical staging performed. Also surgery has been more extensive in many patients, in particular, as concerns pelvic and/or aortic node dissection. Furthermore, concomitant cisplatin (or cisplatinbased combination chemotherapy) is routinely offered to most cervical cancer patients. Modern surgery and pre-/postoperative chemoradiation have improved treatment results, but have also increased the risk of side effects. The most frequent complications related to surgery are hemorrhage, intraoperative genitourinary (bladder or ureteral injury) and gastrointestinal injuries, deep venous thrombosis, pulmonary embolism, and various infections including wound infections. The risk of lymphedema has been described earlier. The complication rate is dependent on the aggressiveness of surgery and the skills of the surgeon. Also bladder and intestinal dysfunction including bowel obstruction are frequently observed following surgery [10]. These complications are believed to be the result of surgical trauma involving the sympathetic and parasympathetic nerve branches innervating pelvic organs. Different kinds of medications have been used to minimize lower urinary tract symptoms (LUTS) that can persist for months (detrusor hypertonia resulting in voiding dysfunction) or, in some patients, for years. Muscarinic receptor antagonists (if symptoms are due to bladder dysfunction) and serotonin or noradrenaline reuptake inhibitors (if symptoms are due to dysfunction of the urethra) can be helpful. Also perioperative anorectal symptoms like constipation, bloating, and the feeling of incomplete evacuation affect a number of women. Sexual dysfunction includes coital and orgasmic problems, dyspareunia, and sexual dissatisfaction. This can be due to surgery involving the top of vagina, surrounding parametrial tissues, or oopherectomy. The reduction of the vagina and damage to the pelvic nerves can cause sexual dysfunction. Major gynecologic surgery can result in disturbances of vaginal blood flow to the vagina which can cause decreased sexual arousal. In a prospective study in 173 women undergoing radical hysterectomy and compared with matched controls, short-term (up to 6  months postsurgery) sexual problems included orgasmic difficulties, dyspareunia, sexual dissatisfaction, distress during intercourse because of a reduced vaginal size, and problems with completing intercourse, while long-term problems (up to 2 years postsurgery)

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included a negative impact on sexual interest and lubrication of the vagina [11, 12].

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adding epirubicin, liposomal doxorubicin, topotecan, or gemcitabine as a third drug [16]. Although these studies are negative, they are important because incorrectly adding a third drug would increase toxicity and the cost of therapy.

Side Effects Induced by Chemotherapy Almost all women with a diagnosis of epithelial ovarian cancer are offered neo-adjuvant or postoperative chemotherapy. Only those with stage I A or B and grade 1 non-clear cell histology are treated by surgery alone. As concerns endometrial cancer, the role of therapy after surgery has been intensively discussed during recent years. Adjuvant radiotherapy decreases the risk of local recurrence, but does not seem to have an impact on survival. Therefore, chemotherapy has become first choice in many oncology centers in patients who need adjuvant therapy. Women with cervical cancer, who need adjuvant radiotherapy and those in whom radiotherapy is the primary treatment will benefit from concomitant chemotherapy. The most commonly used chemotherapeutic agents in gynecologic oncology and the most frequently observed side effects are seen in Table 30.1. The primary approach to best supportive care is to use the least toxic regimen, provided efficacy is maintained. Cisplatin-based chemotherapy was for many years the gold standard in ovarian cancer treatment, but several studies have shown that cisplatin can be replaced by the much less toxic carboplatin without loss of effect [13]. Unfortunately, this is not the case in cervical cancer, and cisplatin (alone or in combination) is still the preferred antineoplastic agent in these patients. Chemotherapy in cancer of the uterus has not been intensively investigated, and many use the same regimens as in ovarian cancer [14, 15]. Guidelines recommend six courses of carboplatin and paclitaxel as first-line treatment in patients with ovarian cancer. This regimen is tolerable to most patients. Studies have shown that patients will not benefit from additional courses of chemotherapy or from the addition of a third agent. During the past years studies have shown that there is no benefit of

Side Effects Induced by Platinum Compounds Nephrotoxicity is the dose-limiting and most clinically significant toxicity. Other toxicities include nausea and vomiting, ototoxicity, neurotoxicity, and bone marrow toxicity. Cisplatin is excreted largely unchanged in the urine primarily within the first 24 h after infusion. Nephrotoxicity is expressed as a reduction in glomerular filtration rate (GFR) due to severe renal tubular damage. For each treatment course there can be a decline in GFR and this can lead to irreversible toxicity or partial recovery after termination of therapy. Women with advanced-stage cervical cancer often have impaired renal function before the start of treatment and a possible uni- or bilateral ureteral obstruction should be explored and relieved before starting cisplatin therapy. Cytoscopic insertion of ureteral stents is preferable, but a percutaneous nephrostomy can be used instead. Renal function should not be based on the measurement of serum creatinine only, but calculation of the glomerular filtration rate (GFR) using the Cockcroft-Gault formula should be used. In the elderly and in patients with an extreme body surface area (very small or very large), use of the Cockcroft-Gault formula leads to inaccurate estimation of renal function, and measurement of GFR is mandatory. There have been several attempts to reduce nephrotoxicity by coadministration of specific compounds, but none of these are routinely used. The dose of cisplatin should be adjusted according to the renal function and cisplatin therapy should be avoided if the GFR is lower than 50–60 ml/h (measured by Cr-EDTA clearance). Hydration with normal saline is important in maintaining a urinary flow of 100  ml/h and

Table 30.1  Incidence of side effects induced by antineoplastic agents frequently used in gynecologic cancer (for CINV is referred to Table 30.2) Antineoplastic Nephro­ agent Anemia Neutropenia Thrombopenia Neurotoxicity Ototoxicity toxicity Alopecia Constipation Diarrhea PPE Cisplatin ++ ++ ++ +++ +++ +++ + ++ ++ 0 Carboplatin +++ ++ +++ + ++ ++ + + + 0 Oxaliplatin ++ +++ ++ +++ + + + + +++ + Doxo-/epirubicin +++ +++ +++ 0 0 + +++ 0 ++ 0 Paclitaxel +++ +++ +++ +++ + 0 +++ 0 ++ 0 Docetaxel +++ +++ +++ ++ 0 0 +++ 0 ++ + Topotecan ++ ++ ++ 0 0 + ++ + ++ 0 Gemcitabine ++ ++ ++ + 0 + + + + 0 + + + 0 0 0 + + + +++ Pegylated liposomal doxorubicin Vinorelbine ++ ++ + ++ 0 + ++ ++ + 0 +++ Side effects may occur in more than 30%. ++ Side effects may occur in 10–30%. + Side effects may occur in 1–10%. 0 Side effects may occur in less than 1%

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concomitant administration of other nephrotoxic agents such as aminoglycosides and loop diuretics should be avoided. Cisplatin leads to magnesium depletion, which can be avoided by adding 40–80 mmol of magnesium in the hydration fluid per cycle of chemotherapy [17]. Carboplatin has limited nephrotoxicity, when dosing is based on GFR and the newer platinum analog, oxaliplatin, is devoid of significant nephrotoxicity. Cisplatin exhibits preferential uptake in the dorsal root ganglia and produces a dose-related large fiber sensory neuropathy [18]. There is an increasing risk of symptoms with dose, but severe symptoms are rarely seen in patients who have received a total dose less than 300  mg/m2 [19]. Symptoms are first characterized by painful paresthesia and numbness. Later on symptoms like loss of vibration sense, severe paresthesia and ataxia can be apparent. Loss of motor function has been reported, but the motor system is rarely affected. Many studies have examined the effectiveness of potential neuroprotective agents such as amifostine, growth factors, glutathione, Org 2766, acetyl-L-carnitine and vitamin E, but none of these seem to significantly prevent or limit neutrotoxicity [18]. Neurotoxicity is much less pronounced with carboplatin, but can be dose-limiting with oxaliplatin. Oxaliplatin can provoke muscle cramps resembling Raynaud’s phenomenon and pharyngeal-laryngeal dysesthesias which can be triggered by drinking cold liquids or touching cold surfaces. Cisplatin-induced hearing loss is usually bilateral and often irreversible. Hearing loss and tinnitus is related to the cumulative dose of cisplatin, patients’ age (children and elderly have a higher risk), and pre-therapeutic hearing impairment [20, 21]. Symptoms can occur within hours to

days after cisplatin administration. The formation of radical oxygen species (ROS) induced by cisplatin may play a role in ototoxicity. Therefore, a number of free radical scavengers, such as amifostine, acetylcysteine, salicylates, and vitamin E, have been tested in animals [21]. So far only amifostine has been investigated in humans, but two randomized trials were unable to demonstrate any significant effect. A recent study in testicular patients demonstrated that cisplatin-induced hearing impairment could be due to genetic predisposition [22]. Chemotherapy-induced nausea and vomiting (CINV) is not a life-threatening side effect and seldom dose-limiting [23, 24]. Nausea and vomiting are, however, two of the most feared side effects induced by chemotherapy. Cisplatin has the highest risk of CINV (almost 100% if no prophylactic antiemetics are provided to the patient), but also carboplatin, oxaliplatin, and the anthracyclines induce a considerable risk (30–90% risk depending on the dosage). The taxanes, liposomal doxorubicin, topotecan, and gemcitabine have a lower risk (10–30%). Prophylaxis with a combination of a single dose of a 5-HT3 receptor antagonist (given before chemotherapy) plus dexamethasone (days 1–3) is usually effective in prevention of CINV induced by carboplatin plus paclitaxel as used in ovarian cancer first-line therapy. Younger women with advanced cervical cancer are at a particular high risk, because young age and the female gender are risk factors for CINV and because they receive a combination of fractionated radiotherapy against the pelvis and concomitant weekly cisplatin. A phase III trial is currently investigating if a neurokinin receptor antagonist can increase antiemetic protection in this setting. Detailed recommendations for antiemetic prophylaxis in gynecologic cancer patients are given in Table 30.2. For general recommendations for CINV

Table 30.2  Antiemetic prophylaxis in gynecologic cancer patients receiving chemotherapy Antineoplastic agents (iv) frequently used in gynecologic cancer a Emetic risk group Prophylaxis of acute CINV (0–24 h) Prophylaxis of delayed CINV (24–120 h) High (>90% risk)

Cisplatinb

Aprepitant + Serotonin receptor antagonist + Dexamethasone Palonosetron + Dexamethasone

Aprepitant days 2–3 + Dexamethasone days 2–4 Dexamethasone days 2–3

Moderate (30–90% risk) Carboplatin Oxaliplatin Epirubicin Doxorubicin Low (10–30% risk) Paclitaxelc Dexamethasone No routine prophylaxis Docetaxelc Topotecand Gemcitabine Liposomal doxorubicin Ixabepilone Minimal (<10% risk) Bevacizumab No routine prophylaxis No routine prophylaxis Vinorelbine a When combination chemotherapy is used, prophylaxis follows recommendation for the agent with the highest emetic risk b No randomized trial has investigated the low dose of weekly cisplatin (40 mg/m2) used in cervical cancer c No extra dexamethasone is necessary, because patients receive dexamethasone as part of their required premedication d Dexamethasone should be given on each day of topotecan therapy

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prophylaxis and doses of antiemetics are referred to in the chapter on nausea and vomiting. Carboplatin induces a higher risk of myelosuppression than cisplatin. Both have a moderate-to-high risk of thrombocytopenia and anemia, whereas the risk of neutropenia is less pronounced. The indications for blood transfusion and use of hematopoietic growth factors are described elsewhere. It should be emphasized that women treated with pelvic radiation should avoid anemia, due to the decrease in the efficacy of radiotherapy. Gynecologic patients in whom the maintenance of dose intensity and dose density are important (first-line chemotherapy in ovarian cancer and first-line chemoradiation in cervical cancer) should receive prophylactic and/or therapeutic granulocyte colony-stimulating factors according to guidelines [25].

Side Effects Induced by Taxanes Premedation with corticosteroids (both paclitaxel and docetaxel) and H1 and H2 inhibitors (paclitaxel) are necessary to avoid allergic reactions (both) and fluid retention (docetaxel). The risk of myelotoxicity, in particular neutropenia, is high with both (most pronounced with docetaxel). Also neurotoxicity is a frequent side effect, primarily with the use of paclitaxel. Nausea and vomiting are rare side effects, contrary to diarrhea that usually responds to treatment with low doses of loperamide. Alopecia is seen in more than 80% (Table 30.1).

erythema (PPE) is dose-limiting, but myelosuppression and mucositis are mild and cardiotoxicity and alopecia are seldom problems.

Side Effects Induced by Other Cytotoxics Frequently Used in Gynecologic Oncology The topoisomerase-1 inhibitor, topotecan is used in the treatment of resistant or recurrent ovarian cancer and in cervical cancer. Myelosuppression, in rare cases complicated with neutropenic enterocolitis, and fatigue are most frequent. Nausea, vomiting, diarrhea, and alopecia are seen in less than 30% of patients. The antimetabolite, gemcitabine induces mild-to-moderate myelosuppression, but used as part of a combination chemotherapy regimen, this can be severe and necessitate omission of gemcitabine day 8 in a treatment course in a significant number of patients. Fever and dyspnea are frequently seen within the first 24 h after administration, whereas nausea, vomiting, and mucositis are seen in less than 30%. Hemolytic uremic syndrome and/or lung toxicity are rare side effects, but can be severe. Drug–drug interactions with oral anticoagulants can be a problem, but as recommended in the chapter on thrombosis, cancer patients with thrombosis should not receive oral anticoagulants, but low-weight molecular heparin which can be administered safely concomitantly with gemcitabine.

Side Effects Induced by Targeted Therapy Side Effects Induced by Anthracyclines The risk of myelosuppression is moderate (when given as single agents), but as well anemia, neutropenia, and thrombocytopenia are seen. Oral mucositis is a problem in approximately 40% of patients and nausea and vomiting can be severe, in particular, if doxorubicin or epirubicin is combined with cyclophospahmide. The dose-limiting side effect is cardiomyopathy. Maximum cumulative (lifelong) doses of doxorubicin and epirubicin have been defined (450–500 mg/m2 and 850–900 mg/m2, respectively). Patients should be monitored using multiple-gated acquisition (MUGA) scanning or echocardiography. Alopecia is ranked as one of the most troublesome side effects by women receiving chemotherapy, and complete alopecia is seen in almost 100% of patients after the first course of anthracycline-based chemotherapy. No pharmacologic treatment is available, but scalp cooling can prevent or decrease alopecia in as many as 80% [26]. Liposomal doxorubicin has a side-effect profile completely different from the other anthracyclines. Palmar-plantar

Targeted therapy has not yet become standard in gynecologic cancer, but we are awaiting the results of large randomized trials investigating the effect of adding one of these agents, e.g., bevacizumab to carboplatin and paclitaxel (ICON-7-GOG 128) or erlotinib (EORTC 55041). The vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, has several side effects, including intestinal perforation, hypertension, and proteinuria, but exploring this and other targeted agents is relevant, because addition of a conventional antineoplastic agent to carboplatin and paclitaxel does not increase efficacy.

Side Effects Induced by Radiotherapy Radiotherapy given with curative intent is used in women with low-stage cervical cancer as an alternative to surgery, in low-stage patients with risk factors, as adjuvant therapy following surgery, and in high-stage inoperable patients. As mentioned before, also women with cancer of the uterus

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receive multiple fractionation radiotherapy, but this primarily results in a decrease in local recurrence, not in prolongation of survival. Palliative radiotherapy is useful despite the diagnosis and can be helpful against bleeding complications and pain. Side effects induced by radiotherapy depend on the dose, the size and location of the radiation field, and of the radiation technique applied. Both external beam radiation and intracavitary brachytherapy are used, often in combination. Concomitant cisplatin improves survival in locally advanced cervical cancer by 10–13% [27], but also increases toxicity. Organs at risk from the radiotherapy for gynecologic cancer are skin and mucosa, the bladder, small bowel, rectum, and bone marrow. For a number of patients, surgery or radiotherapy can be optional. The decision whether to choose surgery or radiotherapy depends on several factors like age, comorbidity, and patients’ preference. In younger women with low-stage disease (IB1) and a desire to maintain fertility, fertility-sparing surgery (radical trachelectomy and lymph node dissection) can be performed with recurrence rates comparable with radical hysterectomy [28]. This will also eliminate the risk of a radiation-induced second malignancy, which is estimated to be 1%.

Acute Radiotherapy-Induced Side Effects Definition of acute toxicity differs, but is in most trials defined as toxicity appearing during radiotherapy or shortly after, and lasting for less than 3  months. The most common acute toxicities include skin and mucosal toxicity which can cause pain; ulceration and dryness of the vagina; enteritis with diarrhoea, abdominal pain, and fecal incontinence; bladder symptoms with urinal incontinence, urgency and pain; and bone marrow toxicity. The risk of proctitis and or enteritis during external radiotherapy to the pelvis is high and is often complicated with diarrhea and abdominal pain. Diarrhea usually begins after 2 weeks of radiotherapy and resolves within 10  days after completion and can be managed with dietary modifications and antidiarrheal medication. Loperamide seems to be more effective than diphenoxylate. The risk of nausea and vomiting induced by pelvic external beam radiation is 30–60% and is most often effectively prevented with a serotonin receptor antagonist [24]. Urologic toxicity is reported in 8–12% of patients and includes bladder irritation (dysuria and frequency) and hematuria. Symptoms of cystitis are frequent, but rarely accompanied by bacterial growth. Dysuria can be managed with phenazopyridine hydrochloride [29]. Concomitant chemoradiation (e.g., weekly cisplatin during fractionation radiotherapy) increases gastrointestinal

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toxicity and the risk of myelosuppression, primarily leukopenia and thrombocytopenia [30, 31]. Use of intensitymodulated radiotherapy (IMRT) decreases the risk of acute hematologic toxicity and the number of missed chemotherapy cycles [32]. The effect of IMRT on long-term toxicity is, however, unknown.

Late and Chronic Radiotherapy-Induced Toxicity The risk of late radiotherapy-induced toxicity is highly dependent on the radiation technique used. Changing from AP-PA fields to four-field a box technique reduced the risk of severe complications from 14.5% to 3.5% [31]. Common late toxicities include dryness, fibrosis and agglutination of the vagina, shortening of the vaginal canal or stenosis, postcoital bleeding, and pain during and after intercourse; gastrointestinal side effects such as small bowel obstruction, fistulae, rectal bleeding, rectosigmoid stenosis; and urinary symptoms like hematuria and ureteric stricture [28]. Symptomatic pelvic insufficiency fracture is reported in 8–13% at 5 years [28], but increases to a 5-year cumulative fracture prevalence of 45.2% if fractures diagnosed with MRI in asymptomatic patients are included [33]. The risk of having a pelvic insufficiency fracture is not increased by the use of concomitant chemotherapy [33]. Vaginal stenosis and vaginal shortening have a specific impact on quality of life. Radiation-induced fibrosis will lead to vaginal dryness. Stenosis occurs as a result of adhesions and fibrosis in the upper vaginal tissue. These factors will compromise the sexual activities for many women because of pain, bleeding, or even low self-esteem. Vaginal dilators can be effective in prevention of vaginal stenosis, and patients should be informed about their use prior to the start of radiotherapy [34]. Although gastrointestinal toxicity can become symptomatic up to 20  years after completion of radiotherapy, most women will develop mild-to-moderate symptoms during the first 2 years after treatment. Up to 80% of all patients will experience a permanent change in bowel habits after radiotherapy and in some cases this will affect physical, psychological, and social aspects of their lives. Small bowel obstruction is caused by adhesions leading to mechanical obstruction and has been described in a little more than 5% after 20 years [35]. Chronic enteritis has been reported in as many as 20% of patients who have received pelvic radiotherapy [36]. There is little evidence on which to base treatment. Potential therapeutic options include nutritional therapy, antidiarrheals, corticosteroids and other anti-inflammatory agents, antibiotics, cholestyramine, pentoxyfilline, and tocopherol. Hyperbaric

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oxygen provides a promising treatment, but is expensive and requires access to specialized centers for administration [36]. One of the most disabling late complications is a vesicovaginal or recto-vaginal fistula. In a retrospective trial in 1,784 patients with cervical cancer treated with external beam irradiation delivered as anterior and posterior opposed fields plus brachytherapy, the overall risk of fistula formation was 3.1% at 20 years and new occurrences were observed as late as 29 years after treatment [35]. Fistula formation often requires surgery which can be difficult because of diminished blood supply in an irradiated area. Fistulae can cause serious distress and especially the odor can compromise well-being and lead to a disrupted social life. Metronidazole can be helpful due to the effect on anaerobic bacteria. Hopefully, use of modern radiotherapy techniques such as imaging-guided brachytherapy and IMRT (intensity modulated radiotherapy will decrease the risk). Symptoms of late radiation effects to the bladder appear with a median of 2–3 years after the completion of radiotherapy and include dysuria, urgency, hematuria, infections, urethral stenosis, and fistula formation [37]. Antimuscarinics can reduce bladder (detrusor) contractions, thereby relieving urgency and urge incontinence and increasing capacity in the bladder. Symptoms of reduced bladder capacity can also be treated with antispasmodics such as oxybutinin or tolterodine [37].

Survivorship Problems Gynecologic cancer patients report specific survivorship problems dependent on the diagnosis, stage of disease, treatment, treatment result, and time since completion of treatment.

Survivorship Problems During the First 6 Months After Completion of Treatment In a study in 1,425 patients, including 90 with gynecologic cancer, patients receiving radiotherapy, chemotherapy, or both were assessed at the end of treatment and again 6 months later. All patients were metastases-free and had not experienced relapse during treatment [38]. One-third of the patients reported five or more moderate-to-severe unmet needs and for 60% of these, the situation did not improve during the 6-month period. Both at baseline and after 6 months the five most frequently reported unmet needs were “fears about the cancer spreading,” “concerns about the worries of those close to you,” “uncertainty about the future,” “worry that the results of the treatment are beyond your control,” and “lack of energy/tiredness.” It is noteworthy that except lack of

energy/tiredness, the most frequently endorsed unmet needs were all psychological and “fear about cancer spreading” was most frequently scored both at baseline and after 6 months [38].

Survivorship Problems 5–25 Years After Completion of Treatment In a study, 5,836 long-term cancer survivors completed a health survey. Overall, the interval between a cancer diagnosis and the completion of the survey was at least 5 years with a mean time of 18.0 +/−8.5 years. A total of 970 gynecologic cancer survivors responded and 28.1% of these indicated that cancer had affected their overall health. The most frequently reported health problems in gynecologic cancer survivors were arthritis/osteoporosis (31.1%), urinary (18.5%), cataracts (16.3%), and heart (13.3%), respectively. It must be emphasized that some of these problems could be due to comorbidities at the time of diagnosis or due to aging [39].

Specific Survivorship Problems in Gynecologic Cancer Many gynecologic cancer survivors adjust well as they recover, but a significant number have physical and/or psychosocial problems [40]. This can be explained by the combination of the impact of being diagnosed with a cancer, undergoing surgery, receiving chemotherapy and/or radiotherapy, and the fear of recurrence. Surgery with bilateral oophorectomy in premenopausal women causes premature menopause and may induce symptoms such as hot flashes, vaginal dryness and atrophy, loss of libido, urinary incontinence, and depression. Loss of estrogen production can also lead to mood changes and changes of the hair and skin. Systemic estrogen supplement is not advised, but topical estrogen can be useful. In addition, loss of fertility can be a psychological challenge. In all, this may have a significant negative impact on quality of life (QoL). Survivorship problems can be disease-related and ovarian cancer survivors seem to report a higher level of unmet needs than endometrial cancer survivors [41]. Also choice of treatment can be important for subsequent survivorship problems. A study [42] compared survivorship problems in women with uterine cervical cancer treated with surgery (n = 99, included 26–82 [median 42] months after surgery) or radiotherapy (n = 111, included 25–85 [median 46] months after completion of radiotherapy). The most common side effects after surgery were constipation (70.3%), urinary incontinence (42.9%), fatigue (41.8%), dysuria (41.8%), and vaginal dryness

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(35.2%). Women treated with radiotherapy most frequently reported fatigue (49.5%), diarrhea (42.2%), urinary frequency (31.5%), lower abdominal skin dryness (28.8%), and urinary incontinence (25.2%). Patients who underwent surgery had a significantly higher incidence of constipation, flushing, dysuria, urinary incontinence, dysparia, and vaginal dryness, whereas women in the radiotherapy group had more diarrhea, bloody stools, and abdominal pain [42]. Neural dysfunction was significantly higher in surgical patients whereas intestinal dysfunction was higher in radiotherapy patients. Sexual dysfunction was reported by both groups, but without significant difference. Sexual dysfunction is reported by almost half of the patients treated with surgery or radiotherapy for cervical cancer [42]. Sexual dysfunction from surgery is caused by vaginal shortening, vaginal dryness, and decreased libido and radiotherapy-induced sexual dysfunction is primarily due to vaginal stenosis which often causes dyspareunia and difficulty in orgasm. Jensen et  al. in two prospective studies investigated women with cervical cancer [11, 43]. In the first study 118 women, disease-free after radiotherapy for locally advanced, recurrent, or persistent cervical cancer were compared with an age- and menopausal status-matched control group (n = 236). All completed questionnaires at baseline (for cervical cancer patients at the completion of radiotherapy) and then at 1, 3, 6, 12, 18, and 24 months later [43]. Persistent sexual dysfunction and vaginal changes were reported throughout the 2-year period. The main results were low or no sexual interest (85%), moderate-to-severe lack of lubrication (35%), mild-to-severe dyspareunia (55%), and dissatisfaction with sexual life (30%). A reduced vaginal dimension was reported by 50%. Despite these problems 63% of those sexually active before treatment remained sexually active after treatment, although with a considerably decreased frequency [43]. The second study [11] used the same design, but compared 173 women with early-stage cervical cancer who underwent radical hysterectomy with a matched control group (n = 328). Short-term complications (up to 6 months after radical hysterectomy) were orgasmic difficulties, dyspareunia, sexual dissatisfaction, and distress by a reduced vaginal size. Long-term side effects (2  years after radical hysterectomy) included decreases in sexual interest, vaginal lubrication, and vaginal dimensions. Furthermore, the combination of radical hysterectomy and pelvic irradiation results in more severe and prolonged morbidity compared with radical hysterectomy alone [11, 44]. In conclusion, gynecologic cancer survivors will have a high risk of experiencing depression and anxiety, chronic fear of recurrent disease, and sexual dysfunction. Supportive care should be initiated early in the treatment phase and counseling should not be restricted to the cancer patient only, but also include the partner. A recent study emphasizes

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that social support is of general benefit for depressive symptoms [45].

End-of-Life Issues in Gynecologic Cancer In women receiving optimal therapy, the overall 5-year survival rates in cervical, endometrial, and ovarian cancer are approximately 70, 85, and 45%, respectively. Consequently, more than 50% of ovarian cancer patients and a significant number of women with cervical and endometrial cancer will develop recurrent disease and eventually die from their cancer. These women will need palliative care, including guidance concerning pain, anorexia and cancer cachexia, bowel obstruction, ascites, psychosocial problems, and spiritual issues all described in other chapters. Today we have a large number of palliative therapies, including surgery, radiotherapy, and chemotherapy. The clinician should continuously protect patients against therapies that will not improve survival or reduce complications and symptoms from the cancer, but undoubtedly will induce side effects (medical futility). This is not an easy task, because the patient at that stage has to accept that therapy with a curative intent is no longer an option [46, 47]. A number of end-of-life complications are frequent in patients with gynecologic cancer. Patients with advanced uterine or cervical cancer have a risk of bilateral ureteral obstruction and uremia due to extension of their cancer. In patients who have not received prior radiotherapy, this modality could be a reasonable treatment option. In patients who have recurrent disease in a previously irradiated area, the decision of whether or not to offer urinary diversion is difficult. Expiration due to uremia (in case urinary diversion is not carried out) could be more beneficial to the patient. This difficult decision should be made in close consultation with the patient and the family. Another problem in cervical and uterine cancer patients is urinary or colonic fistulas. Both types of fistulas have a significant negative impact on patients’ quality of life and every effort should be done to relieve this situation. Specific problems in advanced ovarian cancer are bowel obstruction and recurrent ascites. These problems are reviewed elsewhere.

Conclusion This chapter reviewed supportive care in gynecologic oncology. The conditions for optimal supportive care may well change significantly during the coming years.

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In ovarian cancer, extensive surgery, with the purpose of increasing the numbers of patients who can be macroscopically radically operated upon, has become standard in many centers. We know very little about long-term complications in these patients. In patients with cervical cancer, use of image-guided planning and new radiation techniques such as IMRT has led to a decrease in acute side effects, but the extent of long-term toxicity is unknown. In particular, it is unknown if the risk of inducing a secondary tumor will increase. Targeted therapy may become of considerable use in gynecologic cancer. A study, so far presented as an abstract only, indicates that bevacizumab following conventional therapy with carboplatin plus paclitaxel increases progressionfree survival in ovarian cancer patients [48]. How will the well-known hypertension and proteinuria induced by this agent affect patients in the long run? It should be noticed that this chapter has primarily described complications and side effects from single-modality therapy, although combined-modality therapy becomes more and more frequent. This will increase acute as well as long-term side effects. Fortunately survival rates continue to increase due to more effective therapy. Today, many patients will have to consider themselves as having a chronic cancer disease. This should reinforce the attention on rehabilitation and survivorship issues. It is important that rehabilitation does not continue to be a kind of “damage control” after the end of cancer therapy, but that rehabilitation plans are initiated at the time of diagnosis and start of therapy. In the future, it is expected that pharmacogenetics will be useful, not only in the design of individual cancer therapy but also in the prediction of individual side-effect profiles of cancer­ therapy. Hopefully, this will lead to a decrease in the need for supportive care.

References 1. Parkin M, Bray F, Ferlay J, Pisani P. Global Cancer Statistics 2002. CA Cancer J Clin 2005;55:74–108. 2. Lurie G, Thompson PJ, McDuffie KE, Carney ME, Goodman MT. Prediagnostic symptoms of ovarian carcinoma: A case-control study. Gyn Oncol 2009;114:231–236. 3. Behtash N, Azar EG, Fakhrejahani F. Symptoms of ovarian cancer in young patients 2 years before diagnosis, a case-control study. Eur J Cancer Care 2008;17:483–487. 4. Beesley V, Janda M, Eakin E, Obermair A, Battistutta D. Lymphedema after gynecological cancer treatment, prevalence, correlates and supportive care needs. Cancer 2007;109:2607–2614. 5. Lockwood-Rayermann S. Lymphedema in gynecological cancer survivors. Cancer Nursing 2007;30:E11–E18. 6. Chase DM, Monk BJ, Wenzel LB, Tewari KS. Supportive care for women with gynecologic cancers. Exp Rev Anticancer Ther 2008;8:227–241.

309 7. Roeland E, von Gunten CF. Current concepts in malignant bowel obstruction management. Current Oncol Rep 2009;11:298–303. 8. Mohan S, Page LM, Higham JM. Diagnosis of abnormal uterine bleeding. Best Pract Res Clin Obstet Gynaecol 2007;21:891–903. 9. Shapley M, Jordan J, Croft PR. A systematic review of postcoital bleeding and risk of cervical cancer. Br J Gen Pract 2006;56:453–460. 10. Pieterse QD, Maas CP, Ter Kuile MM et  al. An observational longitudinal study to evaluate miction, defecation, and sexual function after radical hysterectomy with pelvic lymphadenectomy for early-stage cervical cancer. Int J Gynecol Cancer 2006; 16:1119–1129. 11. Jensen PT, Groenvold M, Klee MC, Thranov I, Petersen MA, Machin D. Early-Stage Cervical Carcinoma, Radical Hysterectomy, and Sexual Function. Cancer 2004;100:97–106. 12. Vistad I, Fosså SD, Dahl AA. A critical review of patient-rated quality of life studies of long-term survivors of cervical cancer. Gyn Oncol 2006;102:563–572. 13. Du Bois A, Lück H, Meier W et al. A randomized, clinical trial of cisplatin/paclitaxel vs carboplatin/paclitaxel as first line treatment of ovarian cancer. J Natl Cancer Inst 2000;95:1320–1329. 14. Omura GA. Progress in Gynecologic Cancer Research: The Gynecologic Oncology Group Experience. Seminars in Oncology 2008;35:507–521. 15. Muggia F. Platinum compounds 30 years after the introduction of cisplatin: Implications for the treatment of ovarian cancer. Gyn Oncol 2009;112:275–281. 16. Marchetti C, Pisano C, Fachini G et  al. First line treatment of advanced ovarian cancer: current research and perspectives. Exp Rev Anticancer Ther 2010;10:47–60. 17. Launay-Vacher V, Rey JB, Isnard-Bagnis C, Deray G, Daouphars M. Prevention of cisplatin nephrotoxicity: state of the art and recommendations from the European Society of Clinical Pharmacy Special Interest Group on Cancer Care. Cancer Chemother Pharmacol 2008;61:903–909. 18. Albers J, Chaudhry V, Cavaletti G, Donehower R. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev 2007;1:CD005228. 19. Krarup-Hansen A, Helweg-Larsen S, Schmalbruch H, Rørth M, Krarup C. Neuronal involment in cisplatin neuropathy: prospective clinical and neurophysiological studies. Brain 2007; 130:1076–1088. 20. Rybak LP, Whitworth GA, Mukherjea D, Ramkumar V. Mechanisms of cisplatin-induced ototoxicity and prevention. Hearing Research 2007;226:157–167. 21. van den Berg JH, Beijnen JH, Balm AJM, Schellens JHM. Future opportunities in prevention cisplatin induced ototoxicity. Cancer Treatment Reviews 2006;32:390–397. 22. Oldenburg J, Kraggerud SM, Cvancarova M, et  al. Cisplatininduced long-term hearing impairment is associated with specific glutathione-s-transferase genotypes in testicular cancer survivors. J Clin Oncol 2007; 25:708–714. 23. Jakobsen JN, Herrstedt J. Prevention of chemotherapy-induced nausea and vomiting in elderly cancer patients. Crit Rev Oncol Hematol 2009;71:214–221. 24. Herrstedt J. Antiemetics: an update and the MASCC guidelines applied in clinical practice. Nature Clin Practice Oncol 2008;5:32–43. 25. Aapro MS, Cameron DA, Pettengell R et al. EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. Eur J Cancer 2006;42: 2433–2453. 26. RM Trüeb. Chemotherapy-Induced Alopecia. Sem Cutan Med Surg 2009;28:11–14. 27. Green JA, Kirwan JJ, Tierney J et al. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database Syst Rev 2005;3:CD002225.

310 28. Barbera L, Thomas G. Management of Early and Locally Advanced Cervical Cancer. Sem Oncol 2009;36:155–169. 29. Marks LB, Carroll PR, Dugan TC, Anscher MS. The response of the urinary bladder, urethra, and ureter to radiation and chemotherapy. Int J Rad Oncol Biol Phys 1995;31:1257–1280. 30. Kirwan JM, Symonds P, Green JA, Tierney J, Collingwood M, Williams CJ. A systematic review of acute and late toxicity of concomitant chemoradiation for cervical cancer. Radiotherapy and Oncology 2003;68:217–226. 31. Maduro JH, Pras E, Willemse PHB, de Vries EGE. Acute and longterm toxicity following radiotherapy alone or in combination with chemotherapy for locally advanced cervical cancer. Cancer Treatment Reviews 2003;29:471–488. 32. Brixey CJ, Roeske JC, Lujan AE, Yamada SD, Rotmensch J, Mundt AJ. Impact of intensity-modulated radiotherapy on acute hematologic toxicity in women with gynecologic malignancies. Int J Radiation Oncol Biol Phys 2002;54:1388–1396. 33. Kwon JW, Huh SJ, Yoon YC et al. Pelvic bone complications after radiation therapy of uterine cervical cancer: evaluation with MRI. AJR 2008;191:987–994. 34. Denton AS, Maher J. Interventions for the physical aspects of sexual dysfunction in women following pelvic radiotherapy. Cochrane Database Syst Rev 2009;DOI: 10.1102/14651858. CD003750. 35. Eifel PJ, Levenback C, Wharton JT, Oswald MJ. Time course and incidence of late complications in patients treated with radiation therapy for Figo stage IB carcinoma of the uterine cervix. Int J Rad Oncol Biol Phys 1995;32:1289–1300. 36. Theis VS, Sripadam R, Ramani V, Lal S. Chronic Radiation Enteritis. Clin Oncol 2010;22:70–83. 37. Maher EJ, Denton A. Survivorship, Late Effects and Cancer of the Cervix. Clin Oncol 2008;20:479–487. 38. Armes J, Crowe M, Colbourne L et  al. Patient’s supportive care needs beyond the end of cancer treatment: a prospective, longitudinal survey. J Clin Oncol 2009;27:6172–6179.

S.S. Jeppesen and J. Herrstedt 39. Schultz PN, Beck ML, Stava C, Vassilopoulou-Sellin R. Health profiles in 5836 long-term cancer survivors. Int J Cancer 2003; 104:488–495. 40. Simonelli LE, Fowler J, Maxwell GL, Andersen BL. Physical Sequelae and Depressive Symptoms in Gynecologic Cancer Survivors: Meaning in Life as a Mediator. Ann Behav Med 2008;35:275–284. 41. Hodgkinson K, Butow P, Fuchs A, Hunt GE, Stenlake A, Hobbs KM, Brand A, Wain G. Long-term survival from gynecologic cancer: Psychosocial outcomes, supportive care needs and positive outcomes. Gyn Oncol 2007;104:381–389. 42. Hsu W-C, Chung N-N, Chen Y-C et  al. Comparison of surgery or radiotherapy on complications and quality of life in patients with stage IB and IIA uterine cervical cancer. Gyn Oncol 2009;115:41–45. 43. Jensen PT, Groenvold M, Klee MC, Thranov I, Petersen MA, Machin D. Longitudinal study of sexual function and vaginal changes after radiotherapy for cervical cancer. Int J Radiat Oncol Biol Phys 2003;56:937–949. 44. Juraskova I, Butow P, Robertson R, Sharpe L, McLeod C, Hacler N. Post-treatment sexual adjustment following cervical and endometrial cancer: a qualitative insight. Psychooncology 2003; 12:267–279. 45. Carpenter KM, Fowler JM, Maxwell GL, Andersen BL. Direct and buffering effects of social support among gynecologic cancer survivors. Ann Behav Med 2010;39:79–90. 46. von Gruenigen VE, Daly BJ. Futility: Clinical decisions at the end-of-life in women with ovarian cancer. Gyn Oncol 2005; 97:638–644. 47. Beji NK, Reis N, Bag B. Views of patients with gynecologic cancer about the end of life. Support Care Cancer 2005;13:658–662. 48. Burger RA, Brady MF, Bookman MA et al. phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC) or Fallopian tube cancer (FTC): A Gynecologic Oncology Group study. J Clin Oncol 2010;28(Suppl 18, partII); 946s, LBA1.

Part XI

Neurologic and Muscular

Chapter 31

Central Nervous System Symptoms: Headache, Seizures, Encephalopathy, and Memory Impairment Roxana S. Dronca, Charles L. Loprinzi, and Daniel H. Lachance

Introduction

as compared to their younger counterparts [3]. Infratentorial and intraventricular tumors tend to be accompanied by Central nervous system (CNS) complications are an impor- headache more often than those located supratentorially, tant cause of morbidity and mortality in patients with cancer. probably secondary to the disturbance of CNS flow and The pathogenetic mechanisms are heterogeneous and may development of hydrocephalus and increased intracranial involve direct and indirect tumor effects or may be the result pressure. Many headache patterns have been described, including of antineoplastic therapy. Over the past few decades, major some which are indistinguishable from common migraine advances have been made in the development of more potent and tension-type headache. However, the development of an and effective treatment techniques, resulting in improved atypical, new (less than 10 weeks) [4], or progressive headcure rates and increased survival in many malignancies. ache [5], especially if unresponsive to general therapy, is parAlthough the exact incidence is difficult to assess, the longticularly worrisome for CNS involvement and warrants term morbidity of cancer-related neurotoxicity is becoming increasingly prevalent and can significantly affect patients’ careful scrutiny, particularly in patients with known systemic quality of life and functional ability. The clinical manifesta- malignancies. In patients with primary or metastatic tumors, tions are pleomorphic, ranging from headache, seizures, the headache is typically moderate to severe in intensity, lasts focal neurological deficits, acute encephalopathy, and even for hours at a time, and is usually intermittent without having a regular daily occurrence [5]. Contrary to the classical chronic neurocognitive changes including dementia. teaching, the typical “morning or nocturnal headache” is uncommon, and occurs in only a minority of adult patients Headache with brain tumors [2]. Unlike tension-type headaches, brain tumor headaches are worse ipsilaterally on the side of the Headache is a common symptom in patients with cancer tumor, are often exacerbated by bending over or Valsalvaand can result from tumor involvement of the brain or type maneuvers, and are frequently associated with nausea ­surrounding structures, or as a consequence of cancer-­ and/or vomiting, mental status or personality changes, and related treatment. Up to 60% of patients with primary brain other focal neurological symptoms [2]. It is generally uncomtumors [1] and 48% or more of patients with cerebral mon for a patient to present with isolated headache as the metastases [2] experience chronic or frequent headaches. only symptom of a brain mass. This was illustrated in a study The prevalence of headache depends on tumor type, the of 3,291 children with primary brain tumors, of whom less location and ­structures involved, as well as the patient’s age than 1% had isolated headache and less than 3% had a normal and previous headache history. For example, slow growing neurological examination [1]. Apart from primary and metastatic tumors, other causes low-grade gliomas are less likely to cause headache than of headache in patients with cancer include ischemic or high-grade anaplastic gliomas or glioblastomas; these hemorrhagic strokes, dural sinus thrombosis, posterior patients usually present with seizures before developing reversible encephalopathy syndrome (PRES), meningeal headaches [2]. Previous studies have also reported that carcinomatosis [6] (secondary to disturbance of CSF circuelderly patients are less likely to present with headache and lation or infiltration of pain-sensitive structures in the brain more likely to develop confusion, aphasia, or memory loss or of cranial nerves), or base of the skull metastases. In a seminal paper, Greenberg et al. [7] described five base of R.S. Dronca (*) the skull metastases syndromes: an orbital and parasellar Department of Oncology/Hematology, Mayo Clinic, 200 1st Street syndrome characterized by frontal headache, diplopia, SW, Rochester, MN, 55901, USA e-mail: [email protected] and first-division trigeminal sensory loss; a middle-fossa I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_31, © Multinational Association for Supportive Care in Cancer Society 2011

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syndrome characterized by facial pain or numbness; a jugular foramen syndrome characterized by hoarseness and dysphagia; and an occipital condyle syndrome characterized by unilateral occipital pain and unilateral tongue paralysis. Patients with ipsilateral nonmetastatic lung cancer may present with referred unilateral facial pain caused by invasion and compression of the vagus nerve [8]. In patients suffering from cancer, headache may also be the result of surgery, as well as chemotherapy or radiation therapy. Most patients experience headache in the first few weeks after surgery for brain tumors, but this is usually shortlived, with less than 6% of patients having headache that lasted more than 2 months [9]. Intrathecal (IT) administration of chemotherapeutic agents such as methotrexate (MTX) [10] and, less often, cytarabine (ara-C) [11] has been reported to cause a syndrome of aseptic meningitis characterized by headache, nuchal rigidity, fever, vomiting, and lethargy. Symptoms usually occurr 2–4 h after the drug is injected and can last up to 72 h. The syndrome is typically self-limited and no specific treatment is necessary. Coadministration of IT hydrocortisone and the use of a constant, rather than body-surface area (BSA) adjusted IT dose [12], may decrease the incidence of arachnoiditis in these patients [13]. The posterior reversible encephalopathy syndrome (PRES) is another important consideration in the differential diagnosis of headache in patients with cancer. The most common cause is hypertensive encephalopathy but PRES has also been described with administration of several chemotherapeutic and immunomodulatory drugs. The clinical findings include headache, acute mental status changes, seizures, cortical blindness or other visual disturbances [14] (below). Acute radiation toxicity commonly manifests with severe headache, fever, nausea, vomiting, decreased level of consciousness, and worsening neurological deficits. These symptoms are generally more severe following first radiation dose, with gradual improvement with subsequent treatments. This complication occurs mainly with “rapid-course,” high-dose radiation therapy (>3 Gy) administered to a large brain volume [15] and it is considerably less common with current whole-brain radiation therapy (WBRT) techniques and the conventional use of low fractions (≤3 Gy). The treatment of headache in patients with cancer depends on the etiology and should be aggressive in terms of pain and symptom control. Headache caused by raised intracranial pressure in patients with primary and metastatic brain tumors is primarily managed with corticosteroids, until more definitive therapy, such as surgical resection, stereotactic radiosurgery, or palliative radiation therapy occurs. Analgesics, opioid medications, and palliation of associated symptoms using a multimodality therapy approach may be necessary when symptoms are not relieved by the treatment of the tumor.

R.S. Dronca et al.

Seizures The onset of a new seizure disorder may represent a cardinal symptom of a serious or life-threatening disease, including malignant cerebral neoplasms or metastatic disease. In patients with known malignancies, however, the differential dia­gnosis is extensive, including toxic-metabolic as well as structural causes. For instance, patients may ­experience seizures in the setting of an acute metabolic disturbance, such as hypercalcemia secondary to osteolytic metastases or secretion of parathyroid-related hormone (PTHrP), hypomagnesemia associated with chemotherapy (cisplatin), hyponatremia secondary to dehydration or the syndrome of inappropriate antidiuretic hormone (SIADH) [16], hypo- or hyperglycemia (glucocorticoids), hepatic or renal failure, or hypoxia. Drug withdrawal states are another important consideration, particularly in patients who have been treated long-term with benzodiazepines, opioids, or muscle relaxants such as baclofen or dantrolene [17]. Several chemotherapeutic agents as well as radiation therapy have also been reported to cause seizures, usually in the context of an acute (e.g., PRES) or chronic encephalopathy syndrome (below). Structural causes of seizures include primary or metastatic brain tumors, meningeal carcinomatosis [6], ­ischemic and hemorrhagic strokes, or CNS infections ­(particularly in immunocompromised patients). The tumor type and location may influence the prevalence of seizures. Slower growing meningiomas and low-grade gliomas are more likely to present with seizures than high-grade tumors, as illustrated in a review of 1,028 patients with primary brain tumors. The prevalence of seizures was 49% in glioblastoma (GBM) patients, 69% in patients with anaplastic gliomas, and 85% among those with low-grade gliomas [18]. The incidence of seizures is lower in patients with ­metastatic brain lesions, compared to primary tumors. In a retrospective series of 195 patients with documented cerebral metastases, seizures were the presenting symptom in 18% and developed subsequently in an additional 10% of patients [19]. Similarly, tumors associated with a posterior fossa lesion are less likely to cause seizures, as opposed to hemispheric lesions [19]. Clinically, Patients may present with either generalized tonic-clonic or partial seizures, or even status epilepticus, depending on tumor type and location [20]. Drug-induced seizures are often generalized tonic-clonic, but partial-onset seizures have also been described [21]. A careful and comprehensive metabolic evaluation is essential in all patients who experience a seizure. Most cancer patients with a new-onset seizure disorder will need an imaging study of the brain (CT scan or MRI) and a lumbar puncture may also be required after brain imaging, particularly if meningeal carcinomatosis or an infectious etiology is suspected. The diagnosis of a drug-induced seizure is one of

31  Central Nervous System Symptoms: Headache, Seizures, Encephalopathy, and Memory Impairment

exclusion and should be made only after all other potential etiologies have been ruled out. Treatment should be directed at correction of the underlying cause, if possible. Patients who present with seizures due to a brain tumor should be treated with standard anticonvulsants, preferably those which do not affect cytochrome P450 enzymes, in order to avoid potential interactions with chemotherapeutic agents or other drug–drug interactions [22]. On the other hand, prophylactic therapy is not routinely recommended in patients with primary or metastatic brain tumors who have no history of epilepsy [23]. A recent metaanalysis of five randomized trials concluded that there is no evidence to support antiepileptic drug prophylaxis with phenobarbital, phenytoin, or valproic acid in patients with brain tumors and no history of seizures, regardless of the neoplastic type [24]. These findings were subsequently confirmed by a Cochrane database systematic review, which also found that the risk of an adverse event was higher in patients on prophylactic antiepileptic drugs [25].

Encephalopathy Acute Encephalopathy The differential diagnosis of acute encephalopathy in patients with cancer is complex and includes both toxic-metabolic and structural causes. In patients with advanced malignancies, acute mental status changes can be caused by leptomeningeal carcinomatosis, the presence of CNS leukemia, rapid changes in intracranial pressure due to sudden changes in tumor size (e.g., bleeding into a brain metastasis), paraneoplastic syndromes, or cancer-associated coagulopathies resulting in either cerebral hemorrhage or symptomatic occlusion of cerebral arteries and veins [26]. More commonly, however, acute encephalopathy in cancer patients is caused by electrolyte disturbances, hypo- or hyperglycemia, renal or hepatic dysfunction, hypoxia, narcotic medications, or sepsis. In addition, acute central neurotoxicity can be caused by administration of various chemotherapeutic agents and by radiation therapy. Administration of high doses of intravenous methotrexate has been associated with the development of transient acute encephalopathy, characterized by confusion, somnolence, seizures, as well as focal neurological deficits which usually begin within 2 weeks of MTX administration [27]. Most patients have normal CSF and imaging studies [28] and recover fully. While retreatment is often possible, some patients suffer recurrences during subsequent courses of treatment. Although the exact mechanism of acute MTXinduced neurotoxicity is unknown, a number of ­studies have suggested that profound alterations in cerebral glucose

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metabolism may lead to decreased glucose utilization and protein synthesis [29, 30], and that this could be reversed by administration of intravenous folinic acid (leucovorin) [31]. Acute encephalopathy has also been described after intravenous administration of high doses of ifosfamide, occurring in up to 20% of patients in one study [32]. Agitation, confusion, hallucinations, and aphasia begin anywhere between 2 and 48 h after the administration of the drug and can progress rapidly to seizures, cerebellar or cranial nerve dysfunction, and even coma [33]. The syndrome is usually reversible, but in some patients, long-term CNS sequelae and even death have been reported [34]. Several risk factors have been associated with an increased risk of development of ifosfamide-induced acute neurotoxicity, such as low serum albumin concentration [32], renal insufficiency, pelvic disease [35], prior cisplatin treatment [36], or concurrent administration of drugs (e.g., phenobarbital) which can increase the breakdown of ifosfamide to active metabolites [33]. Although no controlled clinical trials have been conducted, several case reports and retrospective series suggest that methylene blue [37, 38] or thiamine [39] may be useful in both the treatment and prevention of ifosfamide toxicity. However, in most patients, symptoms resolve spontaneously and without any specific treatment [37], and therefore, the role of these agents in the treatment of ifosfamide encephalopathy remains unclear. The main neurotoxicity of 5-fluorouracil (5-FU) is a cerebellar syndrome, but continuous intravenous administration of high doses can rarely cause an acute encephalopathy manifested by an abrupt alteration in mental status with markedly elevated ammonium levels in the absence of organic liver disease [40, 41]. Symptoms include progressive confusion, agitation, ataxia, seizures, stupor, coma, and, frequently, death; the median time of onset of encephalopathy was 2.6 +/−1.3 days from initiation of chemotherapy in one study [42]. Although no specific treatment is available, early recognition and measurement of plasma ammonium, followed by aggressive ammonia-trapping therapy and hemodialysis appears to be critical [41]. Several cases of multifocal inflammatory leukoencephalopathy have been reported with the combined use of 5-FU and levamisole as adjuvant therapy for colon adenocarcinoma [43, 44]. Patients present with a subacute (weeks to months) progressive decline in mental status, ataxia, or transient focal neurological deficits. Characteristically, magnetic resonance imaging with gadolinium demonstrates prominent multifocal enhancing white matter lesions. Pathologically, these lesions are characterized by intense perivascular lymphocytic infiltration and myelin loss, with axonal sparing. The pathogenesis of this syndrome has not been completely elucidated, although levamisole can affect the blood-barrier function and is known to have an immune modulating effect [45]. Complete recovery usually occurs within weeks after cessation of therapy; the role of corticosteroids and

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intravenous immunoglobulin treatment to accelerate improvement is uncertain. Correct diagnosis of 5-FU-associated multifocal inflammatory leukoencephalopathy may require cerebral biopsy and may be important because the clinical presentation and MRI findings may be hard to distinguish from brain metastases. In patients with malignant CNS gliomas, administration of combination chemotherapy with procarbazine, lomustine, and vincristine may be associated with severe central neurotoxic effects with cognitive disturbances or focal neurological deficits which may only be partially reversible with discontinuation of therapy. Of note, procarbazine-induced CNS toxicity worsens with the use of a phenothiazine to control emesis, possibly due to the weak monoamine oxidase inhibitor acti­vity of pro­ carbazine. Other cytotoxic agents known rarely to cause acute or subacute encephalopathy include: L-asparaginase [46]; vincristine [47]; the purine analogs fludarabine, pentostatin, and cladribine [48]; and paclitaxel [49] especially when delivered at high doses (≥600 mg/m [2]) with stem cell support [50]. Biologic response modifiers such as interleukin-2 (IL-2) and the interferons are commonly associated with the development of central nervous system neurotoxicity, which is generally dose-dependent. Up to 50% of patients receiving high-dose IL-2 combined with autologous lymphokineactivated (LAK) cells may experience a transient encephalopathy or a neuropsychiatric syndrome with disorientation, severe cognitive and behavioral changes, delusions, hallucinations, and depression [51]. The vascular leak associated with systemic IL-2 administration may result in cerebral edema which can cause a sudden increase in brain metastases and in intracranial pressure. Less commonly, transient neurological deficits [52] or the development of multifocal acute leukoencephalopathy have been reported [53, 54]. The most common side effects associated with the use of interferons include flu-like symptoms (arthralgias, myalgias, fever, chills, headache), but at higher doses they can also cause

Fig. 31.1  Computed tomography (a) and magnetic resonance imaging with gadolinium (b) demonstrating acute vasogenic edema of the posterior cerebral hemispheres in a patient with acute myelogenous leukemia and cytarabine-induced posterior leukoencephalopathy syndrome (PRES)

R.S. Dronca et al.

s­ ignificant neurotoxicity with confusion, somnolence, ­paresthesias, and extrapyramidal signs [55]. In children, the development of spastic paraplegia or quadriplegia syndrome has been reported 4–15 months after the onset of interferon therapy [56].

Posterior Reversible Encephalopathy Syndrome (PRES) The posterior reversible encephalopathy syndrome, often referred to as reversible posterior edema syndrome or reversible posterior leukoencephalopathy syndrome (RPLS) was first described in 1996 by Hinchey and colleagues [14]. The name is a misnomer, as the syndrome is neither always reversible nor confined to the posterior white matter. The most common causes of PRES are hypertensive encephalopathy, eclampsia, and the use of immunosuppressive and chemotherapeutic drugs. The most common agents associated with the development of PRES include cyclosporine, sirolimus, tacrolimus, cytarabine, cisplatin, gemcitabine, and the monoclonal antibody bevacizumab [57–62]. In cases due to immunosuppressive or chemotherapeutic agents, the presence of toxic drug levels is not required for the development of neurotoxicity. Similarly, patients may be normotensive, although the blood pressure is usually elevated above their baseline. Affected patients commonly develop severe headache, visual disturbances which may progress to cortical blindness, seizures, and altered consciousness ranging from mild somnolence to agitation or stupor and even coma [14, 63]. The hallmark of this diagnosis is vasogenic edema in the territories of the posterior circulation, demonstrated on CT and MR brain imaging [64] (Fig.  31.1). Prompt diagnosis and treatment of this commonly reversible syndrome is critical in preventing permanent neurotoxicity that can otherwise occur if the condition remains unrecognized. Dose reduction or immediate removal of the cytotoxic drug, as well as

31  Central Nervous System Symptoms: Headache, Seizures, Encephalopathy, and Memory Impairment

t­reatment of the associated seizure disorder, hypertension, and fluid overload may result in full recovery with no longterm sequelae. A recent study by Roth and colleagues reported long-term follow-up (mean 2,250 days) of 25 patients with 27 episodes of PRES. Clinical recovery occurred on average after 7.5 days and recurrence was observed in only 8% of patients, even though the causal factors for PRES were repeatedly experienced by the patients [65].

Radiation-Induced Encephalpopathy Recent advances in radiotherapeutic techniques, such as the development of radiosurgery and brachytherapy, and the increased use of radiosensitizers have allowed local dose intensification for the treatment of brain tumors, but have also resulted in increased radiation effects on the surrounding normal tissue. Moreover, improvement in life expectancy and the increasing number of long-term survivors in many cancer types where some form of brain irradiation is employed has uncovered a greater incidence of delayed, chronic radiation-induced neurotoxicity. It is therefore critical for the practicing oncologist and primary care provider to have a thorough understanding of the potential complications associated with brain and spinal cord irradiation in order to properly manage and counsel these patients and their families. The CNS neurotoxicity associated with radiation therapy can be divided into acute (occurring during the course of therapy), early-delayed (occurring weeks to up to 6 months postirradiation), and late-delayed (occurring more than 6 months to several years postirradiation) neurotoxicity [66]. The primary risk factors predictive for the development of radiation side effects include total radiation dose, fractionation schedule, volume and anatomical location of normal brain tissue treated, patient age (i.e., risk is greater in children less than 5  years old and the elderly), and the use of concurrent and sequential chemotherapy [67]. As previously mentioned, acute radiation toxicity is usually characterized by the development of an acute encephalopathy syndrome with severe headache, fever, nausea, vomiting, worsening neurological deficits, and a decreased level of consciousness. While most patients have complete recovery of neurological function, cerebral herniation and death have been rarely reported [15]. In a 1970 study, 6% of 54 patients with cerebral metastases treated with 10  Gy single-dose WBRT died in the first 48  h following treatment [68]. With current WBRT techniques and the conventional use of low fractions (≤3 Gy) the incidence of acute radiation neurotoxicity has substantially declined. The pathogenesis is thought to be the result of disruption of the blood-brain barrier with resultant worsening of cerebral edema. Steroids have been successfully used in the

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treatment and prevention of acute radiation-induced encephalopathy, and they should ideally be started 48–72 h before therapy [69], especially in patients with significant pretreatment brain edema. Early-delayed radiation neurotoxicities include the somnolence syndrome, transient cognitive disturbances, transient focal neurological symptoms, and tumor pseudoprogression. The somnolence syndrome (SS) manifests with drowsiness, followed by anorexia, headache, fever, vomiting, ataxia, and excessive somnolence, which commonly develop in the first 4 weeks to 2 months after completion of radiation treatment. This complication has primarily been described in children undergoing cranial irradiation for acute leukemia or lymphoma [70–72], but can also affect adult patients [73]. The incidence varies widely, with a reported incidence anywhere between 13% and 71% according to age, treatment modalities, and prophylactic steroid dose. Two studies have reported a significantly lower rate of SS in children receiving greater or equal than 15 mg/day of prednisone [70] or 4 mg/day of dexamethasone [71] during the entire course of cranial radiation therapy. Complete resolution is usually expected within 2–3 weeks, therefore the patients and their families should be counseled about the transient nature of this syndrome. The tumor pseudoprogression phenomenon is described mainly after combined radiochemotherapy for glioma, and occurs 6 weeks to 3 months after the end of treatment. The condition can mimic tumor recurrence both clinically and on standard imaging techniques (MRI) [74] and it is thought to correspond to early onset necrosis [75]. Recent prospective studies indicate that the incidence of pseudoprogression may be as high as 50% in glioblastoma patients treated with concomitant radiotherapy and temozolomide [76, 77]. The lesions often remain asymptomatic and may stabilize or decrease in size without additional treatment, although it has been suggested that steroids may be beneficial in some cases. In clinically symptomatic patients, surgery should be consi­ dered [74]. Failure to recognize this development can lead to premature abandonment of an effective adjuvant therapy.

Chronic Encephalopathy and Memory Impairment Chronic cognitive dysfunction associated with chemotherapy is an important and often underestimated long-term side effect of cancer treatment. The term “chemo brain” refers to persistent postchemotherapy cognitive changes in cancer survivors that are independent of anxiety, depression, or fatigue [78]. It is a source of great anxiety and concern for patients and their families and a frequent topic of cancer support groups [79]. Although the true incidence of mild-tomoderate delayed cognitive impairment is difficult to assess,

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several prospective longitudinal studies have reported a definite decline in neuropsychological function after chemotherapy [80–82]. These changes are often subtle but can impact patients’ ability to work and function. Frontal subcortical areas are most likely affected, resulting in difficulties with attention, processing speed, memory retrieval, and executive functions [78]. Magnetic resonance brain imaging may show reduced grey and white matter volumes of brain structures important for executive functions, attention, concentration, or visual memory [83–85]. A recent functional neuroimaging study by Silverman and colleagues showed that, during performance of a short-term recall task, modulation of cerebral blood flow in specific regions of frontal cortex and cerebellum was significantly altered in chemotherapy-treated subjects [86]. The mechanism for these effects remains unclear, and may vary with cancer type, specific therapeutic regimen, age, preexisting conditions, and biological predisposition. The syndrome is often reversible. Leukoencephalopathy, characterized by progressive cognitive slowing, dementia, gait disorder, and other motor dysfunction usually results from treatment with chemotherapy and/or radiation therapy directed at the central nervous system. Severe chronic cognitive dysfunction is usually reported in children with acute leukemia treated with high-dose intravenous or intrathecal methotrexate [87–90] but has also been described in a significant percentage of adult patients treated with high-dose methotrexate and radiation therapy for primary CNS lymphomas [91]. In addition, cranial irradiation therapy, particularly when administered before chemotherapy, greatly increases the risk for development of late neurotoxicity [92]. Neurological deficits are often irreversible. There is no known effective treatment, and the syndrome may progress to severe dementia, coma, or even death. Brain imaging with CT or MRI generally shows diffuse atrophy, intracerebral calcifications, and widespread destruction of white matter [90]. Pathologically, the lesions consist of coalescing areas of coagulation necrosis, with demyelination, and axonal loss; during later stages the white matter is reduced to a thin gliotic calcified layer [93]. A similar syndrome has also been reported with the use of intrathecal or high-dose intravenous ara-C, and with intra-arterial cisplatin or carmustine (BCNU) treatment [94].

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Chapter 32

Neuromuscular Disease and Spinal Cord Compression Roxana S. Dronca, Charles L. Loprinzi, and Daniel H. Lachance

Peripheral Neuropathy Peripheral nervous system (PNS) involvement in patients with cancer may result from cancer therapy, compression or infiltration by the tumour, nutritional deficiencies, metabolic processes, or rarely, paraneoplastic syndromes. Any level of the PNS can be involved from the lower motor neuron to the neuromuscular junction [1]. Depending on the etiology, patients may present with nerve root syndromes (radiculopathy or polyradiculopathy), focal or diffuse plexopathy, mononeuropathy, multifocal neuropathy (mononeuritis multiplex), or more diffuse syndromes defined by distribution of weakness and type and distribution of changes in loss of sensory function. Radiculopathies present with specific patterns of weakness defined by the root level, sensory loss in the same dermatomal distribution, loss of reflexes defined by the root level affected, and frequently, pain following readily identifiable patterns. The most common causes are leptomeningeal spread of lymphoma [2] and carcinoma [3], bone or dural metastasis, or infections (varicella zoster virus, cytomegalovirus). Plexopathy can result from trauma, tumor infiltration [4] or radiation injury. Malignant plexus infiltration occurs in approximately 1% of patients with cancer [1], particularly head and neck tumors (cervical plexus), lung and breast cancer (brachial plexus) [5], prostate, cervical, bladder, or colorectal cancer (lumbosacral plexus) [6]. Patients present with neuropathic pain, which is usually severe and progressive and varying combinations of sensory loss, weakness, muscle atrophy, and areflexia [1]. Radiation-induced plexopathy typically occurs many months to years after completion of treatment and it is often difficult to distinguish from local tumor recurrence. A syndrome of insidiously progressive

R.S. Dronca (*) Department of Oncology/Hematology, Mayo Clinic, 200 1st Street, Rochester, MN 55901, USA e-mail: [email protected]

paresthesias, weakness, and lymphedema without severe pain is more suggestive of radiation-induced plexopathy, while more rapidly evolving deficits with severe pain and, in cases of lower brachial plexus lesions, focal signs such as Horner’s syndrome are more common with metastatic infiltration [5]. Electromyography (EMG) can suggest the diagnosis of radiation-related injury by demonstrating myokimic discharges [7]. Magnetic resonance imaging (MRI), sometimes in combination with Positron Emission Tomography (PET), is best to distinguish tumor infiltration [8]. At times, surgical exploration with nerve fascicle biopsy may be needed to make an accurate diagnosis. Mononeuropathy is defined as involvement of a single nerve, and is usually secondary to local causes, such as nerve compression or entrapment. Malignant tumors of the peripheral nerve sheath or metastases from local extension of solid tumors or non-Hodgkin lymphomas [4] are rare causes of mononeuropathy. Systemic amyloidosis is a rare cause of median nerve injury at the wrist (carpal tunnel syndrome). More common examples of mononeuropathy are carpal tunnel syndrome in patients already affected with more diffuse neuropathy syndromes such as those with diabetes and chemotherapy-associated neuropathy, or peroneal nerve palsy at the fibular head occurring in association with severe weight loss. Mononeuritis multiplex refers to the involvement of multiple nerve trunks and can be seen with multiple compressive neuropathies, vasculitic syndromes, or rarely, metastatic occlusion of the vassa nervorum resulting in multiple nerve infarcts [1]. Polyneuropathy refers to more generalized, diffuse involvement of peripheral nerves. Although any variation in patterns of involvement is possible, most commonly, distal nerve ­segments are more severely affected. The clinical presentation depends on whether sensory or motor nerve fibers are affected, the subtype of sensory fiber injury, whether the primary pathology affects nerve myelin or the nerve (axonoaxonal versus demyelinating), and the rate of progression of nerve injury. In patients with cancer, polyneuropathy can be caused by a wide variety of factors, such as toxins (chemotherapy), metabolic or endocrine disturbances (cachexia; uremia; diabetes mellitus;

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hypothyroidism; vitamin B1, B6, or B12 deficiency), or ­critical illness. Malignancy-related syndromes include autoimmune paraneoplastic disorders, paraproteinemia of multiple myeloma and POEMS syndrome [9], amyloidosis, or cryoglobulinemia. In cancer patients, acute or subacute axonal neuropathies are most often seen as complications of certain chemotherapeutic agents such as platinum compounds, taxanes, vinca alkaloids, ixabepilone, and others [10–12]. Idiopathic acute (GuillainBarre Syndrome) or chronic inflammatory demyelinating neuropathies, thought to be immune-mediated, are rarely encountered in patients with cancer.

Chemotherapy-Induced Peripheral Neuropathy (CIPN) Chemotherapy-induced peripheral neuropathy (CIPN) is a substantial oncologic clinical problem. It is one of the most common chemotherapy-induced complications of a number of cytotoxic agents. It can affect the majority of patients receiving these drugs and 30–40% of all patients receiving chemotherapy. Symptoms, which are usually peripheral and start in a stocking glove distribution, include numbness, tingling, and neuropathic pain. These symptoms generally increase over time with repeated doses of chemotherapy. Chemotherapyinduced peripheral neuropathy limits cytotoxic chemotherapy doses, potentially inhibiting the efficacy of chemotherapy against malignant processes. While these symptoms are often times reversible upon chemotherapy cessation, it can take a long time for them to reverse and some patients do not report resolution of their symptoms for years. Efforts have been ongoing in the past several years to try to prevent this condition from occurring, or when established, alleviate symptoms of nerve injury.

Prevention of Chemotherapy-Induced Peripheral Neuropathy Calcium/Magnesium Infusions A recent pilot study showed that the use of intravenous calcium and magnesium infusions, both before and after oxaliplatin-based chemotherapy, decreased chemotherapyinduced peripheral neuropathy when compared to patients who received similar chemotherapy but without calcium and magnesium [13]. Based on this experience, the North Central Cancer Treatment Group (NCCTG) developed a prospective, placebo-controlled clinical trial [14] which unfortunately was stopped early due to a data safety monitoring error. However, analysis of the 102 patients entered

R.S. Dronca et al.

on the trial, nonetheless, supported the hypothesis that ­calcium and magnesium decreased chemotherapy-induced peripheral neuropathy. The percentage of patients receiving calcium/magnesium with grade II or greater chemotherapy-induced peripheral neuropathy (as judged by the United States National Cancer Institute Common Terminology Criteria for Adverse Events-CTCAE) was decreased from 41% in the patients who received placebo to 22% in the patients receiving the calcium and magnesium (p = 0.03). Data derived from an oxaliplatin-specific neuropathy scale revealed similar results. Further clinical trials are ongoing.

Acetyl-L-Carnitine Acetyl-L-Carnitine provides an important component utilized in the Krebs cycle. It appears to prevent paclitaxel-induced peripheral neuropathy in animals, possibly through mitochondrial metabolism [15]. In humans, this relatively well-tolerated agent has been used with some success in diabetic- and HIV-associated neuropathy [16–19]. Based on these data and data from a small pilot trial in patients with chemotherapy-induced peripheral neuropathy [20], this drug is the subject of an ongoing placebo-controlled, randomized, double-blind trial being conducted by the Southwest Oncology Group (SWOG) for patients receiving adjuvant taxane-based chemotherapy. A similar trial design is being conducted in patients receiving sagopilone, a new epothilone agent that appears to cause neuropathy. The results of these clinical trials will hopefully delineate the potential utility of this agent.

Glutathione Glutathione is a naturally occurring tripeptide that is generally well-tolerated and can be administered intravenously, intramuscularly, or by inhalation. While initially proposed as a helpful agent for preventing cisplatin-induced nephrotoxicity [21], it appeared to decrease the appearance of cisplatin-induced neurotoxicity [22–25]. Five small randomized, placebo-controlled, doubleblind clinical trials in patients receiving cisplatin or oxaliplatin [26–30] have provided evidence to suggest that this drug decreases neurotoxicity. Importantly, it did not interfere with the antitumor activity of these agents. Another small trial with N-acetyl-L-cysteine, which can increase glutathione concentrations in vivo, also showed decreased oxaliplatin-associated neurotoxicity [31]. Based on this evidence, a double-blind, placebo-controlled clinical trial is underway in patients receiving carboplatin/paclitaxel therapy for ovarian cancer.

32  Neuromuscular Disease and Spinal Cord Compression

Alpha-Lipoic Acid/Thiotic Acid Alpha-lipoic acid has been studied in seven randomized trials involving patients with diabetic peripheral neuropathy, and a meta-analysis supports a benefit for this compound, which appears to be quite safe [32]. It is thought to work by decreasing oxidative stress as a lipophilic antioxidant. At the time of writing, a clinical trial involving over 200 patients receiving cisplatin or oxaliplatin-based chemotherapy designed to test whether this agent could decrease the incidence or severity of neuropathy, has completed accrual. Here also, results will hopefully delineate the potential utility of this agent.

Glutamine Glutamine is an amino acid, a neurotransmitter precursor, and important in many neuronal and glial systems and pathways. Data from animal studies suggest that it can decrease chemotherapy-induced peripheral neuropathy although the mechanism is unclear. A randomized, but not placebocontrolled, clinical trial involving approximately 40 patients per arm evaluated this agent in patients receiving oxaliplatin [33]. Another smaller trial looked at this drug in patients receiving high doses of paclitaxel (825  mg/m²) [34]. The authors felt that the results indicated glutamine as helpful for decreasing chemotherapy peripheral neuropathy. Prospective clinical trials are needed.

Vitamin E Vitamin E is another agent that has been proposed, based on its antioxidant properties, as being helpful for decreasing chemotherapy-induced peripheral neuropathy. Pilot data and an interim analysis of a placebo-controlled trial supported that this agent may decrease neuropathy in patients receiving cisplatin [35,36]. However, a large doubleblind, placebo-controlled clinical trial of approximately 200 patients getting neuropathy-inducing cytotoxic chemotherapy, mainly taxanes, did not provide any suggestion of benefit [37,38].

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human leukemia inhibitory factor (RHU LIF) [45] have all failed in clinical trials.

Treatment of Established Chemotherapy-Induced Peripheral Neuropathy Tricyclic Antidepressant Agents Tricyclic antidepressants, such as nortriptyline and amitriptyline have been utilized to treat neuropathic pain from a variety of insults. Based on this, two trials have been conducted looking at nortriptyline and amitriptyline for treating established chemotherapy-induced peripheral neuro­pathy [46,47]. Both of these studies were doubleblind, randomized, and placebo-controlled. They each involved 40–60 patients. Neither of them was able to demonstrate any evidence that the tested tricyclic antidepressant agent was any better than placebo. Given the relatively small numbers of patients on these clinical ­trials, it is possible that a small amount of efficacy might be seen with these agents if a larger numbers of patients were studied.

Gabapentin Gabapentin was developed as an anticonvulsant but has proven to be helpful in patients with neuropathic pain syndromes, particularly related to herpes zoster and diabetic neuropathy. Based on positive clinical trial results in both of these situations, it has been utilized in clinical practice for patients with chemotherapy-induced peripheral neuropathy. This is despite evidence from a prospective rand­ omized, double-blind crossover clinical trial studying gabapentin at a target dose of 2,700  mg/day. This trial, which involved 115 patients, was unable to demonstrate any benefit in numbness, tingling, or neuropathic pain between the two study arms [48]. A related compound, pregabalin, has also been utilized in practice for treating neuropathic pain from a variety of sources. Nonetheless, there is no prospective trial information demonstrating the benefit of this drug for alleviating chemotherapy-induced peripheral neuropathy.

Other Drugs Lamotrigine A number of drugs have been evaluated and have not shown any discernible benefit for preventing or reducing manifestations of neuropathy complicating chemotherapy. Zaliproden [39], Amifostine [40], carbamazepine [41], oxcarbazepine [42], nimodipine [43], ORG-2766 (an adrenal corticotropic hormone analog) [44], and recombinant

Lamotrigine, like gabapentin, was developed as an anticonvulsant. Based on results from trials suggesting that it might be helpful for neuropathic pain from a variety of sources, a randomized, double-blind crossover placebo-­ controlled trial was developed to test the utility of this agent

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in patients with established chemotherapy-induced peripheral neuro­pathy [49]. This trial, which involved 131 subjects, did not demonstrate any suggestion of benefit for this agent for established CIPN.

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c­ urrent time to further evaluate the utility of this agent for treating chemotherapy-induced peripheral neuropathy.

The Paclitaxel Acute Pain Syndrome Topical Baclofen, Amitriptyline, and Ketamine (BAK) Based on suggestive evidence that baclofen, amitriptyline, and ketamine (BAK) might help alleviate neuropathic pain, a clinical trial was conducted whereby these agents were given topically to patients with established chemotherapy-induced peripheral neuropathy [50]. This double-blinded and placebocontrolled clinical trial, while not strongly positive, did suggest that this topical preparation moderately decreased chemotherapy-induced peripheral neuropathy. It appeared to work better in the upper extremities as opposed to the lower extremities. While the above-noted trial was developed and conducted, another group independently developed a clinical trial evaluating topical amitriptyline and ketamine, based on similar background information. This double-blind, placebocontrolled, 6-week clinical trial is currently accruing patients. Thus, at this time, there is suggestive evidence that topical agents may provide some help for patients with chemotherapyinduced peripheral neuropathy. Nonetheless, further work is necessary to confirm this suspicion and better delineate appropriate drug doses.

Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) Pilot data suggest that two different SNRIs, venlafaxine and duloxetine, might be helpful agents for treating established chemotherapy-induced peripheral neuropathy. A Cochrane report, along with other manuscripts, concluded that venlafaxine can be helpful for patients who have neuropathy from a variety of causes [51–53]. Additionally, data in animals also suggest that this drug can decrease hyperalgesia [54]. More specifically, with regards to chemotherapy-induced peripheral neuropathy, there are four reports suggesting that venlafaxine can treat and/or prevent chemotherapy-induced peripheral neuropathy [55–58]. Results of a small, placebo-controlled, randomized clinical trial presented at the 2009 American Society of Clinical Oncology meeting supported that venlafaxine was helpful for the treatment and prevention of oxaliplatin-caused neuropathy [59]. A larger prospective clinical trial is being developed to further evaluate the utility of venlafaxine for treating chemotherapy-induced peripheral neuropathy. Duloxetine has been established to be helpful for patients with diabetic peripheral neuropathy and is well-tolerated [60]. A clinical trial, being conducted by the Cancer and Leukemia Group B (CALGB), is accruing patients at the

Paclitaxel causes an acute toxicity which is not seen with most other cytotoxic agents. This consists of pain occurring 1–3 days after the drug has been given and lasting for up to a week or longer. In the past, this has been termed paclitaxelinduced arthralgias/myalgias [61–64]. It has recently been hypothesized that these aches and pains are neurogenic [65]; they are most common in the lower extremities but also affect the back, shoulders, and other areas. The pain is generally noted to be a deep aching pain. Patients describe it as radiating, shooting, stabbing, and/or pulsating. One prospective, double-blind, placebo-controlled clinical trial evaluated glutamine for prevention of this painful syndrome in patients who had this pain from a prior cycle of paclitaxel-based ther apy and were about to receive subsequent further therapy [66]. Unfortunately, this trial did not demonstrate a benefit. Small pilot reports or trials have investigated gabapentin [67,68], antihistamines [69], corticosteroids [70], opioid analgesics [71], amifostine [72], and Shakuyaku-Kanzo-To (a Japanese herb) [73]. None of these can be recommended for clinical practice at this time.

Summary Chemotherapy-induced peripheral neuropathy is a prominent clinical problem. There have not been any widely accepted therapies for prevention and/or treatment of this problem. The most promising appearing compounds, calcium/magnesium infusion, oral agents such as glutathione, acetyl-L-carnitine, alpha-lipoic acid/thiotic acid, venlafaxine, duloxetine, and topical baclofen/amitriptyline/ketamine are awaiting the completion of placebo-controlled clinical trials.

Paraneoplastic Syndromes Although the exact incidence of paraneoplastic neurologic autoimmunity is difficult to assess, these conditions are rare, affecting less than 1% of patients with cancer [1,74]. In the majority of cases, the neurological disorder occurs months or years before the primary malignancy is diagnosed [74] and it often follows a subacute course, leading to severe and disabling symptoms [74]. The discovery of cancer-related antibodies that react with both the tumor and the nervous system (onconeural antibodies) in the serum and/or cerebrospinal

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fluid of many patients with paraneoplastic syndromes ­suggest that many of these syndromes are immune-mediated. However, many paraneoplastic syndromes are not associated with known marker antibodies [75]. Conversely, several marker antibodies, known to be associated with a variety of neurological disorders, may occur simultaneously in the same patient. Moreover, some well-defined onconeural antibodies may occur in patients with or without identifiable cancer, and without a neurological illness. Therefore, the identification of these antibodies alone is neither sufficient nor necessary for defining a neurological condition as being paraneoplastic [76]. The antibodies do not predict the neurological disorder, as more than one syndrome can be associated with any given antibody marker. However, the identification of one or more antibodies often predicts the associated cancer and directs the search for occult disease. Paraneoplastic neurological autoimmunity can affect any level of the nervous system. For the purpose of this discussion, several well-known syndromes are discussed, which manifest as spinal cord or neuromuscular disease. Subacute or chronic myelopathy, associated with CRMP-5, and acute transverse myelopathy associated with ANNA-1 are predictors of small-cell lung cancer (SCLC). ANNA-1 and ANNA-2 have been associated with subacute motor neuropathy, and are highly predictive of an underlying small-cell cancer. ANNA-1 has been associated with sensory neuronopathy, and CRMP-5 with polyradiculopathy and plexopathy. An array of antibodies and paraproteinemias has been associated with sensory-motor neuropathy of varying severity, but some of the antibodies are clearly predictive of the associated neoplasm. Myasthenia gravis is associated with antibodies to muscle acetyl choline receptors, muscle-associated proteins (striational antibodies), voltage-gated potassium channels, neuronal acetyl choline receptors, and glutamic acid decarboxylase. When seen in some combinations, these antibodies may often predict thymoma. While approximately 75% of patients with MG have thymic disease (most commonly thymic hyperplasia), thymic carcinoma is present in only about 10% of patients. Conversely, approximately 30–40% of patients with thymoma have associated MG [77,78]. Occasionally, MG is diagnosed in patients with tumors other than thymomas, especially lung cancer or non-Hodgkin ­lymphomas [79,80]. Another disorder of neuromuscular transmission, Lambert Eaton Syndrome, directly related to the presence of antibodies to P/Q-type voltage-gated calcium channels [81], predicts the presence of an occult SCLC in 50–60% of patients, but when found with additional onconeural antigens such as AGNA-1, is 80–90% predictive of SCLC [82]. Disorders of neuromuscular hyperexcitability (acquired neuromyotonia) may be associated with voltage-gated potassium channel antibodies. When found in high titer, the presence of these antibodies has a low, but not insignificant predictive value for determining the presence of an underlying cancer.

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Lambert-Eaton myasthenic syndrome (LEMS) is a ­disorder of the presynaptic nerve terminal at the neuromuscular junction. Autoantibodies accelerate internalization and degradation of P/Q-type voltage-gated calcium channels and impair acetylcholine release in response to action potentials. The dominant neurological features include proximal limb muscle weakness, most prominent in the legs, worse at rest and repairing somewhat with activity; autonomic dysfunction with mouth or eye dryness; blurred vision; constipation; impotence; orthostatic hypotension is a frequent accompa­ niment [82]. Characteristically, EMG shows a significant increment in the compound muscle action potential (CMAP) following high-frequency repetitive stimulation or brief maximal isometrical muscle activation. Successful treatment of cancer leads to improvement in many patients. Symptomatic treatment with medications that increase the amount of or effects of acetylcholine at the postsynaptic membrane (pyridostigmine, guanidine, 3,4-diamynopriridine [83, 84]), or immunotherapy with plasma exchange, intravenous immune globulins, or combinations with prednisone, azathioprine, or cyclophosphamide may be considered [83]. Myasthenia gravis (MG) is a postsynaptic disorder of the neuromuscular junction, caused by autoantibodies that accelerate acetylcholine receptor degradation [85]. Weakness that often worsens with sustained muscle activity may present with disorders of ocular motor function, dysphagia, and dysarthria. Some patients present with more generalized weakness, while others evolve to a more generalized, proximal weakness after a period with a more restricted ­pattern of ocular muscle or bulbar muscle weakness. This generalization may progress subacutely and can prominently affect the muscles of ventilation leading to respiratory failure. As with the LEMS, treatment includes symptomatic therapies to increase the availability of acetylcholine at the postsynaptic membrane, immunotherapy, and thymectomy, even in patients who do not have thymomas [86]. In patients with severe generalized weakness, plasma exchange or IVIG can lead to rapid improvement over days to weeks. Paraneoplastic neuromyotonia (Isaac Syndrome) produces continuous motor unit activity with muscle stiffness, cramps, twitching, or weakness [87]. Treatment is primarily symptomatic, focusing on agents used to stabilize neuronal hyperexcitability, such as anticonvulsants. In more severe cases, immunotherapy is considered. In general, the approach to paraneoplastic autoimmunity is mainly directed at removing the source of antigen by treatment of the underlying cancer or plasma exchange, and/or suppression of the immune system [74]. Those syndromes associated with antibodies to cell surface antigens or cation channels have the greatest potential for reversibility, while those associated with antibodies to cytoplasmic or nuclear antigens fair most poorly, with often irreversible neurological disability by the time the cancer is identified, treatment

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initiated, and immune-mediated injury arrested. Although no specific guidelines exist, some authors have used the combination of intravenous immune globulin, corticosteroids, and cyclophosphamide [88]; the experience with tacrolimus is more limited [89].

Muscle Disease In patients with cancer, myopathy is often a consequence of treatment, but may also be secondary to metabolic/electrolyte disturbances, endocrine disorders, infections, rhabdomyolysis (e.g., seizures), or paraneoplastic syndromes. Many patients with advanced malignancies complain of generalized weakness. It is important to distinguish between true myopathy and cancer asthenia secondary to cachexia, anemia, or depression. This is often possible by formal assessment of muscle strength on physical examination, given that strength is often preserved in patients with asthenia. In addition, history and physical examination is useful in localizing the site of the lesion causing muscle weakness to the upper or lower motor neuron, peripheral nerve, or muscle. Corticosteroid treatment is a well-known cause of myopathy. Weakness is proximal, affecting neck flexors, the muscles of the shoulder and pelvic regions. Creatine kinase is normal. Chemotherapy drugs rarely cause isolated myopathy, but cases have been described with the use of paclitaxel [61], vincristine, or interferon [90]. In addition, certain ­chemotherapy drugs can cause significant electrolyte abnormalities resulting in muscle weakness, such as hypomagnesemia seen with cisplatin administration [91], or hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone produced by vincristine [92]. Inflammatory myopathies, such as dermatomyositis and polymyositis, may also have a cancer association. Whether the mechanisms of this association are immune-mediated is unclear. Approximately 15% of patients with dermatomyositis and 9% of patients with polymyositis develop a neoplasm [93]; the most common tumors are breast, ovarian, lung, and gastrointestinal carcinomas, as well as non-Hodgkin lymphomas [94]. The clinical presentation of paraneoplastic poly- and dermatomyositis is similar to that of patients without cancer [75]. Treatment is directed primarily at controlling the underlying cancer and suppression of the immune system (steroids, intravenous immune globulins [95], azathioprine [96]). Acute necrotizing myopathy is a rare disorder that may be associated with certain connective tissue diseases; and in some circumstances there is serological evidence of autoimmunity. It can be seen in patients with cancer, primarily with gastrointestinal, genitourinary, and lung carcinoma. It is characterized by severe painless muscle weakness, with a markedly elevated creatine kinase and histological evidence of muscle necrosis [97].

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Spinal Cord Compression Malignant epidural spinal cord compression (ESCC) is one of the most feared complications of metastatic cancer and a true oncological emergency. Left untreated, ESCC will result in permanent loss of neurological function in the vast majority of affected patients. The incidence is difficult to estimate accurately, as some patients with advanced cancer may have subclinical spinal cord involvement, while others may decline further invasive diagnostic testing or therapy late in the course of their illness. In one large Canadian populationbased study, the cumulative probability of experiencing ESCC in the 5 years before death from a known malignancy was 2.5% overall, ranging from 0.2% in pancreatic cancer to almost 8% in multiple myeloma [98]. Similarly, the frequency of ESCC in autopsy studies has been found to be approximately 5% in patients dying with cancer [99]. However, with improved imaging modalities and recent advances in therapy, it is likely that the incidence of metastatic spinal disease will increase as overall survival improves for many cancers. It is therefore important that medical and radiation oncologists, neurologists, and all other physicians caring for patients with cancer understand the pathophysiology, clinical presentation, diagnostic workup, and management of this complex oncological problem. The most accepted definition of ESCC encompasses both clinical and radiographic criteria. As a general rule, any radiologic evidence of thecal sac indentation causing clinical symptoms (local or radicular pain, motor weakness, sensory disturbance, and/or sphincter disturbance) is considered evidence of ESCC [100]. Subclinical cord compression, on the other hand, is defined by the presence of radiographic abnormalities of spinal cord compression in the absence of clinical symptoms [100]. Therefore, in adults, the spinal cord ends at L1 and below this level compression of the thecal sac causes impingement of the lumbosacral nerve roots only, commonly referred to as cauda equina syndrome. Nonetheless, since the pathophysiology of this syndrome is similar to that of spinal cord compression, most authors include compression of cauda equina in the syndrome of ESCC. Malignant tumors reach the epidural space and compress the dural sac and its contents (spinal cord and/or cauda equina) via three main mechanisms. The most common mechanism is hematogenous spread to the vertebral body [101]. Therefore, the initial anatomic location of the metastasis is in the posterior portion of the vertebral body in the vast majority cases [102]. This gives rise to a vertebral mass that progressively enlarges and eventually causes secondary compression of the spinal cord or an acute vertebral body collapse with dislocation of bony fragments into the epidural space. Less common mechanisms of ESCC include growth of a paraspinal mass through the vertebral neural foramen (lymphomas, neuroblastomas [103]), or direct metastasis to the epidural space without

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involvement of the vertebral body or a paraspinal mass component. The most common site of metastasis is the thoracic spine, proportional with the relative bone mass and the blood flow (approximately 60% of cases), followed by the lumbosacral (30%) and cervical spine (10%) [104]. Thirty to 40% of patients with ESCC have multiple epidural metastases resulting in multiple sites of spinal cord compression [105,106]. ESCC is often a late event in the clinical course of patients with advanced systemic malignancies. Most cases are due to tumors with a high tendency to metastasize to the spinal column, such as carcinoma of prostate, breast, and lung, which account for 15–20% of cases each. Other common causes of ESCC are renal cell carcinoma, multiple myeloma, and non-Hodgkin lymphoma, with the remaining cases being caused by metastatic colorectal cancers, sarcomas, cancers of unknown primary and, less commonly, other tumors [98,105,107,108]. However, up to 20% of patients can present with spinal epidural metastases as the initial manifestation of cancer. The great majority of neoplasms presenting with ESCC in a Mayo Clinic study were carcinoma of the lung, cancers of unknown primary, multiple myeloma, and non-Hodgkin lymphoma [109].

Clinical Presentation The most common symptom of ESCC is back pain, which is present in 80–95% of patients at diagnosis [103,107,110]. Initially, the pain is localized to the spine, confined to the affected region, and is caused by extension of metastasis from the vertebral bone marrow to the periosteum or surrounding soft tissues [104]. The pain is usually worse at night and with recumbency (possibly due to distension of the epidural venous plexus [104]) and is often exacerbated by movement and Valsalva-type maneuvers. Mechanical back pain in a patient with ESCC may also be caused by a pathological fracture or vertebral body collapse, and may result in spinal cord instability and impending cord compression. Radicular pain results from compression or invasion of the nerve roots and is most common in patients with lumbosacral spine metastases [110]. In patients with thoracic spine involvement, the pain is often bilateral and wraps around anteriorly, in a “girdle-like” fashion. Approximately 60–70% of patients with ESCC exhibit some degree of motor weakness and gait abnormalities at diagnosis [107,110]. The pattern and magnitude of the motor deficit depends on the location of the spinal cord lesion and the involvement of upper versus lower motor neuron tracts. Upper motor neuron deficits usually result in fairly symmetrical weakness of the upper or lower extremities, whereas lower motor neuron weakness is commonly asymmetrical [104].

The progression of motor weakness is followed by loss of gait function and ultimately paralysis; in large series, up to twothirds of patients were non-ambulatory at diagnosis [107,111]. Isolated sensory deficits are uncommon, but are present at diagnosis in up to 70% of patients, often in association with back pain or weakness [103,110]. Patients may report ascending paresthesias, but tend to be less aware of radicular sensory deficits. Cauda equina lesions usually result in sensory loss in a saddle-type distribution, in contrast to lesions located above this level which commonly spare sacral dermatomes. When a sensory level is present, the anatomic localization of the spinal lesion is typically one to five segments above the level of the sensory deficit. Lhermitte’s phenomenon, described as brief electric-like shock sensations down the spine with neck flexion, can be seen in patients with cervical or thoracic ESCC [112]; it also has been described in patients suffering from chemotherapy or radiation therapy associated myelopathy. Other clinical findings, such as bowel or bladder dysfunction or autonomic symptoms tend to occur late in the clinical course of ESCC [104]. However, up to 50% of patients have some degree of bowel or bladder dysfunction at diagnosis [107] and they are generally a poor prognostic sign for preservation of ambulatory status [104].

Diagnosis Early recognition of ESCC is crucial since the main determinant of clinical outcome and posttreatment ambulatory function is the patient’s pretreatment functional status [113,114]. Unfortunately, delays in diagnosis and referral are common and are associated with loss of motor and bladder function which may be irreversible [111]. In a prospective study of 301 patients with ESCC [111], the median delay to treatment was 73.5 days from the onset of back pain, 13.5 days from onset of weakness, and 4 days from loss of ambulation. While 3–4 day delays were due to lack of patients seeking attention, the majority were attributable to diagnostic delays at general practitioner (3  days) and general hospital level (4  days). Because the outcome can be devastating, a high index of suspicion is vital especially in a patient with known cancer and new onset of back pain or neurological complaints. Magnetic resonance imaging (MRI) is the method of choice for the diagnosis of ESCC and can provide an accurate evaluation of the vertebral bones, paraspinal soft tissues, and the spinal cord. MRI has an overall accuracy of 95% (sensitivity 93%, specificity 97%) [115]. The importance of imaging the entire spine was illustrated in a retrospective Mayo Clinic study in which failure to image the thoracic or lumbar spine would have missed secondary epidural deposits in 21% of patients [105]. Myelography, often used in combination with computed tomography (CT) was the imaging modality of choice prior to the widespread use of MRI and it is still used when

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MRI is not feasible or is contraindicated (e.g., severe claustrophobia, metallic implants). However, myelography is more invasive and requires a lumbar or cervical puncture and the use of intrathecal contrast agents. Positron emission tomography (PET) scans are not used in the diagnosis or treatment planning of ESCC as their anatomic resolution is suboptimal comparative to MRI and are not informative enough about thecal sac compression [104]. Although plain films are often obtained, they have a 10–17% false-negative rate [116]; additionally, paraspinal masses may not be visualized on plain roentgenograms of the spine if there is no bone erosion.

Treatment Treatment of ESCC includes administration of corticosteroids followed by surgery and/or radiation therapy (RT). Studies in animals have shown that spinal cord compression by tumor causes occlusion of the epidural venous plexus with breakdown of the blood-brain barrier and vasogenic edema, which can be partially or completely reversed by the administration of dexamethasone [117]. In the late stages of cord compression, the arterial supply to the spinal cord is impaired resulting in infarction and irreversible cord damage.

Corticosteroids To date, three randomized controlled trials (RCTs) [118,119], one phase II trial [120], and one case-control study [121] addressed the efficacy and optimal dose of corticosteroids in ESCC. In a study by Sorensen and colleagues [119], 57 patients undergoing RT for ESCC were randomized to highdose corticosteroids (96 mg bolus intravenously, followed by 96 mg orally for 3 days and a 10 day taper) or no steroid treatment. A statistically significant higher percentage of patients in the dexamethasone arm remained ambulatory at the end of therapy (81% versus 63%) and at 6 months (59% versus 33%) compared to patients in the control group. Significant side effects associated with steroid treatment were reported in three patients (11%), two of whom discontinued treatment. The optimal loading dose of dexamethasone was addressed in the study by Vecht et al., in which 37 patients with complete myelographic obstruction were randomized to high-dose (100 mg) versus moderate-dose intravenous bolus dexamethasone (10 mg), followed by 16 mg per day orally. The average pain score improved significantly with steroid therapy in all patients, but there were no significant differences between the two groups in pain reduction or neurological outcome. Although the study was small and insufficiently powered, the authors concluded that a lower loading dose could be used, given similar results. Moreover, for selected patients, steroid

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therapy may not be required. A small study by Maranzano et al. [120], suggested that selected patients with subclinical cord compression, no neurologic deficit, and limited involvement of adjacent spinal elements on MRI or CT imaging can be treated successfully with RT alone, therefore avoiding the effects of steroid treatment. A recent Cochrane meta-analysis concluded that there is insufficient evidence about the role of corticosteroids in ESCC and that serious adverse events were most frequently seen in patients treated with high dexamethasone doses [122]. Currently, there is no consensus in regards to the best loading dose and maintenance corticosteroid regimen in patients with ESCC. Some authors recommend reserving the high-dose regimen for patients with paraparesis/ paraplegia or rapidly progressive neurological symptoms, while ambulatory patients with minimal or nonprogressive motor symptoms could be treated with moderate doses (10 mg bolus followed by 16 mg daily) [104].

Surgery In the past, surgical management of ESCC in patients with neurological compromise consisted mainly of posterior decompression of the spinal cord using a laminectomy. However, the bulk of the tumor is usually located in the vertebral body, anterior to the thecal sac, and laminectomy is therefore unsuccessful in removing the tumor from the epidural space in many cases. Given that the results of laminectomy did not differ from that of RT alone [103,122–124], surgical treatment was largely abandoned until recently, when new techniques of tumor resection, circumferential decompression, and spine reconstruction were developed. A recent randomized trial compared the role of aggressive tumor debulking by circumferential decompression within 24  h of study entry followed by RT (30 Gy over 10 days within 14 days of surgery) with the same RT alone in 101 patients with a known diagnosis of cancer and metastatic ESCC. Both groups were started on 100 mg dexamethasone loading dose followed by 24 mg every 6 h until they began treatment, followed by a taper until completion of RT. The study was stopped after a planned interim analysis showed a significantly better outcome in the group who had surgery followed by radiation compared to those who had RT alone. Patients treated with surgery had a higher ambulatory rate (84% versus 57%; p = 0.001) and were able to walk for a significantly longer period (median 122 versus 13 days; p = 0.003). In addition, a higher number of patients regained the ability to walk (ten of 16 patients) compared to those treated with RT alone (three of 16 patients). Median survival was also longer in the surgery group (126 versus 100 days, respectively; p = 0.003). While the results of this trial indicate that radical resection followed by RT is effective in regaining the ability to walk and maintain ambulation, careful interpretation of the conclusion and adequate selection

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of patients who qualify for this aggressive approach is required. For instance, the trial excluded patients with more than one site of ESCC or certain radiosensitive tumors (multiple myeloma, lymphomas, leukemias, germ-cell tumors). In addition, a later unplanned subgroup analysis suggested that preservation of ambulation was significantly prolonged in patients under the age of 65 years, but not in older individuals [125].

Bisphosphonates Bisphosphonates have a proven benefit in reducing bone pain and pathological fractures [127,128] as well as the risk of bone metastases [129] in patients with cancer. In a recent meta-analysis by Ross and colleagues [130], the use of bisphosphonates significantly decreased skeletal morbidity, but did not significantly decrease the risk of ESCC despite a positive trend (OR 0.71; 95%CI 0.47–1.08; p = 0.113).

Radiation Therapy External beam RT is used in the treatment of ESCC in patients who are not surgical candidates or in association with surgery (see above). RT results in preservation or improvement of function particularly in patients who have tumors that are radiosensitive and who are ambulatory at presentation [104]. The optimum dose and treatment regimen are still controversial and a variety of radiation schedules have been used. A prospective nonrandomized trial compared 30  Gy in ten fractions versus 40  Gy in 40 fractions in 231 patients with ESCC; although both regimens resulted in similar functional outcomes and overall survival, the long-course RT was associated with significantly better local control (77% versus 61%; p = 0.032) and 12  months progression-free survival (72% versus 55%; p = 0.034) [113]. In a retrospective analysis of 1,304 patients, Rades et al. looked at five radiotherapy schedules: one 8 Gy dose in 1 day (n = 261), five doses of 4 Gy in 1 week (n = 279), ten doses of 3 Gy in 2 weeks (n = 274), 15 doses of 2.5 Gy in 3 weeks (n = 233), and 20 doses of 2 Gy in 4 weeks (n = 257). Once again, the five RT schedules provided similar functional outcomes, but the protracted regimens seemed to result in fewer in-field recurrences. Also, high daily doses may be more toxic resulting in acute necrotizing injury to the spinal cord [126]. In general, short courses of radiation, ranging from 8 Gy in one fraction to 20 Gy in five fractions are reserved for patients with ESCC who have a relatively short life expectancy, while more protracted courses of treatment with 30 Gy in ten fractions or 40 Gy in 20 fractions are usually used for all other patients [104].

Chemotherapy Chemotherapy is rarely used in the acute management of ESCC, even in patients with chemosensitive tumors, as the response in generally too slow and unpredictable [104]. However, chemotherapy is sometimes used in combination with radiation therapy where dictated by the circumstances of the systemic malignancy. For those who have a recurrence in a previously irradiated field precluding further treatment, and no surgical options, chemotherapy may be the only appropriate treatment choice.

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Chapter 33

Eye Symptoms and Toxicities of Systemic Chemotherapy April Teitelbaum

Introduction Many malignancies have become chronic in nature due to advances in treatments and development of new therapies that target cancer-cell-specific pathways on a molecular level. Patients are living longer, often with exposure to multiple treatment regimens, each with their own toxicities. Attributing a toxicity to a specific agent is often difficult when drugs are administered in combination, even with the preclinical identification of a potential toxicity. Some toxicities are dose-dependent and may be unique to high doses (e.g., cytosine arabinoside, methotrexate) or to cumulative doses of the drug. Toxicity may vary by route of administration (oral, intravenous, intrathecal, intra-arterial) and by inadvertant prolonged exposure to the drug due to coexistent renal or hepatic insufficiency. Visual complications may come to light as part of a questionnaire or as a result of a complaint of a visual change or as an observed manifestation of toxicity. Most ophthalmic complications are mild-to-moderate in nature and are readily reversible with dose modification or cessation of the drug, if the toxicity is recognized early; others are more severe, and may be irreversible. Descriptions of ocular effects in this chapter are limited to oral, intravenous, or intrathecal administration chemotherapy agents. Ocular effects from intra-carotid administration, instillation in the eye, or those due to opportunistic infection, such as reactivation of latent viral infections as a consequence of chemotherapy-related immunosuppression, are not included in this review. Common chemotherapy-related ocular effects include development of blepharitis (chronic and persistent eyelid inflammation), cataracts, glaucoma, conjunctivitis, dry eye (keratotoconjunctivitis sicca, sicca syndrome) or watery eye (epiphora) syndromes, keratitis (corneal ulcers), and photophobia and may be manifest initially by subtle changes A. Teitelbaum (*) AHT BioPharma Advisory Services, 3525A Del Mar Heights #312, San Diego, CA 92130, USA e-mail: [email protected]

such as blurred vision, itchy eyes, gritty sensation in the eye, or eye pain. Retinal and optic nerve damage are more serious potential consequences of some chemotherapy drugs and if unrecognized can result in visual loss which may be irreversible [1, 2]. Residual effects may persist even when ocular effects appear to have resolved. Corneas from donors recently treated with systemic chemotherapy are susceptible to development of ocular surface disease and central corneal opacification that is a direct consequence of the effect of the chemotherapy on the corneal epithelium. It is estimated that up to 4% of recipients from chemotherapy-treated patients may be affected [3]. Individual drugs and their associated ocular toxicities are reviewed by categories as defined by the mechanism of action of the agent.

Alkylating Agents Non-Platinum Alkylating Agents: Chlorambucil, Cyclophosphamide, Ifosfamide, Busulfan, Nitrosoureas Ocular effects of chlorambucil are likely due to cumulative exposure to the drug. The most frequently reported effect is keratitis, with a single case of diplopia with bilateral papilledema and retinal hemorrhages reported [4] as well as visual failure and optic atrophy after several years of chlorambucil [5]. Because cyclophosphamide is rarely administered as a single agent, it is often difficult to determine if ocular side effects are due to the drug alone or to combination therapy. Transitory blurred vision is common and can occur anywhere from minutes to 24 h after administration, especially with high doses, and generally resolves after 1–14 days [2]. Up to 50% of patients treated with cyclophosphamide develop dry eyes (keratoconjunctivitis sicca) and blepharoconjunctivitis and conjunctivitis have been attributed to an irritative and a direct toxic effect of the drug in tears [6]. Pinpoint pupils and recurrent transitory myopia have been

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reported following intravenous bolus administration of the drug [2]. A case of irreversible lacrimal duct stenosis and watery eyes in a patient undergoing combination cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) ­chemotherapy led to a retrospective study over 2.5 years of 128 women undergoing the same treatment regimen. In that review, 18% of women reported ocular side effects, including four additional cases of epiphora that resolved completely in all but one patient when chemotherapy ended [7]. Lacrimal outflow obstruction from sclerosing caniculitis following CMF has been documented, with histology showing changes of chronic inflammation, and fibrosis of the lacrimal apparatus noted [8]. A case report describes reversible blurred vision and conjunctivitis, similar to that observed with cyclophosphamide, during the third day of ifosfamide infusion, with resolution of symptoms after the infusion ended [9]. The most common and characteristic ocular side effect of busulfan is development of posterior subcapsular cataract with a polychromatic sheen, although nonspecific blurred vision and dry eye syndromes may occur also [2]. Busulfan is secreted in tears and may have a direct irritative effect on the conjunctiva, and as such could potentially aggravate preexisting dry eyes. The incidence and severity of cataract formation is proportionate to the total cumulative dose and duration of treatment. Imperia et  al. reported that patients who developed a posterior subcapsular cataract had a mean duration of therapy of 113.5 months [10], although cataract development after only 4  days of high-dose treatment (212 mg/day) has been reported [11]. Al-Tweigeri et al. [4] suggested that busulfan-induced cataracts are mechanistically related to decreased DNA synthesis in proliferating lens epithelial cells. The incidence of cataract formation increases when busulfan is combined with corticosteroids, which are cataractogenic in their own right.

Nitrosoureas The nitrosoureas (carmustine, CCNU, methyl CCNU) cross the blood–brain barrier, and as such, penetrate the blood–retinal barrier and can be associated with increased neuro-retinal toxicity [6]. Nonspecific and transient blurred vision, loss of depth perception, acute conjunctival hyperemia, and retinopathy have been reported [2, 12]. Toxicity is ­usually worse with higher doses such as those used with autologous marrow rescue, often with delayed onset. Shingleton et  al. [13] described delayed bilateral ocular toxicity in two of 50 patients treated with high-dose intravenous BCNU with autologous bone marrow rescue. Segmental perivascular staining, retinal artery destruction, widespread late capillary leakage, and optic nerve head hyperfluorescence was evident with fluorescein angiography [13],

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and others have reported focal optic nerve demyelination [14]. Johnson et al. described ten cases of ocular toxicities with varying degrees of vision loss and ischemic microvascular lesions of the retina and optic disc that developed around the same time as pulmonary toxicity after highdose BCNU, cyclophosphamide, and cisplatin followed by autologous hematopoietic progenitor cell support. Cottonwool spots were noted at 1–4 months post-transplant and three patients developed optic disc edema and variable vision loss associated with the onset of BCNU-induced pulmonary toxicity [15]. All of the ocular toxicities resolved and the cotton-wool patches and hemorrhages faded away within 2–3 months.

Platinum Agents (Cisplatin, Carboplatin, Oxaliplatin) Cisplatin-associated neurotoxicity is dose-limiting and when administered intravenously, neuro-retinal side effects, including blurred vision, color vision defects, and electroretinographic (ERG) changes may occur [2, 6]. Optic nerve changes including edema, neuritis, and retrobulbar neuritis have been reported for high dose as well as cumulative lower doses of the drug [2]. Higher doses are associated with transient cortical blindness and temporary homonymous hemianopsia, as well as macular pigmentary changes which may persist after discontinuation of treatment [2]. All but the pigmentary changes are reversible. Wilding et al. reported on 13 women treated with high cumulative doses of platinum (400–800 mg/ m2) over 2–4 cycles for ovarian cancer, noting that eight patients experienced blurred vision, three experienced decreased color vision (blue–yellow axis), six developed irregular pigmentation in the macula, and some cone dysfunction as demonstrated by color vision testing or ERG was noted in nine patients [16]. Blurred vision improved after discontinuing the drug, but color defects persisted for up to 16 months. Katz described a patient who developed bilateral irreversible visual loss after four cycles of cisplatin; fundoscopic exam was normal but there were coexistent ERG changes and bilateral central scotomas on visual field exam [17]. A single case of monocular vision loss after the fifth cycle of combination cisplatin and gemcitabine has been reported [18]. Reversible segmented nerve demyelination similar to that seen with heavy metal CNS toxicity may occur with cisplatin and nystagmus secondary to cisplatin-induced vestibular pathology may occur and may be of greater severity in those with darker irises since cisplatin is sequestered in melanocytes [19]. Maculopathy, optic neuropathy, cortical blindness, sore eyes, blurred vision, and choroidoretinitis and optic neuritis have been reported with intravenous carboplatin.

33  Eye Symptoms and Toxicities of Systemic Chemotherapy

Fischer et al. reported the case of a patient with carboplatin dosed by AUC who developed bilateral papilledema and only partially reversible visual impairment [20]. After the fourth cycle the patient complained of lack of focus and scattered blind spots in the right eye. Slightly reduced visual acuity was present in both eyes and bilateral papilledema was noted on fundoscopy, with a more prominent optic nerve head in the right eye and some hemorrhages in the nerve fiber layer. After the fifth cycle, visual acuity decreased and new visual field losses in the left eye had developed. Increased papilledema was noted bilaterally, particularly in the left eye, the hemorrhages in the right eye had almost disappeared, and some signs of ischemia were noted. Visual acuity in the left eye worsened and there was a left relative afferent pupillary defect. With tapering doses of oral prednisolone over 10  weeks, visual acuity in the right eye was stable, and the left eye improved over 2 years although residual optic atrophy persisted. Varying degrees of papilledema and blindness have been reported following high dose (AUC 12) [21] and fixed dose (400 mg/m2) carboplatin [22] and after simultaneous carboplatin and cisplatin administration [23]. Vision abnormalities, in particular transient vision loss which is reversible following discontinuation of treatment, have been reported with oxaliplatin. Episodes of transient blindness lasting for seconds or minutes may recur repeatedly and last for hours to days. Cranial nerve dysfunction may occur by itself or along with ptosis [24] or diplopia, eye pain, decrease of visual acuity, visual field disorders, and/or transient blindness [25]. Tunnel vision, visual loss with postural changes, and papilledema have been reported at various times following treatment with oxaliplatin [26].

Antimetabolites Pyrimidine Analogs (5-Fluorouracil, Capecitabine, Cytarabine Arabinoside) 5-Fluorouracil (5-FU) is sometimes administered as a single agent, often as a continuous infusion, or in combination with other agents. Because therapeutic doses of 5-FU are often close to its toxic level, almost one-third of patients develop some type of ocular side effect manifested by blurred vision, ocular pain, photophobia, excess tearing, eye irritation, and conjunctivitis out of proportion to clinical findings, periorbital edema, ectropion (turning out of the lower eyelid), and/or ­keratitis. Effects may occur early in the course of treatment or after long-term exposure [27]. Rapidly proliferating cells such as the epithelial cells on the eye surface are especially ­susceptible to 5-FU, which has been isolated in tears at levels

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comparable to plasma levels of patients with excessive tearing but not in patients without eye symptoms. With long-term therapy and if left undetected, lacrimal duct stenosis and excessive tearing may occur [28], sometimes with severe squamous metaplasia of the lacrimal canaliculi [29] Toxic effects to the cornea, including corneal opacities, can also occur. Oculomotor effects, including nystagmus and diplopia, may occur as a result of drug-related neurotoxicity [28]. Severe toxicity, including ocular effects, has been reported in patients with complete or partial deficiency of dihydropyrimidine dehydrogenase, the rate-limiting enzyme in 5-FU catabolism [30]. Ocular symptoms can be managed by use of artificial tears or topical steroids during peak serum levels of 5-FU and with use of ocular ice packs [31]. Capecitabine is ultimately metabolized enzymatically to 5-FU and essentially mimics continuous infusion 5-FU. Ocular irritation similar to that observed with 5-FU has been reported in at least 10% of capecitabine-treated patients. Superficial white corneal deposits in a whorl pattern have been reported in two patients with antecedent keratoconjunctivitis sicca prior to initiation of capecitabine [32]. In one case there were two positive rechallenges with complete clearing in between reexposures. Figure 33.1 demonstrates the corneal deposits observed with use of capecitabine [32]. Signs and symptoms may develop in 4–6 weeks, with resolution after a similar period of time has elapsed without reexposure. Decreasing the dose may lessen the degree of toxicity. The most frequent side effect of cytosine arabinoside is time- and dose-dependent ocular toxicity. Blurred vision and keratoconjunctivitis are the most frequent ocular effects noted, and lateral gaze nystagmus, diplopia, and lateral rectus nerve palsy often occur with drug-related cerebellar dysfunction. While little ocular toxicity is noted with low doses [33] most patients experience ocular effects with prolonged exposure and with high doses of the drug. High dose cytarabine penetrates the blood–brain barrier and the drug is found in tears, in part explaining the high prevalence of keratitis. Ocular effects usually occur after 5–7 days of exposure and are characterized by eye pain, excess lacrimation, a foreign body sensation, photophobia, and blurred vision with bilateral conjunctival hyperemia. Central punctuate corneal opacities, subepithelial granular deposits, refractile epithelial microcysts due to profound degeneration of rapidly dividing basal epithelial cells, superficial punctuate keratitis, and rarely, mild corneal edema with stria may be seen with high doses [34]. Symptoms improve after a few days once the drug is discontinued, vision improves in 1–2  weeks, and corneal opacities normalize within 4 weeks after cessation of the drug. Prophylactic use of topical steroids or topical 2-deoxycytidine, a competitive inhibitor of cytarabine, are effective in the management of cytarabine-associated corneal toxicity [34]. Individual case reports of transient visual loss and anterior uveitis following high-dose cytarabine describe

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Fig. 33.1  Corneal deposits due to capecitabine (From [32]. Copyright © 2000 Massachhusetts Medical Society. All rights reserved)

the clinical course of these events [35, 36]. Optic nerve atrophy and blindness may occur with either intravenous highdose cytarabine or with intrathecal administration. Ocular side effects are also noted with a liposomal formulation of cytarabine for intrathecal administration, as noted in the DEPOCYT package insert [37]. A similar incidence of blurred vision was noted in a head-to-head trial comparing DEPOCYT (12%) with intravenous Ara-C (14%), and across all Phase I–IV clinical trials in adults, 11% reported blurred vision.

Folic Acid Analogs (Methotrexate, Pemetrexed) Methotrexate is administered in multiple dosing regimens and via different routes of administration (low-dose oral, low-dose intravenous, high-dose intravenous {which crosses the blood–brain barrier}, and intrathecal). Approximately 25% of patients treated with high-dose methotrexate develop

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ocular toxicity within 2–7  days after starting therapy. Periorbital edema, ocular pain, blurred vision, photophobia, conjunctivitis, blepharitis, conjunctival hyperemia, and both decreased and increased lacrimation have been reported [2, 4]. Symptoms usually resolve within 10 days of discontinuing the drug and are ameliorated with artificial tears. Methotrexate levels in tears mirror serum levels, but without correlation between tear concentration and ocular effects. Ocular symptoms are likely related to the anti-mitotic effect of the drug in the rapidly dividing cells of the corneal and conjunctival epithelium [2]. Ocular muscle weakness and palsy, usually transient in nature, may occur with intrathecal or low-dose oral methotrexate dosing schedules [38]. Exaggerated effects, especially transient ophthalmoplegia, may occur when intrathecal methotrexate is administered with concomitant radiotherapy and even with lower-than-routine doses [6]. Retinal and optic nerve effects of methotrexate may occur with low-dose therapy and effects may not be fully reversible. Only partial improvement of vision and persistent abnormal ERG findings were documented as late as 3 years after discontinuation of long-term (8.5 years) weekly low-dose methotrexate [6, 39, 40]. Pemetrexed is often administered in combination with cisplatin as well as alone as monotherapy. An additive effect of the two drugs on ocular toxicity is evident from a clinical trial comparing pemetrexed monotherapy to pemetrexed in combination with cisplatin. With pemetrexed monotherapy, 1% of patients developed conjunctivitis, while 5% reported conjunctivitis when the two drugs were administered concomitantly [41].

Purine Analogs (Fludarabine, Deoxycoformycin) Fludarabine-related ocular effects are infrequent but may be rapidly progressive, sight-threatening, and are largely irreversible. Fludarabine development was almost discontinued due to serious toxicities, including neurotoxicities and blindness, in Phase I trials. Early reports of diplopia, photophobia, and decreased visual acuity probably secondary to optic neuritis with or without disc edema, and/or cortical blindness occurred in patients treated with doses that are higher than those used in current clinical practice. In a comprehensive review of fludarabine-related ocular effects, Ding et al. [42] noted that ocular susceptibility to fludarabine toxicity is not limited to high-dose therapy. At the 5  year follow-up of a National Cancer Institute study of patients with chronic lymphocytic leukemia treated with fludarabine, 1% of the 705 evaluable patients had developed grade 3 (generalized symptomatic subtotal loss of vision)

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visual toxicity while grade 4 (blindness) toxicity had occurred in 0.3% of patients [43]. With standard doses of fludarabine, visual loss may be hallmarked by the onset of visual hallucinations, floaters, and diminished visual acuity. Dramatic loss of retinal ganglion cells, bipolar cell damage, and extensive optic nerve atrophy has been noted at postmortem exam. The etiology of the ocular damage is not clear and could be due to direct neuronal toxicity from fludarabine and/or retrograde neuronal atrophy. Fludarabine-related neurotoxicity and ocular toxicity appear to be largely irreversible, although visual recovery has been reported in some cases with immediate cessation of the drug at the first signs of neurotoxicity [42]. Bilateral conjunctivitis and keratitis have been reported rarely with deoxycoformycin and generally occur after long-term use. Symptoms generally resolve within a week after discontinuation of the drug, and corneal ulcerations heal after 3 weeks [43].

Antibiotics (Doxorubicin, Epirubicin, Mitoxantrone, Mitomycin C) Increased tearing and conjunctivitis are the most frequently reported ocular effects of doxorubicin and the liposomal formulation of the drug. Up to 25% of patients treated with doxorubicin develop conjunctivitis during the course of treatment and conjunctivitis is noted in roughly 15% of patients treated with epirubicin [2]. Mitoxantrone in aqueous solution for intravenous injection is dark blue in color and blue-tinged eyelid, sclera, and conjunctiva have been reported. Conjunctival discoloration is selflimiting and resolves within 24 h after infusion. Pigmentation of the sclera and eyelids is transitory, due to deposition of the dark blue drug, and regresses over time [44]. Mitomycin C may cause blurred vision [2] and damage to the corneal epithelium may occur as a result of tear film changes [45].

Mitotic Inhibitors (Taxanes and Vinca Alkaloids) Taxanes Paclitaxel-related neurotoxicity can be dose-limiting. Transient scintillating scotoma (a localized area of diminished vision edged by shimmering colored lights, most often associated with the aura that precedes the onset of migraine headaches), visual impairment, photopsia (flashing lights),

and possible ischemic optic neuritis have been reported. Photopsia usually lasts from 15  min to 3  h after infusion and was noted in six of 25 patients treated with paclitaxel (250–275 mg/m2) as a 3-h infusion [46]. Patients described seeing flashing lights across the entire visual field, usually beginning during the last 30 min of the drug infusion. Photopsia recurred on rechallenge at the same or slightly reduced dose without any apparent chronic sequelae. Ophthalmologic examination was normal in three of these patients and visual acuity was not affected. Photopsia was not observed with doses less than 250 mg/m2 and did not correlate to peak plasma levels. Capri et al. reported similar ocular toxicities in nine of 47 patients (19%) treated with paclitaxel at doses of 175–225 mg/ m2 as a 3-h infusion [47]. These individuals described small luminous dots (or flies) in the visual fields of both eyes at about the time of the end of the infusion. The events always resolved spontaneously and did not necessarily recur with subsequent cycles. Three of the nine patients also reported a subjective reduction in vision. One of the patients had an abnormal visual evoked potential (VEP), suggesting an effect on the optic nerve, and a normal ERG. Fundoscopic and ERG exams were normal in the other two, but abnormal VEP was noted. These abnormalities did not worsen and recovered somewhat. Scaioli et al. evaluated 30 patients with breast cancer treated with either paclitaxel alone or in combination with doxorubicin and found electrophysiological changes involved both the retina and anterior optic pathway, with only a weak correlation between visual symptoms and electrophysiologic changes suggestive of retinal hypoxia due to vascular dysregulation and ischemia in the optic pathways [48]. Ocular/visual changes are also associated with the administration of an albumin-bound formulation of paclitaxel (Abraxane). Ocular toxicity (superficial keratopathy and blurred vision) was a dose-limiting toxicity in the Phase I trial but has not been evident in subsequent studies at doses at or below the MTD [49, 50].

Docetaxel Canalicular and nasolacrimal duct obstruction, leading to excessive tearing, and conjunctivitis are the most commonly reported ocular side effects of treatment with docetaxel and have been noted with every 3  week and more commonly, with weekly dosing schedules [51]. Nasolacrimal duct obstruction may be due, at least in part, to stromal fibrosis in the mucosal lining of the lacrimal drainage apparatus. Tsalic et al. [52] prospectively evaluated the incidence of excessive tearing in 21 consecutive patients with different malignancies undergoing weekly docetaxel (35  mg/m2/week iv for 6  weeks, with cycles repeated every 49  days), including a standard baseline questionnaire before each dose of ­docetaxel.

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In their study, seven of 21 (33%) patients developed excessive tearing related to canalicular stenosis at a cumulative docetaxel dose of 208–645 mg/m2 (median: 400 mg/m2). In all patients, the tears extravasated over the eyelids, onto the face, causing significant interference with normal activities. Patients continuously rubbed the eyes, causing additional irritation and ectropion (turning out of the lower eyelid) formation. Fundoscopy was normal. Two patients developed complete canalicular stenosis requiring surgery, loss of eyelashes was often present, and additional irritation of the cornea and lacrimal tissues was caused by the transformation of normally moist epithelium of the palpebral conjunctiva into keratinized squamous epithelium. The excess tearing resolved completely in three patients 4–6 weeks after cessation of docetaxel but persisted for 5–12 months after discontinuing therapy in four patients [52]. Because of the severity of the excessive tearing, some patients undergoing treatment with docetaxel may benefit from prophylactic temporary placement of silicone or similar tubes to maintain the patency of the lacrimal apparatus [52]. There is one report in the literature of possible taxaneinduced open-angle glaucoma that developed in a woman with metastatic breast cancer treated initially with docetaxel 100  mg/m2 at 3-week intervals along with routine steroid premedication [53]. She developed progressively diffuse fluid retention after the first cycle and complained of loss of vision after the fifth cycle. Open-angle glaucoma was diagnosed with elevated intraocular pressure (44 mm Hg) in both eyes. Docetaxel was discontinued and the increased intraocular pressures normalized with treatment. She was then treated with vinorelbine for nine months and went without any specific treatment and without recurrence of the glaucoma for eight additional months. When treatment with paclitaxel 135 mg/m2 q 21 days was initiated, fluid retention occurred after the second cycle and open-angle glaucoma (intra-ocular pressures of 35 mm Hg and 40 mm Hg) recurred after the third cycle. Paclitaxel was continued along with treatment for the glaucoma, which did not improve. Fundal exam showed typical cupping and bilateral scotoma [53].

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neuropathy, including optic nerve atrophy, cortical blindness, or night blindness [2, 6]. Effects may be noted as soon as 2 weeks after the initial dose and most will experience at least partial resolution with cessation of the drug. Individual reports of reversible vincristine-related nerve palsy describe the clinical course of events [54–56]. Amelioration of vincristine-related neuropathy and cranial nerve effects may be achieved with pyridoxine or pyridostigmine [57]. Vincristine-associated optic neuropathy and bilateral optic atrophy have been documented, with improvement and sometimes complete recovery after discontinuation of the drug [58] and retinal damage has been observed at autopsy [6]. Irreversible blindness, transient cortical blindness (lasting from 24  h to 14  days) with recovery in 1–14  days [59], and development of night blindness after vincristine have been reported [60]. Vinblastine-associated ocular effects are less frequent than with those observed with vincristine, possibly due to incorporation of vincristine rather than vinblastine in many childhood malignancy treatment regimens. Nonetheless, there is a report of vinblastine-associated ptosis 6 weeks after starting vinblastine in a 2-year-old [61]. Inadvertant drug exposure, such as that which can occur by accidental splashing of vinblastine into the eye, can have especially serious consequences. A characteristic keratopathy, including microcystic edema, superficial punctuate keratitis, and corneal erosion with or without low-grade anterior uveitis has been described [6]. Decreased vision and damage to the cornea are noted in the first few days after exposure and the keratitis can take weeks to months to resolve and may be permanent. There is one report of increased astigmatism developing after inadvertant exposure to vinblastine [6].

Hormonal Agents (Selective Estrogen Receptor Modulators, Aromatase Inhibitors, Anti-Androgens) Tamoxifen

Vinca Alkaloids Vincristine, Vinblastine, Vindesine, Vinorelbine The most common ocular side effects of treatment with vinca alkaloids are related to neurotoxicity of the drugs and are dose-related. Cranial nerve palsies (ptosis, extraocular muscle palsies, and internuclear ophthalmoplegia, corneal anesthesia or hypoesthesia, and lagophthalmos) may occur in one form or another in up to 50% of patients treated with vinca alkaloids [2, 6]. Other effects are optic

Visual problems associated with tamoxifen have been reported for over 30  years, and comprehensive profiles of tamoxifen-associated ocular toxicity have been published [62–64]. An increased risk of posterior subcapsular cataracts, color vision changes, optic neuritis, and intra-retinal crystals are the most commonly noted ocular effects associated with tamoxifen. While some reports suggest no increased risk of cataract formation compared to women with other malignancies not treated with tamoxifen [65], the vast majority of studies cite an increased incidence of cataracts with tamox-

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ifen therapy [62–64]. A small relative risk of developing cataracts and, more specifically, a higher risk of undergoing cataract surgery were reported from the NSABP breast cancer prevention trial [66]. The longer the duration of exposure, the higher is the likelihood of cataract development. Women exposed to tamoxifen for 4–5 years were at slightly elevated risk of cataracts compared to nonusers, whereas women exposed for 6+ years were at greater risk. Cataract pathogenesis may in part be due to interference by tamoxifen of chloride channels essential for maintaining lens hydration [67]. In a study that included patient questionnaires, Gallichio et al. reported that 13% of tamoxifen users noted an adverse ocular side effect and found that the presence of visual complaints correlated with high serum levels of tamoxifen and its N-desmethyltamoxifen metabolite [68]. While tamoxifen can affect vision, serious side effects are not common, and if present, generally occur at doses >10  g (standard dose is 20  mg daily). Compared with non-treated participants, tamoxifen-treated women had no limitation or differences in vision-dependent daily activities, visual acuity measurements, or other tests of visual function except for subclinical changes in color discrimination, especially with long-term tamoxifen use [64]. Effects on the retina can be acute and not well-defined, consisting of loss of vision, localized edema, optic disc swelling, and hemorrhage after even only a few weeks of therapy. These acute effects are likely due to the estrogenic effect of tamoxifen and associated thrombotic phenomena of the retinal vein and are reversible when the drug is discontinued [69, 70]. Tamoxifen is secreted in tears, which may be a factor in symptoms of reduced vision, photophobia, and ocular irritation. Penetration of the drug to at least the basal surface of retinal pigmented epithelium is suggested by case reports of stabilization of optic nerve head metastases and reduction in size of retinal metastases after starting treatment with tamoxifen [71]. Typical tamoxifen retinopathy consists of small refractile or crystalline dot-like yellowish deposits in the perimacular area and may be the products of axonal degeneration [69]. These changes are more likely to occur after a year of more of tamoxifen [72], although retinopathy may be present in their absence [70]. Goren et  al. reported that any retinal occlusive disease in their study was consistent with chance occurrence rather than due to tamoxifen [70] while a twofold higher incidence of deep-vein thrombosis, pulmonary embolism, or retinal vein thrombosis during the active treatment period, relative to placebo, was reported in long-term followup in the International Breast Cancer Intervention Study (IBIS-I), although specifics isolating retinal vein thrombosis from other thromboembolic events were not reported [73]. Characteristic white, whorl-like subepithelial corneal deposits have been reported, may be dose-related, and when present are of little clinical significance [34].

Because of the potential for the development of ocular effects due to tamoxifen, a baseline ophthalmologic exam within the first year of treatment is warranted, with periodic follow-up, especially if ocular symptoms occur [6]. However, even if cataracts develop, they are likely to progress even after the drug is discontinued.

Raloxifene and Anastrazole Both raloxifene and anastrazole are associated with an increased risk of cataract development, although perhaps slightly less so than with tamoxifen [74, 75].

Leuprolide Ocular toxicities are also likely to some extent with leuprolide. Transitory blurred vision may occur shortly after each injection or after multiple injections and usually lasts for 1–2 h, although in rare instances, the duration may be as long as 2–3  weeks. Other effects that have been reported include pseudotumor cerebri and papilledema, ocular vascular accidents, eye pain, and lid edema [76].

Nilutamide The most frequent ocular effect of nilutamide is delayed adaption to darkness after exposure to bright light, which is dosedependent and occurs in up to 90% of patients. Photostress recovery time is prolonged to 10–30 min (normal is roughly 1  min). No retinal changes are found on examination. Adaptation to darkness may normalize while continuing on the drug or with dose reduction or discontinuation of the drug, in which case recovery may take up to a year, likely due to delayed regeneration of visual pigments [77].

Steroids Corticosteroids such as prednisone and dexamethasone are often included in treatment regimens for hematologic malignancies and are often administered just prior to chemotherapy as an adjunct to antiemetic therapy. The cataractogenic properties of long-term steroid usage have been identified in patients with rheumatologic diseases as well as malignancies [12]. Increased intraocular pressure and ­subsequent ­glaucoma is another potential ocular effect of ­long-term steroid usage [69].

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Molecular Targets Imatinib mesylate was the first molecularly targeted agent in clinical practice and the ocular effects of the drug have been documented extensively [78, 79]. The most commonly reported findings are blurred vision, periorbital edema as well as edema of the eyelid and conjunctiva, and excessive tearing. Mild-to-moderate periorbital edema occurs in approximately 70% of patients treated with imatinib [78, 79]. Results of a chart review reported by Fraunfelder et al. [79] noted that 73 of 104 imatinib-treated patients (70%) with chronic myelogenous leukemia (CML) developed periorbital edema (29% of whom also had concomitant peripheral edema), and 18% reported increased tearing. Demetri et al. [80] reported a similar incidence of periorbital edema (74.1%) in imatinib-treated patients with gastrointestinal stromal tumor. The periorbital edema can become apparent early (as soon as 24 h) or late (after 1 year) after initiation of imatinib, although it is most frequently noted after 2 or 3  months of treatment. The reaction appears to be dosedependent, with a higher incidence with doses higher than the usual 400 mg/day. In a case report of a patient with periorbital edema causing visual obstruction that required surgical debulking, Esmaeli et  al. noted that imatinib-related inhibition of PDGFR (platelet-derived growth factor receptor) in dermal dendrocytes of periorbital skin may cause decreased interstitial fluid pressure that results in localized edema [81]. Figure 33.2 is a very dramatic instance of periorbital edema that occurred as a result of treatment with imatinib [81]. Other ocular problems reported in Fraunfelder’s review included abnormal vision (ten patients), blepharoconjunctivitis (nine patients), and increased intraocular pressure, ptosis, photosensitivity, and an isolated retinal hemorrhage, each occurred in one patient [79]. Increased tearing was the primary ocular complaint in some patients who also had periorbital edema and were treated with mean daily doses of 540 mg [82]. Retinal macula edema has been reported after two months of treatment with imatinib 600  mg daily, with resolution 2  weeks after discontinuation of the drug [83]. Individual cases of macular ischemia, optic neuritis, and optic disc edema with photopsia have been reported with standard (400 mg/day) doses of imatinib [84–86]. Glaucoma and conjunctival hemorrhage have been reported infrequently [78, 87]. For the most part, ocular effects of imatinib resolve with discontinuation of the drug and side effects can be managed conservatively and with low doses of diuretics and topical steroids, without discontinuation of the drug. Concomitant oral short-term steroid therapy without discontinuation of imatinib may also be of benefit, especially when doses greater than 400 mg are needed [88]. Visual disturbances (dry eye, blurred vision, conjunctivitis, and reduced visual acuity) have been reported in patients

Fig.  33.2  Imatinib-related periorbital edema (From [81]. Reprinted with permission from John Wiley & Sons, Inc.)

treated with dasatinib after failure of imatinib. Bajel et  al. reported a case of safe treatment of a patient with CML who has previously developed retinal edema while on treatment with imatinib [89, 90].

Targeted Monocloncal Antibodies Epidermal Growth Factor Receptors (Gefitinib, Cetuximab, Panitumumab) Ocular toxicities associated with EGFR inhibitors include squamous blepharitis, trichomegaly (excess growth of eyelashes or brow) or madarosis (loss of eyelashes), inflammation of the meibomian glands (the sebaceous glands of the eye that secrete tears), dysfunctional tear syndrome due to suboptimal tearing, and miscellaneous changes such as iridiocyclitis and

33  Eye Symptoms and Toxicities of Systemic Chemotherapy

defects in the corneal epithelium [91]. The Skin and Eye Reactions to Inhibitors of EGFR and Kinases Clinic at the Northwestern University and the Robert H. Lurie Cancer Comprehensive Cancer Center report that in their experience, approximately one-third of patients treated with EGFR inhibitors experience adverse ocular effects [91]. See references [91] and [95] for an example of the eyelash changes that frequently occur in patients treated with an EGFR inhibitor. Gefitinib-related conjunctivitis (mostly grade 1 or 2) was reported in 15.6% of patients in one Phase I clinical trial and in another Phase I study one patient was reported to have a grade 3 epithelial defect in the cornea caused by abnormal eyelash growth [92, 93]. Marked lengthening of both the eyebrows and eyelashes has been reported after 7 weeks of treatment with gefitinib [94]. Cetuximab-related ocular toxicities include conjunctival hyperemia, conjunctivitis, and squamous blepharitis, as well as photophobia, excessive tearing, and itching. Tonini reported a case of squamous blepharitis and associated ocular discomfort that began after 3  weeks of cetuximab treatment [95]. The patient reported discomfort in both eyes characterized as itchiness all around the eyelids, photophobia, foreign body sensation, tearing associated with exfoliated skin, oil secretions, and crusty scaling of the eyelids and eye lashes. Fundoscopic examinations, visual acuity, and intra-ocular pressure were normal, although mild conjunctival hyperemia was noted. Recovery was evident within 1 week after cessation of the drug but recurred 2 weeks after cetuximab was restarted. Tonini et  al. [95] postulated that ocular symptoms were related to the altered secretion of tears due to the drug’s targeting of the EGFR-expressing cells of the meibomian glands. The clinical spectrum of ocular side effects related to cetuximab monotherapy is illustrated in Fig. 33.3 [95]. Cetuximab-related trichomegaly may develop within a few months of starting treatment. Excess hair growth does not usually occur in other sites and the eyelash lengthening may be very bothersome and has the potential to cause significant eye irritation [96]. Cutting of the eyelashes may be necessary for ocular comfort. Eyelash effects resolve within 1 month after stopping the drug. Erlotinib use is associated with mild ocular toxicity [97]. The prescribing information notes that conjunctivitis and keratoconjunctivitis sicca each occurred in 12% of patients with non-small-cell lung cancer [98]. Another EGFR antagonist, panitumumab, is also associated with ocular effects. In clinical trials, ocular toxicities occurred in 15% of patients and included, but were not limited to, conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%), all predominantly grade 1 or 2. Growth of eyelashes was reported in 6%. The median time to the development of ocular toxicity was 14 days after the first dose [99].

341

Biological Response Modifiers (Interferons, Interleukins) Most reports of ocular effects of interferons have been due to treatment with interferon alpha, although similar side effects have been reported to a lesser degree with beta and gamma interferon as well as with consensus interferon and pegylated interferon. Changes in vision, nonspecific conjunctivitis, and ocular pain are the most frequently reported ocular side effects, and cotton-wool spots and retinopathy may occur as well [6]. Ocular effects are more likely with higher doses and with coexistent diabetes or hypertension. The onset of effects may be as rapid as 15 min after the initial exposure to interferon or ocular effects may not be noted for many months. Decreased vision is usually transitory, may occur after each injection, and is rarely permanent. Visual changes may include transient bright after-images. The presence of the drug in tears likely contributes to the development of conjunctivitis, subconjunctival hemorrhages, and transient corneal microcysts [100]. Deng-Huang et al. reported a case of Graves’ ophthalmology that developed in a patient with chronic hepatitis after 6 months of treatment with interferon. Reversible impaired tear dynamics and squamous metaplastic changes on the ocular surface were noted and persisted for up to 6 months after interferon was discontinued [101]. Interferon-associated overgrowth of eyelashes has been reported [6]. Retinal effects usually develop as early as 2  weeks and generally before 3  months of treatment with interferon and are more common with high doses. Less than 1% of interferon-treated patients develop these changes. Spontaneous regression may occur while continuing on the drug or when it is discontinued, although the changes are not always self-limiting and may be progressive. Retinal ischemic changes of large vessels and capillaries may be noted with fluorescein angiography. Retinal changes and cottonwool spots due to vascular occlusion can occur even with an absence of ocular complaints or without any apparent impairment in visual acuity. Retinopathy is likely due to immune complex deposition in the retinal vasculature and leukocyte infiltration, resulting in retinal ischemia and nerve fiber layer infarcts [102]. Interleukin-2 may cause ocular effects, usually of a neuroophthalmic nature. Scotomas and palinopsia (after images) are dose-related [103]. Diplopia, blurred vision, and conjunctival irritation have been reported also. Conjunctival injection and disc edema, especially in children, is a reported ocular effect of Interleukin-11. Conjunctival injection was noted in 13% of patients in Oprelvekin clinical trials but the most serious effect is disc edema (1% in adults but 16% in children), which prompted a cautionary letter to health-care professionals [104]. Disc edema resolves with discontinuation of the drug.

342

A. Teitelbaum

Fig. 33.3  Clinical spectrum of ocular side effects of cetuximab monotherapy (From [95], with permission of the Oxford University Press)

Miscellaneous Agents (Denileukin Diftitox) Only rarely have ocular side effects been noted with treatment with some of the newer agents introduced into clinical practice, such as the immunomodulatory drugs thalidomide and lenalidomide, the epothilone ixabepilone, the mammalian target of rapamycin (mTOR) inhibitor temsirolimus, or the proteasome inhibitor bortezomib. When noted, ocular effects are reported as mild in nature and are usually as a result of adverse event reporting in a clinical trial. More serious ocular effects are noted with Denileukin diftitox, such that the FDA mandated a change in the prescribing information: “Loss of visual acuity, usually with loss of color vision, with or without retinal pigment mottling has been reported following administration of ONTAK. Recovery was reported in some of the affected patients; however, most patients reported persistent visual impairment” [105]. This addition

was based on post-marketing reports of ophthalmic toxicity and the incidence of such events was not specified. It is possible that the vascular leak syndrome that can be caused by this drug may be a contributory factor to the development of these ocular toxicities. An overview of the key ocular effects of chemotherapy agents is provided in Table 33.1.

Conclusion Ophthalmologic effects of chemotherapy drugs occur less frequently than other chemotherapy-related toxicities, and ocular complications tend to be less severe than other toxicities. Most ocular effects improve or resolve completely upon discontinuation of the offending drug; sequelae are often minimized by early recognition.

Keratitis

Keratitis

Keratitis

Chlorambucil

Cyclophosphamide

Ifosfamide Busulfan Nitrosoureas

Corneal deposits Corneal opacities and deposits

Capecitabine

Doxorubicin Mitoxantrone

Fludarabine

Methotrexate

Cytosine arabinoside

Keratitis; corneal opacities

5-FU

Oxaliplatin

Carboplatin

Cisplatin

Cornea

Drug

Conjunctivitis Blue-tinged conjunctiva

Conjunctivitis

Keratoconjunctivitis

Conjunctivitis

Conjunctivitis Conjunctivitis Conjunctival hyperemia

Conjunctivitis

Conjunctiva

ERG changes possible

Macular changes

Retinal damage ERG changes

Retina

Table 33.1  Summary of the ocular effects of selected chemotherapy agents

Optic neuritis, cortical blindness

Optic nerve damage Neuritis; transient cortical blindness Neuritis, transient cortical blindness Transient loss of vision, papilledema Optic neuropathy

Rare papilledema, optic nerve atrophy after several years

Optic nerve

Glaucoma

Yes

Yes, esp. with high doses

With CMF

With CMF

Excessive tearing

Yes

Cataract

Diplopia

Nystagmus, diplopia

Nystagmus, diplopia

Ptosis

Nystagmus

Neurotoxicity

(continued)

Visual hallucinations

Prophylactic topical steroids

Photophobia; prophylactic topical steroids, ocular ice packs

With high dose BCNU and ASCT Decreased color vision

Lacrimal outflow obstruction from sclerosing caniculitis with CMF

Cumulative effect of drug

Other/comment

33  Eye Symptoms and Toxicities of Systemic Chemotherapy 343

Denileukin diftitox

IL-2 IL-11

Corneal microcysts

Interferons Conjunctivitis Conjunctivitis

Conjunctivitis

Conjunctivitis

Rare keratopathy

EGFRs

Conjunctivitis

Conjunctiva

Conjunctivitis

Subepithelial corneal deposits

Cornea

Steroids Imatinib

Nilutamide

Raloxifene Anastrazole Leuprolide

Tamoxifen

Docetaxel Vincas

Paclitaxel

Drug

Table 33. 1  (continued)

Retinal pigment mottling

Retinopathy

Retinal macula edema

Intra-retinal crystals

Retina

Disc edema, esp. in children

Rare papilledema

Optic neuropathy, cortical blindness Optic neuritis

Ischemic optic neuritis

Optic nerve

Yes Rare

Rare

Rare

Glaucoma

Yes

Yes

Yes

Excessive tearing

Yes

Yes Yes

Cataract

Periorbital edema

Cranial nerve palsies

Neurotoxicity

Loss of visual acuity; color vision loss

Palinopsia

Trichomegaly; meibomian gland inflammation; squamous blepharitis Trichomegaly

Transitory blurred vision after injection Delayed adaptation to dark

Color vision changes

Canalicular stenosis Night blindness

Photopsia

Other/comment

344 A. Teitelbaum

33  Eye Symptoms and Toxicities of Systemic Chemotherapy

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Part XII

Skin

Chapter 34

Extravasation Lisa Schulmeister

Introduction Various classification systems are used to describe chemotherapy drugs. They may be classified by their chemical structure, mechanism of action, or by their poten­ tial to cause tissue necrosis. Vesicant chemotherapy drugs cause blistering, sloughing of the skin, and varying degrees of localized tissue damage when they leak from a vein or are inadvertently administered into the tissue [1]. Vesicant extra­ vasation injuries also may occur in the mediastinum, lung, and other areas when central venous catheters are misplaced, rupture, or migrate outside of the venous system [2–4]. Lastly, tissue damage can occur when vesicants intended for intravenous (IV) administration are inadvertently given into the muscle or tissue by direct injection [5]. Non-vesicant chemotherapy drugs do not cause damage when they infiltrate into the tissue. Typically, only swelling and mild discomfort occur and these symptoms can be effec­ tively managed by heat and elevation [1]. Irritants may inflame and irritate peripheral veins when they are administered or infiltrate into the tissue. Most che­ motherapy drugs are irritating because of their low pH; con­ sequently, central venous catheters or implanted ports are routinely used in clinical practice to deliver chemotherapy. When given via a central line, irritating agents are rapidly diluted. In contrast, when irritants are given peripherally, patients may experience discomfort and tightness along the vein. The vein may redden or darken. Application of heat often is helpful to reduce local pain and inflammation. Swelling and moderate-to-severe discomfort typically occur when irritants infiltrate into the tissue and can be managed by application of heat, elevation, and mild analgesics [6]. One of the consequences of infiltration of non-vesicant chemotherapy and extravasation of vesicant chemotherapy is that in most cases, the amount of chemotherapy that entered the tissue cannot be determined and estimates of the amount

L. Schulmeister (*) 282 Orchard Road, River Ridge, LA 70123, USA e-mail: [email protected]

may not be accurate. The amount of chemotherapy that the patient received properly (intravenously) is likely to be a sub-therapeutic dose, thus potentially compromising the effectiveness of cancer treatment and patient outcomes. Potential consequences of untreated vesicant extravasa­ tions include scarring, sensory and motor impairment, infec­ tion, and disfigurement. In addition, patients may need to postpone or discontinue chemotherapy treatment while receiving wound care or undergoing surgical debridement of their extravasation injuries. Further, the indirect costs associ­ ated with extravasation management are unknown but may include loss of wages, reassignment of job duties, and wound care supply and travel costs.

Extravasation Terminology Chemotherapy drugs are designated as irritants, nonvesicants, and vesicants by their manufacturers. However, some of these drugs are inconsistently classified in the literature or are described using confusing terminology. For instance, oxaliplatin has been classified as both an irritant [5, 7] and a vesicant [1, 8]. Although the manufacturer of melphalan states that extravasation may cause tissue damage, it has been classified as a non-vesicant, irritant, and vesicant in various sources [1, 5–7]. The manufacturer of vinorelbine classified it as “an irritant, and extravasation may cause local tissue necrosis and/or thrombophlebitis” [9]. Paclitaxel is often classified as an irritant [10]; however, case reports suggest that paclitaxel is a weak vesicant, regardless of its concentration [1, 7, 10]. Table  34.1 lists chemotherapy drugs and their classification as vesicants, non-vesicants, or irritants. Vesicant chemotherapy drugs can be further divided into two classifications, DNA binding vesicants and DNA nonbinding vesicants. Vesicants that bind to nucleic acids in DNA (e.g., anthracylines) bind to the DNA in the cells of healthy tissue when they extravasate from the vein and promptly cause cell death. DNA-doxorubicin complexes are released from dead cells in the tissue and are taken up by

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Table 34.1  Chemotherapy drugs classified by their potential to cause tissue irritation or damage Classification DNA-Binding Vesicants Dactinomycin Daunorubicin Doxorubicin Epirubicin Idarubicin Mechlorethamine (nitrogen mustard) Mitomycin Mitoxantronea

Etoposide Floxuridine Irinotecan Ixabepilone Melphalan Nelarabine Oxaliplatina Streptozocin Teniposide Topotecan Triptorelin Non-vesicants Arsenic trioxide Asparaginase Bleomycin Cladribine Clofarabine Cyclophosphamide Cytarabine Fludarabine 5-Fluorouracil Gemcitabine Ifosfamide Methotrexate Pemetrexed Pentostatin Temsirolimus Thiotepa

Non-DNA-Binding Vesicants Amsacrine Docetaxela Paclitaxelb Trabectedin Vinblastine Vincristine Vindesine Vinorelbinea Irritants Bendamustine Busulfan Carboplatin Carmustine Cisplatin Dacarbazine Daunorubicin liposomal formulation Doxorubicin liposomal formulation Source: Data from [1, 5, 6] a  Has been classified as both an irritant and vesicant b  Injection site reactio.ns have been reported, including reactions sec­ ondary to extravasation, that were usually mild and consisted of ery­ thema, tenderness, skin discoloration, or swelling at the injection site. These reactions were observed more frequently with a 24-h infusion than with a 3-h infusion

adjacent healthy cells by endocytosis. This process of cellu­ lar uptake of extracellular substances sets up a continuing cycle of tissue damage as the anthracycline is retained in the tissue and recirculated in the surrounding area [11]. High dermal concentrations of anthracyclines have been detected in patients 28 days post-extravasation, at both the adminis­ tration site and at a distance of 5 cm [12]. When left untreated, these extravasation injuries become larger in size, deeper in depth, and more painful over time. The liposomal formulations of anthracyclines, such as doxorubicin liposome injection and daunorubicin liposome injection, are irritants. Their long half-life and liposomal encapsulation are thought to reduce their toxicity. In case reports, infiltration of these drugs caused swelling, skin dis­ coloration, and mild tenderness. Extensive tissue necrosis has not been reported [13, 14]. If tissue necrosis occurs, a “mix-up” between doxorubicin or daunorubicin and their liposomal formulations should be suspected.

Although mechlorethamine (nitrogen mustard) is a DNA-binding vesicant, it is rarely used in clinical practice. Cisplatin is classified in some sources as a vesicant when 20  mL or more of a 0.5  mg/mL solution extravasates; however, concentrated cisplatin solutions are unsafe for IV use and this drug should routinely be diluted [1, 5, 6]. Vesicants that do not bind to DNA (e.g., plant alkaloids) have an indirect rather than a direct effect on the cells in healthy tissue when they extravasate. Non-DNA-binding vesicants are eventually metabolized in the tissue and are more easily neutralized than DNA-binding agents [5]. This type of extravasation injury generally remains localized, is mildly to moderately painful, and improves over time.

Extravasation Incidence Vesicant chemotherapy extravasations are rare occurrences and incidence data are sparse because no centralized report­ ing mechanism exists. Although published vesicant extrava­ sation incidence rates range from 0.01% [15] to 6.5% [16], a variety of calculation methods have been used, and they reflect estimated incidence only. The true incidence of vesi­ cant extravasation is determined by dividing the number of extravasations that occurred during a specified time period by the total number of vesicants administered during that time period. The 6.5% incidence rate was derived by divid­ ing the number of patients with extravasations (nine) by the number of patients who received doxorubicin (138 patients) during the 2-year period 1976–1978 [16]. A 4.7% extravasa­ tion incidence was calculated by Wang, Cortes, Sinks, & Holland [17] by dividing the number of extravasations that occurred (four) by the number of patients who received dox­ orubicin (86 patients). These higher incidence rates, reported in the 1970s, reflect early experience with doxorubicin when its toxicities were being studied, and occurred when the spe­ cialized field of oncology nursing was in its infancy and rigid “scalp” vein or “butterfly” needles were commonly used to administer vesicants. Langstein, Duman, Seelig, Butler, & Evans [15] based their more recent 2002 calculation of a 0.01% extravasation incidence rate on 44 extravasations that occurred during a 6-year study period at M. D. Anderson Cancer Center in Houston, Texas, USA. During this time period, “40,000– 60,000 individual doses of chemotherapy were administered per year” (p. 370). The use of the term “doses of chemo­ therapy” implies that this number reflects non-vesicant as well as vesicant chemotherapy that was administered. Other examples of extravasation incidence estimates and the basis for their calculation include an incidence rate of 0.45% at the University of South Florida in Tampa, Florida, USA where nine extravasations occurred among approximately 2,000

34  Extravasation

adult and pediatric patients who received doxorubicin from 1975 to 1978 [18]. At Helsinki University Central Hospital, Pitkänen et  al. [19] reported in 1983 that during a 2-year period, 16 extravasations occurred among 6,000 infusions of chemotherapy that were administered, resulting in an inci­ dence rate of 0.27%. Bertelli et  al. [20] observed that 144 patients experienced extravasations at the National Institute for Cancer Research in Genova, Italy, estimated that 18,000 IV infusions of chemotherapy were performed, and calcu­ lated an incidence rate of 0.8%. Therefore, published extrava­ sation incidence rates are imprecise, and the only conclusion that can be drawn from them is that vesicant chemotherapy extravasations infrequently occur.

Extravasation Prevention Patients receiving a vesicant need to be informed that an extravasation injury is a known risk of vesicant administra­ tion. Although every effort is made to reduce this risk, vesi­ cant extravasations sometimes occur. The only way a patient can entirely avoid the risk of extravasation is to not receive vesicant chemotherapy, and this may not be an option for the patient [21]. Extravasation prevention includes patient education about the risk of extravasation and measures that the patient can take to reduce this risk (e.g., refrain from movement). Patient education should also include the signs and symptoms of a vesicant extravasation and instruction to immediately report any change in sensation. Before vesicants are administered, a blood return should be obtained from the IV device. If a blood return is not obtained from a peripheral IV device, a new peripheral IV should be inserted in another location. If a blood return is not obtained from a central venous access device (VAD), the patient should be repositioned or placed in a supine position, and the line flushed very gently with a 10 mL syringe filled with normal saline (0.9% sodium chloride solution). If a blood return is still not obtained, a 20  mL syringe can be used to attempt to aspirate blood; the larger diameter size decreases the force on the inside of the central VAD catheter and may make a blood return obtainable. If a blood return continues to not be present, institutional policies should be followed, which may include declotting the central VAD catheter using a thrombolytic agent (e.g., alteplase – a tissue plasminogen activator) or obtaining a dye study to confirm catheter placement and patency [21]. Vesicants should never be administered in an IV site that is below the site of a recent venipuncture or recent or unhealed extravasation injury. Peripheral vesicants should not be infused using an infusion pump since the pump may not alarm when an extravasation occurs, causing the vesicant

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to be delivered into the tissue. The vesicant administration site and patient should be monitored in accordance with institutional policy. Institutional policies should specify monitoring guidelines, such as frequency of site and bloodreturn checks [6]. Extravasations cannot always be prevented; patients move and IV devices can malfunction or break. Consequently, efforts to promptly detect an extravasation should be employed.

Risk Factors for Extravasation Numerous risk factors for extravasation have been identified, and patients are at high risk for extravasation when multiple risk factors are present. Prior to commencing a treatment regimen that contains one or more vesicants, the healthcare team should consider the duration of planned treatment and patient factors, such as peripheral vein integrity or prior sur­ gery that may limit venous access. Some patients may be candidates for placement of a central VAD, such as an implanted port or Hickman catheter, or may require insertion of a central VAD at some point during treatment. Risk factors for extravasation from peripheral veins include the presence of small and/or fragile veins, obesity that obscures veins from view and palpation, multiple previ­ ous venipunctures, and prior treatment with low-pH and caustic drugs, such as chemotherapy. There also may be lim­ ited vein availability because of lymph node dissection, lym­ phedema, limb removal, or other conditions. Sensory deficits that impair the patient’s ability to detect a change in sensa­ tion at the site of chemotherapy administration (e.g., postcerebral vascular accident, paralysis) increase the risk that an extravasation, should it occur, may go unnoticed by the patient. Similarly, sedation, somnolence, impaired cognition, and altered mental status impair the patient’s ability to detect and report a change in sensation at the site of vesicant che­ motherapy administration [6, 22]. Probing during IV catheter insertion into a peripheral vein may inadvertently puncture the vein wall, causing the vesi­ cant to seep out into the tissue. The risk of extravasation is increased when vesicants are administered via rigid IV devices, such as steel-winged “scalp” or “butterfly” needles, since they can easily puncture the vein upon patient move­ ment. Inadequately secured peripheral IV catheters and cath­ eters with wet or loose dressings are at risk for backing out of the vein. When the tip of the catheter is no longer in the vein and a vesicant is administered, an extravasation will occur. Greater tissue damage occurs when vesicants extravasate on the dorsum of the hand, wrist, or antecubital area because there is minimal tissue in these areas and vesi­ cant extravasation will likely cause damage to the underlying veins, arteries, nerve, tendons, and muscle [6].

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Risk factors for extravasation from central VADs include difficulty encountered during insertion of the device, such as probing and inability to advance the guidewire or cathe­ ter. Central VAD catheters also can be inadvertently sliced, pierced, or nicked prior to or during insertion. Device mis­ placement may occur, with the catheter tip being placed outside of the venous system (e.g., inadvertently placed in the pleural space) instead of the superior vena cava. Catheter migration may also occur, and the catheter tip may migrate from the vein into the tissue. Long dwell time (6 months or longer) increases the risk of extravasation; soft catheter materials are prone to weakening and fracture from “pinchoff” syndrome, which occurs when the catheter is com­ pressed between the clavicle and first or second rib. The risk of extravasation also is increased when a fibrin sheath or thrombus is present at the catheter tip. The fibrin or thrombus may cause vesicant chemotherapy to backtrack along the catheter and leak from the vein at the venotomy site [6, 23]. The risk of extravasation is increased when ports are deeply implanted. Non-coring needles need to be of suffi­ cient length so that they may be securely inserted into the port septum. If a needle is too short or if patient movement causes “rocking” of the non-coring needle, the risk of vesi­ cant extravasation is increased. Risk also is increased when implanted ports are inserted in locations where it is difficult to secure and stabilize the non-coring needle (e.g., IV port placed in patient’s abdomen with catheter threaded to the inferior vena cava).

Etiology of Extravasation Possible etiologies of peripheral extravasation include vein wall puncture, piercing, or trauma during cannulation of the vein. Veins also can be pierced by indwelling peripheral IV devices, especially if the device is placed in or near an area of flexion, such as the wrist or elbow. Patient movement and accidental tugging on IV tubing can dislodge a peripheral IV device from the vein. When patients have blood drawn from a vein in the antecubital area and receive a vesicant in a vein below this area within 24 h, they are at risk for extravasation at the blood-drawing site. Vesicants administered lower in the arm will leak into the tissue at the venipuncture site in the antecubital area if the vein in that area has not fully healed. Similarly, administration of a vesicant in a vein below a recent or non-healed vesicant extravasation site may worsen the pre­ existing extravasation, as it is likely that the veins in that area were damaged. Lastly, inadvertent intramuscular or subcuta­ neous vesicant administration may cause tissue necrosis. This type of injury occurs when vesicant chemotherapy

L. Schulmeister

intended for IV administration is inadvertently “mixed-up” with chemotherapy given by intramuscular (IM) or subcuta­ neous (SC) injection, or when it is thought that the vesicant is an additional drug that needs to be given by the IM or SC route [6]. Possible etiologies of extravasations from central VADs, including implanted ports, include accidental perforation of the internal jugular or subclavian vein, or superior vena cava that occurs during device insertion. Extravasation may occur when vesicants are given into central VADs that leak or were damaged prior to or during insertion. Etiologies of extravasations from implanted ports include separation of a catheter from the portal body, which occurs when the “O” ring or catheter sleeve is not attached securely or slips off and detaches the catheter. Non-coring needles that are inserted on but not in the portal body (have not pierced the silicone septum) and non-coring needles that have dis­ lodged from the portal body will have their tips in the tissue overlying the portal body. If a vesicant is given, it will be administered into the tissue and not the venous system. Lastly, backflow of a vesicant along the catheter to the venotomy site secondary to fibrin sheath or thrombus at catheter tip may cause the vesicant to extravasate into the tissue [6, 23, 24].

Signs and Symptoms The most common signs of vesicant extravasation are swelling and redness. Discomfort may or may not occur. There also is a loss of a blood return from the IV device. Swelling and redness may not be as easily detected, or may not be detectable at all, when an extravasation occurs deep in the tissue. In this situation, the most reliable indicator of a possible extravasation is loss of a blood-return. When vesicants are administered by bolus (IV “push”), a feeling of resistance suggests that the IV device may no longer be in the vein. Vesicants administered by gravity drip may slow or stop, and vesicants administered via infusion pump may cause the pump to alarm when an IV device is no longer in the vein. Whenever a vesicant is given and there is resis­ tance, a slow infusion, an alarming pump, or any degree of swelling, redness, or discomfort, vesicant administration should immediately be discontinued. Patients and their IV devices should immediately be assessed and a blood-return should be verified. If there is any question that an extravasa­ tion has occurred, clinicians should err on the side of cau­ tion, presume that an extravasation has indeed occurred, restart the IV in another location (when indicated), and implement institutional extravasation management proce­ dures [1, 6, 7, 21].

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Initial Management

Topical Cooling and Heating

Extravasation management is a collaborative process that ide­ ally includes the patient, the nurse administering the vesicant, the pharmacist, and the patient’s oncologist. The patient is a vital member of the multidisciplinary team and can provide important information about changes in sensation that may or may not have been felt at the vesicant administration site. A healthcare team approach is used to determine details about the extravasation and decide the best course of action to take. When an extravasation occurs or is suspected, the first action is to stop the infusion or discontinue pushing the syringe containing the vesicant. If the vesicant was adminis­ tered via an implanted port, the non-coring needle should be assessed for correct placement. The affected area should be inspected for skin discoloration and swelling, and palpated for tenderness at rest and upon movement [6, 25]. The residual vesicant in the IV device should be aspirated using a small (1–3  mL syringe) [6]. There is a very small amount of the vesicant in the IV device (e.g., IV catheter or non-coring needle) that could be deposited into the tissue as the device is removed. Although some authors recommend aspirating residual vesicant from the site [7], multiple punc­ tures in the area of the vesicant extravasation may be painful for the patient, disrupt the integrity of the skin, and may increase the patient’s risk of infection. If an extravasation is suspected to have occurred as the vesicant was being administered, the concentration and vol­ ume of the vesicant that remains in the syringe or infusion bag should be noted. The volume remaining in the infusion bag should be measured rather than estimated. The maxi­ mum number of milligrams of the vesicant that may have entered the tissue can then be calculated. Documentation in the patient’s medical record should include the date on which and time at which the vesicant extravasation occurred or was suspected, the location, type, and size of the peripheral IV device or type of central VAD, and gauge/length of non-coring needle (implanted ports). The number and location of venipuncture attempts for peripheral vesicant administration should be noted. Documentation also should include information about a blood-return, method of administration (e.g., bolus, infu­ sion), concentration and estimated amount of extravasated vesicant, and symptoms reported by the patient (e.g., burn­ ing, pain). A description of the appearance of the administra­ tion site (including measurement of edema and/or redness if present), and digital photographs of the site may be helpful to include. Lastly, documentation should include immediate interventions, follow-up recommendations (e.g., return appointments), and patient teaching that includes skin assessment, temperature monitoring, and reporting worse­ ning discomfort [25].

Local cooling (ice packs, cold gel packs) is widely recom­ mended for extravasations of DNA-binding vesicants (e.g., anthracyclines and mechlorethamine). Docetaxel is a taxane that can cause hyperpigmentation, redness, and tenderness when it extravasates [6]. Paclitaxel is a taxane that is classi­ fied as a mild vesicant; extravasation may cause induration and blistering but rarely necrosis [6]. Application of cold packs is the only treatment currently recommended for tax­ ane extravasations [6, 10]. Cooling the area has been thought to constrict blood ves­ sels and help prevent the vesicant from spreading to adjacent tissues [5, 26]. However, a 2009 review of topical cooling found that there is insufficient scientific and clinical evidence to recommend cooling [27]. Despite cooling, the majority of untreated DNA-binding vesicant extravasations progress to ulceration [27]. Further, even when cooled to 0°C there is still measurable uptake of DNA-binding vesicants into cells [28]. Another consideration is the effectiveness of topical cooling in decreasing tissue temperature; after 15 min, skin temperature only decreases a mean of 10°C [29]. Therefore, if an extrava­ sation of a DNA-binding vesicant occurs deep in the tissue, topical cooling will not reach this area. However, topical cool­ ing is known to produce a nerve conduction block and may have a role in reducing discomfort (e.g., burning sensation, tenderness) caused by extravasation of DNA-binding vesi­ cants. Topical cooling should be removed at least 15 min prior to and during dexrazoxane (Totect® in the USA or Savene® in Europe) treatment of anthracycline extravasations [30]. Local warming (dry heat) is indicated for non-DNAbinding vesicant extravasations to increase blood flow to the area, which helps distribute the extravasated vesicant and promotes its absorption [5, 6, 31]. Non-DNA-binding vesi­ cants include the plant alkaloids vincristine, vinblastine, and vindesine. Heat application also is recommended for extravasation of oxaliplatin. Because cold packs cause local vasoconstriction, they may precipitate or worsen the cold neuropathy that many patients receiving oxaliplatin experience [6]. The frequency and duration of topical cooling and heating vary in clinical practice and in the published literature. Immediate application, then on/off for 24 h has been recommended [7]. The Oncology Nursing Society and European Oncology Nursing Society recommend intermittent cooling or heating for 15–20 min at least four times daily for 24–48 h [6, 32].

Management Considerations Every vesicant extravasation is unique. Extravasations of small amounts of non-DNA-binding vesicants usually heal

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without a break in skin integrity ever occurring. In contrast, untreated extravasations of small amounts of DNA-binding vesicants are likely to cause some degree of blistering and tissue damage. The severity of vesicant extravasation injuries generally is influenced by the type of vesicant that extravasates (e.g., DNA-binding or non-binding), the concentration and amount of the vesicant in the tissue, and the location of the injury. Vesicant extravasation injuries in areas of flexion, such as the wrist and elbow, or in areas with minimal overly­ ing tissue, such as the dorsum of the hand and wrist, tend to be more serious injuries than those that occur in other areas, such as the forearm. Further, patient factors, such as older age, comorbidity (e.g., diabetes, which prolongs wound heal­ ing), and impaired immunocompetence influence the sever­ ity of extravasation injuries and patients’ responses to treatment of these injuries [25].

Conservative Management Conservative management, or a “watch and wait” approach, has historically been commonly used to manage vesicant extravasations. However, in most cases, and especially those involving DNA-binding agents (e.g., anthracyclines, mechlo­ rethamine), tissue necrosis requiring surgical intervention occurred [27]. There remains some controversy regarding the manage­ ment of small-to-intermediate-sized vesicant extravasa­ tions. Some clinicians recommend a “watch and wait” approach; however, it is difficult at best to estimate the amount of the vesicant that may be in the tissue and there is a finite period of time in which an extravasation can be successfully treated. Missing the opportunity to treat an extravasation can result in poor patient outcomes and potential litigation [27, 33].

Surgical Management With the advent of new and highly effective pharmacologic extravasation treatments, surgical intervention for vesicant extravasation injuries is now rarely performed, and is only indicated when a vesicant extravasation goes untreated and necrosis occurs, or when necrosis occurs despite pharmaco­ logic treatment. Wound cleaning and debridement may be required in the weeks following an untreated vesicant extravasation to remove necrotic tissue and prevent infection. Application of a skin flap along with skin grafting may be required to cover and close defects created by vesicant extravasation injuries. Repeated debridement procedures may be required [25].

L. Schulmeister

Saline and Suction Techniques Scuderi and Onesti [34] theorized that local injection of nor­ mal saline solution into an area of vesicant extravasation would reduce the concentration of the vesicant and facilitate its reabsorption. The doxorubicin extravasation sites of 26 patients treated in Rome, Italy were injected with saline solu­ tion in varying amounts depending on the location of injury (20 mL on wrists, 40 mL on dorsum of hands, 60–90 mL for forearm and antecubital fossa areas) three to six times daily for 3  days. Pain and erythema resolved within 4  days and superficial ulcerations healed in 10–14 days. However, three patients with deep lesions still required surgery despite saline flushing. Variations in the sequencing and technique of combining saline lavage with suction have been reported, with varying results [35–39]. However, the extravasations were not con­ firmed by biopsy and details about them are lacking. Also, based on the conflicting results, it is apparent that despite flushing, some of the vesicant remains behind in the tissue and causes necrosis [25, 27].

Pharmacologic Management Various medications and substances, including some referred to as “antidotes,” have been injected into or topically applied to vesicant extravasation injuries. In animal and human stud­ ies, as well as anecdotal clinical reports, there have been varying degrees of success in using these agents to treat extravasation injuries. Several drugs, such as glucocorti­ coids, hydrocortisone, antihistamines, sodium bicarbonate, heparin, and lidocaine have been found to be ineffective in preventing or treating extravasation injuries [31]. The herb ginkgo biloba, alpha-tocopherol (vitamin E), and granulocytemacrophage colony stimulating factor (GM-CSF) were somewhat effective in treating extravasation injuries [7, 31]. However, in these studies and reports, none of the extravasa­ tions were biopsy-confirmed and concurrent treatments were administered, such as systemic or topical antibiotics, which make it difficult to interpret and apply these findings in clini­ cal practice. Dimethyl sulfoxide (DMSO) is a topically-applied solvent that increases skin permeability, promotes absorption of extravasated vesicants, and scavenges free radicals. DMSO has been studied in rodents and humans in various amounts, concentrations (50–100%), application frequencies (every 2–8 h), duration of treatment (2–14 days), and in combination with other treatments (e.g., ice, topical creams, and/or systemic antibiotics). Because of the variations in DMSO treatment and concurrent use of additional extravasation treatments, the efficacy of DMSO remains uncertain. Side

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34  Extravasation

effects associated with DMSO include mild burning at the site of application and development of a distinct breath odor [20, 40]. The use of DMSO in the USA is limited by its availability; medical grade DMSO at concentrations greater than 50% is not available [25]. Some vesicant manufacturers state extravasation manage­ ment recommendations in their prescribing information. However, since most vesicants received approval for use many years ago, these extravasation recommendations are now outdated. In addition, extravasation antidotes and treat­ ments have sometimes not been commercially available, as occurred from 2000 to 2004 when hyaluronidase was no lon­ ger being manufactured.

Guidelines and Recommendations The third edition of the Oncology Nursing Society’s Chemotherapy and Biotherapy Guidelines and Recommen­ dations for Practice [6], published in 2009, includes the recommendations to treat anthracycline extravasations with Totect, administer the antidote sodium thiosulfate when mechlorethamine extravasations occur, and administer the antidote hyaluronidase when plant alkaloid extravasations occur. Use of topical DMSO as an extravasation antidote or treatment is not recommended. The European Oncology Nursing Society (EONS) pub­ lished extravasation guidelines in four languages in 2007 [32, 41]. Savene®, the equivalent of Totect in the USA, is recommended for anthracycline extravasation treatment. Sodium thiosulfate is not recommended for mechlorethamine extravasations “due to lack of evidence”; however, further rationale for this recommendation is not discussed in the EONS guidelines. Hyaluronidase is “suggested as a possible antidote in many literature sources” and “due to lack of evi­ dence it is recommended that this is further studied.” Topical DMSO (99% solution) is “suggested as a possible antidote for anthracycline and mitomycin C extravasations in many literature sources” and “due to lack of evidence it is recom­ mended that it is further studied.” The United Kingdom Oncology Nursing Society adapted the EONS guidelines and published Anthracycline Extrava­ sa­tion Management Guidelines in January 2008 [42] Savene® is recommended for anthracycline extravasations exceeding 1.5 mL, with “volumes based on clinical judgment.” The American Society of Clinical Oncology, European Society for Medical Oncology, Hematology/Oncology Pharmacy Association, International Society of Oncology Pharmacy Practitioners, Multinational Association of Supportive Care in Cancer, and National Comprehensive Cancer Network have to date, not developed or published vesicant

chemotherapy extravasation management guidelines or recommendations [43].

Sodium Thiosulfate Sodium thiosulfate is indicated for the treatment of mechlo­ rethamine (nitrogen mustard) extravasations and is available as a 10% or 25% solution. Although its exact mechanism of action is unknown, sodium thiosulfate is believed to chemi­ cally neutralize the reactive alkylating species of mechlore­ thamine and reduce the production of hydroxyl radicals that cause tissue injury [44]. A 1/6 molar solution of thiosulfate is recommended, which can be obtained by mixing 4 mL of 10% sodium thiosulfate with 6 mL of sterile water for injec­ tion. Subcutaneously inject 2  mL of the solution for each milligram of meclorethamine suspected to have extravasated into the area of extravasation [6].

Hyaluronidase Hyaluronidase is indicated for the treatment of plant alkaloid extravasations. It is an enzyme that modifies the permeability of connective tissue through hydrolysis of hyaluronic acid and helps disperse plant alkaloid vesicants throughout the tissue and promotes their absorption [45]. Several formula­ tions of hyaluronidase are available; most are animal-derived products (e.g., AmphadaseTM, HydaseTM, and Vitrase®). Hyelenex® is a purified preparation of the enzyme recombi­ nant human hyaluronidase. Hyaluronidase product selection is based on prescriber preference; some prescribers prefer a recombinant human product over animal-derived products to lessen the likelihood of local injection reactions. Current rec­ ommendations are to subcutaneously inject 1–6  mL of a 150  Units/mL solution into the area of extravasation in a clockwise manner. The usual dose is 1 mL of solution for 1 mL of extravasated drug [6, 46].

Local Injection The antidotes sodium thiosulfate and hyaluronidase are locally injected into the extravasation area. While these antidotes are mentioned in a number of articles and guide­ lines, details of how they should be administered often are inconsistent or not mentioned. The EONS Guidelines, for instance, recommend that hyaluronidase is locally injected into the subcutaneous tissue around the extravasated area [32]. Some authors suggest that these antidotes are given into

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the extravasation site through the existing IV line and/or if the line has been removed, in a clockwise manner [5]. Administering an antidote into the existing IV line is based on the presumption that the tip of the IV device lies in the subcutaneous tissue, which is the intended injection site. However, it is possible that the tips of peripheral and central IV devices may actually be in the venous system (e.g., when central line catheter nicking causes the extravasation or when repeated venipuncture occurs prior to peripheral IV placement). The antidote would then be administered intra­ venously instead of the intended subcutaneous route of administration. Further, much of the antidote could remain in the device if the antidote is injected through the device prior to its removal. For these reasons, it may be preferable to remove the peripheral IV device or non-coring implanted port needle and then locally inject the antidote into the extravasation area [33].

Totect and Savene The Totect (dexrazoxane for injection) anthracycline extrava­ sation treatment kit is available in the USA and its equiva­ lent, Savene, is available in Europe and the UK. The kits contain a complete 3-day treatment and are packaged for single-patient use. Dexrazoxane has been used for several years to minimize doxorubicin cardiotoxicity and recently was found to have a protective effect against the development of doxorubicin extravasation injuries as well. The drug binds to iron and pre­ vents the formation of free radicals, which are thought to play a major role in the development of extravasation-induced tissue necrosis. It also binds to DNA topoisomerase II at a different step in the catalytic cycle than anthracyclines and locks the enzyme in a form that is no longer affected by the anthracyclines [47]. In animal studies and case reports, dexrazoxane was successful in reducing or eliminating tissue necrosis [48, 49]. In two prospective clinical trials, 54 European patients with anthracycline extravasations confirmed by fluorescence microscopy were treated with dexrazoxane. Patients had extravasations of doxorubicin or epirubicin with a mean extravasation area of 23.6 cm2 in the first study and 39 cm2 in the second study. All patients received dexrazoxane as soon as possible and within 6 h of the extravasation for 3 consecu­ tive days at a dose of 1,000 mg/m [2] on days 1 and 2, and a dose of 500 mg/m2 on day 3. None of the 18 patients in the first study and only one of the 36 patients in the second study had tissue necrosis occur (overall efficacy 98%). Mild pain (19%) and mild sensory disturbances (17%) were the most frequent sequelae. Most of the patients (71%) were able to continue chemotherapy treatment as scheduled and the most

L. Schulmeister

common side effects of extravasation treatment were nausea, injection site reactions, and myelosuppression. However, all side effects were transient and reversible [50]. Anthracycline extravasation from central VADs and implanted ports have been successfully treated with Savene [51] and Savene also has been used to successfully treat intra­ pleural epirubicin extravasation in a case report [52]. Because of their efficacy in treating anthracycline extravasations, Totect and Savene have the potential to reduce the risk of accidentally inducing additional patient morbidity and it is recommended that this treatment is available in every institu­ tion in which anthracyclines are administered [53, 54].

Summary Safe administration of vesicant chemotherapy continues to be the best measure for preventing extravasation. However, despite nurses’ best efforts, extravasations may still occur when patients move or IV devices are damaged or malfunc­ tion. A blood-return should be obtained prior to vesicant administration and the IV site should be assessed for signs of extravasations (e.g., redness, swelling). Oncology healthcare providers need to be well informed of current extravasation management recommendations and guidelines in order to most effectively treat patients receiving vesicant chemotherapy.

References 1. Sauerland C, Engelking C, Wickham R, Corbi D. Vesicant extrava­ sation part I: mechanisms, pathogenesis, and nursing care to reduce risk. Oncol Nurs Forum. 2006;33:1134–1141. 2. Bozkurt AK, Uzel B, Akman C, et al. Intrathoracic extravasation of antineoplastic agents: case report and systematic review. Am J Clin Oncol. 2003;26:121–123. 3. Jost K, Leithäuser M, Grobe-Thie C, et al. Perforation of the supe­ rior vena cava–a rare complication of central venous catheters. Onkologie. 2008;31:262–264. 4. Uges JWF, Vollaard AM, Wilms EB, Brouwer RE. Intrapleural extravasation of epirubicin, 5-fluouracil, and cyclophosphamide, treated with dexrazoxane. Int J Clin Oncol. 2006;11:467–470. 5. Ener, RA, Meglathery SB, Styler M. Extravasation of systemic hemato-oncological therapies. Ann Oncol. 2004;15:858–862. 6. Polovich M, Whitford JM, Olsen M. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 3rd ed. Pittsburgh, PA: Oncology Nursing Society; 2009. 7. Goolsby TV, Lombardo FA. Extravasation of chemotherapeutic agents: prevention and treatment. Semin Oncol. 2006;33:139–143. 8. Baur M, Kienzer HR, Rath T, et  al. Extravasation of oxaliplatin (Eloxatin®)– clinical course. Onkologie. 2000;23:468–471. 9. Vinorelbine [Package insert]. 2005; Bedford, OH: Beford Labs. 10. Stanford BL, Hardwicke F. A review of clinical experience with paclitaxel extravasations. Support Care Cancer. 2003;11:270–277. 11. Luedke DW, Kennedy PS, Rietschel RL. Histopathogenesis of skin and subcutaneous injury induced by adriamycin. Plas Reconstr Surg. 1979;63:463–465.

34  Extravasation 12. Sonneveld P, Wassenaar HA, Nooter K. Long persistence of doxorubicin in human skin after extravasation. Cancer Treat Rep. 1984;68:895–896. 13. Madhavan S, Northfelt DW. Lack of vesicant injury following extravasation of liposomal doxorubicin. J Natl Cancer Inst. 1995;87:1556–1557. 14. Laufman LR, Sickle-Santanello B, Paquelet J. Liposomal doxoru­ bicin extravasation. Commun Oncol. 2007;4:464–465. 15. Langstein HN, Duman H, Seelig D, et al. Retrospective study of the management of chemotherapeutic extravasation injury. Annal Plast Surg. 2002;49:369–374. 16. Barlock AL, Howser DM, Hubbard SM. Nursing management of adriamycin extravasation. Am J Nurs. 1979;79:94–96. 17. Wang JJ, Cortes E., Sinks LF, Holland JF. Therapeutic effect and toxicity of adriamycin in patients with neoplastic disease. Cancer. 1971;28:837–843. 18. Laughlin RA, Landeen JM, Habal MB. The management of inad­ vertent subcutaneous adriamycin infiltration. Am J Surg.1979;137: 408–412. 19. Pitkänen J, Asko-Seljavaara S, Gröhn P, Sundell B, Heinonen E, Appelqvist, P. Adriamycin extravasation: surgical treatment and possible prevention of skin and soft-tissue injuries. J Surg Oncol. 1983;23:259–262. 20. Bertelli G, Gozza A, Forno GB, et al. Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: a prospective clinical study. J Clin Oncol. 1995;13:2851–2855. 21. Schulmeister L. Managing vesicant extravasations. Oncologist. 2007;13:284–288. 22. Doellman D, Hadaway L, Bowe-Geddes LA, et al. Infiltration and extravasation: update on prevention and management. J Infus Nurs. 2009;32:203–211. 23. Schulmeister L, Camp-Sorrell D. Extravasations from implanted ports. Oncol Nurs Forum 2000;27:531–540. 24. Jordan K, Behlendorf T, Surov A, Kegel T, et  al. Venous access ports: frequency and management of complications in oncology patients. Onkologie. 2008;31:404–410. 25. Schulmeister L. Extravasation management. Sem Oncol Nurs. 2007;23:184–190. 26. Schrijvers DL. Extravasation: a dreaded complication of chemo­ therapy. Ann Oncol. 2003;14(suppl 3):26–30. 27. Langer SW, Sehested M, Jensen PB. Anthracycline extravasation: a comprehensive review of experimental and clinical treatments. Tumori. 2009;95:273–282. 28. Lane P, Vichi P, Bain DL, Tritton TR. Temperature dependence studies of adriamycin uptake and cytotoxicity. Cancer Res. 1987;47:4038–4042. 29. Belitsky RB, Odam SJ, Hubley-Kozey C. Evaluation of the effec­ tiveness of wet ice, dry ice, and cryogenic packs in reducing skin temperature. Phys Ther. 1987;67:1080–1084. 30. Schulmeister L. Totect: a new agent for treating anthracycline extravasation. Clin J Oncol Nurs. 2007;11:387–395. 31. Wickham R, Engelking C, Sauerland C, Corbi D. Vesicant extrava­ sation part II: evidence-based management and continuing contro­ versies. Oncol Nurs Forum. 2006;33:1143–1150. 32. Extravasation guidelines 2007. http://www.cancernurse.eu/docu­ ments/EONSClinicalGuidelinesPostSymposiumReport.pdf. Accessed September 5, 2009.

359 33. Schulmeister L. Vesicant chemotherapy extravasation antidotes and treatments. Clin J Oncol Nurs. 2009;13:395–398. 34. Scuderi N, Onesti MG. Antitumor agents: extravasation, man­ agement, and surgical treatment. Ann Plast Surg. 1994;32: 39–44. 35. Vandeweyer E, Deraemaecker R. Early surgical suction and wash­ out for treatment of cytotoxic drug extravasations. Acta Chir Belg. 1994;100:37–38. 36. Fleming A, Butler B, Gault D. (1998). Letter to the editor in response to “Surgical management after doxorubicin and epirubicin extravasation.” J Hand Surg. 1998;24:390. 37. Gault DT. Extravasation injuries. Br J Plast Surg. 1993;46:91–96. 38. Giunta R. Early subcutaneous wash-out in acute extravasations. Ann Oncol. 2004;15:1146. 39. Van Wijck R. Liposuction to the radiologist’s rescue. Plast Reconstr Surg. 1993;92:175. 40. Olver IN, Aisner J, Hament A, et al. A prospective study of topical dimethyl sulfoxide for treating anthracycline extravasation. J Clin Oncol. 1988;6:1732–1735. 41. Wengström Y, Margulies, A. European Oncology Nursing Society extravasation guidelines. Eur J Oncol Nurs. 2008;12:357–361. 42. UKONS Anthracycline Extravasation Management Guidelines. London, England: United Kingdom Oncology Nursing Society; 2008. 43. Morganstern D, Held-Warmkessel J. Survey of practice guidelines for management of anthracycline extravasation (ae). Support Care Cancer. 2008;16:755. 44. Dorr RT, Soble M, Alberts DS. Efficacy of sodium thiosulfate as a local antidote to mechlorethamine skin toxicity. Cancer Chemother Pharmacol. 1988;22:299–302. 45. Dorr RT. Antidotes to vesicant chemotherapy extravasations. Blood Rev. 1990;4:41–60. 46. Bertelli G, Dini D, Forno BG, et al. Hyaluronidase as an antidote to extravasation of vinca alkaloids: clinical results. J Cancer Res Clin Oncol. 1994;120:505–506. 47. Hasinoff BB. The use of dezrazoxane for the prevention of anthra­ cycline extravasation injury. Expert Opin Investig Drugs. 2008;17: 217–223. 48. Langer SW, Sehested M, Jensen PB. Treatment of anthracycline extravasation with dexrazoxane. Clin Cancer Res. 2000;6: 3680–3686. 49. Langer SW, Sehested M, Jensen PB. Dexrazoxane is a potent and specific inhibitor of anthracycline induced subcutaneous lesions in mice. Ann Oncol. 2000;12:405–410. 50. Mouridsen HT, Langer SW, Buter J, et al. Treatment of anthracy­ cline extravasation with Savene (dexrazoxane). Results from two prospective clinical multicenter studies. Ann Oncol. 2006;18: 546–550. 51. Langer SW. Treatment of anthracycline extravasation from cen­ trally inserted venous catheters. Oncol Rev. 2008;2:114–116. 52. Uges JWF, Vollaard AM, Wilms EB, Brouwer RE. Intrapleural extravasation of epirubicin, 5-fluouracil, and cyclophosph­ amide, treated with dexrazoxane. Int J Clin Oncol. 2006;11: 467–470. 53. Langer SW. Dexrazoxane for anthracycline extravasation. Expert Rev Anticancer Ther. 2007;7:1081–1088. 54. Schulmeister L. Dexrazoxane treatment for intrathoracic anthracy­ cline treatment. Onkologie. 2008;31:634.

Chapter 35

Dermatologic Toxicities Eugene Balagula and Mario E. Lacouture

Introduction Chemotherapy and radiation can potentially lead to numerous side effects, affecting skin and its adnexae (i.e., hair and nails) and mucous membranes. Frequent side effects such as alopecia and stomatitis associated with conventional cytotoxic agents are well-known to health-care providers. In addition, novel targeted chemotherapy agents may lead to a variety of dermatologic toxicities that occur in the majority of the patients and have been described only recently. This chapter will address skin, hair and nail toxicities induced by both conventional cytotoxic and recently introduced agents, as well as radiation-induced effects. Underlying mechanisms and clinical presentation will be delineated, and management strategies will be emphasized.

Grading of Dermatologic Toxicities Accurate grading is critical to assess response to antitoxicity interventions and impact on patients [1]. The most widely used system is the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, published by the US Department of Health and Human Services on May 19, 2009 (Refer to Table 35.1). CTCAE version 3.0, its predecessor, was the most commonly used system to grade toxicities in clinical trials. The most recent version takes into consideration the degree to which activities of daily living (ADLs) may be affected (e.g., instrumental and self-care for grades 2 and 3 of severity, respectively). It also modified the percentages of body surface area (BSA) affected by papulopustular (acneiform) rash. In the 4.0 version, hand and foot skin reaction (HFSR) has been renamed to palmar-plantar erythrodysesthesia syndrome and takes into consideration hyperkeratotic

Mario E. Lacouture (*) Department of Dermatology, Memorial Sloan Kettering Cancer Center, 160 East 53rd Street, New York 10022, USA e-mail: [email protected]

lesions typically seen in HFSR to multikinase inhibitors. In addition, the new version segregated nail toxicity into separate categories of nail discoloration, ridging, and loss. The use of CTCAE v4.0 may be useful in the research realm, but its application in daily clinical practice may be difficult.

Toxicities of the Skin Papulopustular (Acneiform) Rash Papulopustular (also referred to as acneiform) rash is the most common cutaneous side effect of epidermal growth factor receptor inhibitors (EGFRIs) and can be seen in 75–90% of treated patients [2]. Several EGFRIs are currently being used in the treatment of cancer, including the small molecules erlotinib, gefitinib, and the monoclonal antibodies cetuximab and panitumumab. Lapatinib is a dual inhibitor of the epidermal growth factor receptor (EGFR) and Her2, which has a lower incidence of dermatologic side effects. In addition to EGFRIs, the multikinase inhibitors (MKIs) sorafenib and sunitinib are also associated with papulopustular rash. Clinically, it presents similar to the EGFRI-induced rash but is less frequent (40% and 20% with sorafenib and sunitinib, respectively) and of lower severity [3]. Epidermal growth factor receptors (EGFRs) play a critical role in normal skin physiology, development, and integrity, by regulating keratinocyte proliferation, differentiation, and survival [4]. Direct inhibition of EGFRs is believed to underlie the pathophysiology of rash. Exposure of epithelial cells to these drugs leads to increased synthesis of a variety of chemokines which recruit inflammatory cells such as leukocytes and neutrophils, generating an inflammatory response [4]. A therapeutically relevant fact is that the mechanism of inflammation is likely not dependent on the arachidonic-acid-prostoglandin pathway, since celecoxib did not affect the skin toxicity profile of cetuximab [5]. The papulopustular rash is characterized by papules and pustules which are associated with pruritus and pain, and

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_35, © Multinational Association for Supportive Care in Cancer Society 2011

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Table 35.1  Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Skin and subcutaneous tissue disorders Grade

Adverse events

1

Dry skin

Covering <10% BSA Covering 10–30% BSA and associated with and no associated erythema or pruritus; erythema or pruritus limiting instrumental ADL

2

3

4

5

Covering >30% BSA and associated with pruritus; limiting self-care ADL

–

–

Definition: A disorder characterized by flaky and dull skin; the pores are generally fine, the texture is a papery thin texture – – – Nail discoloration Asymptomatic; clinical or diagnostic observations only; intervention not indicated Definition: A disorder characterized by a change in the color of the nail plate Symptomatic separation – Nail loss Asymptomatic of the nail bed from separation of the the nail plate or nail nail bed from the loss; limiting nail plate or nail instrumental ADL loss Definition: A disorder characterized by loss of all or a portion of the nail – – Nail ridging Asymptomatic; clinical or diagnostic observations only; intervention not indicated Definition: A disorder characterized by vertical or horizontal ridges on the nails Severe skin changes (e.g., Minimal skin changes Skin changes (e.g., Palmar-plantar peeling, blisters, peeling, blisters, or dermatitis (e.g., erythrodysesthesia bleeding, edema, or bleeding, edema, or erythema, edema, syndrome hyperkeratosis) with hyperkeratosis) with or hyperkeratosis) pain; limiting self-care pain; limiting without pain ADL instrumental ADL

–

–

–

–

–

–

–

Definition: A disorder characterized by redness, marked discomfort, swelling, and tingling in the palms of the hands or the soles of the feet Death Life-threatening conseErythema covering >30% Photosensitivity Painless erythema and Tender erythema quences; urgent BSA and erythema with covering 10–30% erythema covering intervention indicated blistering; photosensitivBSA <10% BSA ity; oral corticosteroid therapy indicated; pain control indicated (e.g., narcotics or NSAIDs) Definition: A disorder characterized by an increase in sensitivity of the skin to light Intense or widespread; Intense or Pruritus Mild or localized; constant; limiting widespread; topical intervention self-care ADL or sleep; intermittent; skin indicated oral corticosteroid or changes from immunosuppressive scratching (e.g., therapy indicated edema, papulation, excoriations, lichenification, oozing/crusts); oral intervention indicated; limiting instrumental ADL

–

–

(continued)

35  Dermatologic Toxicities

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Table 35.1  (continued) Definition: A disorder characterized by an intense itching sensation Papules and/or Rash acneiform Papules and/or pustules covering pustules covering 10–30% BSA, <10% BSA, which which may or may or may not be may not be associated with associated with symptoms of symptoms of pruritus or pruritus or tenderness tenderness; associated with psychosocial impact; limiting instrumental ADL

Papules and/or pustules covering >30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; limiting self-care ADL; associated with local superinfection with oral antibiotics indicated

Papules and/or pustules covering any % BSA, which may or may not be associated with symptoms of pruritus or tenderness and are associated with extensive superinfection with IV antibiotics indicated; lifethreatening consequences

Death

Definition: A disorder characterized by an eruption of papules and pustules, typically appearing in face, scalp, upper chest, and back – – Macules/papules covering Macules/papules covering Rash maculo-papular Macules/papules >30% BSA with or 10–30% BSA with or covering <10% without associated without symptoms BSA with or symptoms; limiting (e.g., pruritus, without symptoms self-care ADL burning, tightness); (e.g., pruritus, limiting instrumental burning, tightness) ADL Definition: A disorder characterized by the presence of macules (flat) and papules (elevated). Also known as morbilliform rash, it is one of the most common cutaneous adverse events, frequently affecting the upper trunk, spreading centripetally and associated with pruritus – – – Hyperpigmentation Skin hyperpigmentation Hyperpigmentation covering >10% BSA; covering <10% associated psychosoBSA; no cial impact psychosocial impact Definition: A disorder characterized by darkening of the skin due to excessive melanin deposition – Skin hypopigmentation Hypopigmentation or Hypopigmentation or depigmentation depigmentation covering >10% BSA; covering <10% associated psychosoBSA; no cial impact psychosocial impact Definition: A disorder characterized by loss of skin pigment Moderate induration, Skin induration Mild induration, able to slide skin, able to move skin unable to pinch parallel to plane skin; limiting (sliding) and instrumental perpendicular to ADL skin (pinching up)

Severe induration, unable to slide or pinch skin; limiting joint movement or orifice (e.g., mouth, anus); limiting self-care ADL

–

–

Generalized; associated with signs or symptoms of impaired breathing or feeding

Death

Definition: A disorder characterized by an area of hardness in the skin ADL – activities of daily living, BSA – body surface area, NSAIDs – non-steroidal anti-inflammatory drugs Source: http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev4.pdf Accessed on 10.05.09

are distributed in the seborrheic areas, such as the scalp and face (Fig.  35.1). The onset of the rash is during the first 2  weeks of treatment [4]. It is noteworthy that this papulopustular rash is not acne but a separate entity, since no comedones are seen and the histopathology differs [2].

There is a correlation between both the occurrence and severity of the rash with the tumor response and overall survival, underscoring the need to treat patients who develop rash so that they can continue receiving EGFRI therapy [1].

364

Fig.  35.1  Papulopustular rash (Reprinted with permission from CMPMedica. Source: Cancer Management: A Multidisciplinary Approach, 11th edition. Pazdur R, Wagman L, Camphausen K, et al. (Eds), Color atlas. Copyright 2008, All rights reserved)

Although most of the cases are mild to moderate, up to 32% of providers discontinue and up to 76% hold treatment, which may affect clinical outcome [6]. It is important to notify patients about the potential side effects and their signs and symptoms prior to initiation of therapy. Lifestyle modifications such as taking baths in tepid water as opposed to hot showers, using emollients that are alcohol-free to avoid skin dryness, avoidance of sun, and using other sun-protective methods such as sunscreen, are recommended to reduce skin toxicity [4]. There have been several randomized controlled trials (RCTs) to evaluate prophylactic management of EGFRI-induced skin toxicities. The Skin Toxicity Evaluation Protocol with Panitumumab (STEPP) compared preemptive treatment with a skin moisturizer, sunscreen, 1% hydrocortisone cream, and doxycycline 100  mg twice daily versus reactive treatment which was decided by each separate investigator involved in the study. Not only did preemptive treatment diminish the occurrence of grade 2 or greater rash by more than 50%, but it also significantly delayed the time period to the first manifestation of any grade 2 or greater skin toxicity. In addition, a similar effect was seen with severe (grade 3) skin toxicity, where the time to onset was

E. Balagula and M.E. Lacouture

significantly delayed [7]. Another study examined the benefits of prophylactic oral minocycline as opposed to placebo in patients with metastatic colon cancer prior to cetuximab therapy [8], showing a decrease in both the total facial lesion count and occurrence of moderate to severe pruritus in the treatment arm. Another conclusion of this study was that a topically applied tazarotene was found to be an irritant and was not recommended for treatment of cetuximab-induced rash. A similar study used oral tetracycline 500 mg bid as a prophylactic agent in patients prior to EGFRI treatment. Tetracycline did not possess the ability to prevent the rash. However, it decreased grade 2 rash from 55% to 17% [9]. Whereas prophylactic treatment is recommended, given the high incidence of rash, reactive management may be necessary in some cases. One of the weaknesses in the available arsenal for the reactive treatment of EGFRI-associated skin toxicity is that these therapies are based on anecdotal experience and have not been validated in RCT. Multiple treatment algorithms have been designed over the years in an attempt to reduce and/or eliminate the rash and improve quality of life (QOL) [1, 10] (See Fig. 35.2 for treatment algorithm). The pathophysiology of skin toxicity induced by EGFRI does not appear to involve an underlying bacterial infection but an apparent benefit from oral semisynthetic tetracycline antibiotics may be secondary to their anti-inflammatory properties [6]. Nevertheless, superinfection can occur in up to 38% of patients and should be recognized and treated. For example, signs like a sudden change in the appearance of the lesions, oozing of fluid, and yellow and/or brown crusting may suggest an underlying superinfection, which is of bacterial origin in the majority of cases.

Hand–Foot Skin Reaction Despite striking similarities to hand and foot syndrome (HFS) as seen with multiple conventional cytotoxic chemotherapy agents such as 5 FU, cytarabine, methotrexate, and doxorubicin, a distinction should be made between HFS to cytotoxic agents and HFSR to MKIs. They share qualities such as a palmoplantar distribution, dose dependency, and pain, but they differ in clinical as well as histopathological features [11]. HFSR usually manifests itself within the first 2–4 weeks after therapy initiation. Clinically, HFSR presents with erythema, paresthesias, or dysesthesias, involving the palms and soles with blisters followed by thick hyperkeratotic, tender lesions. Lesions commonly occur in the regions of friction and/or trauma, arising on the flexural surface of interphalangeal joints, distal phalanges, or heels and can significantly influence weight-bearing ability and mobility (Fig. 35.3). This is in contrast to diffuse regions of erythema and edema seen in HFS [3, 11].

365

35  Dermatologic Toxicities

Severity (CTCAE v.4)

Papulopustular Rash

Grade 0

Grade 1

Intervention (Reactive)* Prophylactic therapy with sunscreen SPF≥30; Moisturizing creams; Gentle skin care instructions given

Continue anticancer agent at current dose and monitor for change in severity Hydrocortisone 2.5% cream and Clindamycin 1% gel qd Reassess after 2 weeks (either by healthcare professional or patient self-report); if reactions worsen or do not improve proceed to next step

Grade 2

Continue anticancer agent at current dose and monitor for change in severity Hydrocortisone 2.5 % cream AND Doxycycline 100mg OR minocycline 100mg bid Reassess after 2 weeks (either by healthcare professional or patient self-report); if reactions worsen or do not improve proceed to next step

Grade 3

Dose modify as per PI; obtain bacterial/viral cultures if infection is suspected and Continue treatment of skin reaction with the following: Hydrocortisone 2.5 % cream AND Doxycycline 100mg OR minocy cline 100 mg bid AND Prednisone 0.5mg/kg for 5 days

*It is recommended that patients treated with EGFR inhibitors begin prophylactic rash therapy with doxycycline or minocycline 100mg bid and a low potency topical steroid bid for first 6 weeks of therapy

Reassess after 2 weeks; if reactions worsen or do not improve, dose interruption or discontinuation per PI may be necessary

Fig. 35.2  Treatment algorithm for papulopustular rash

Fig. 35.3  Hand–foot skin reaction (Reprinted with permission from CMPMedica. Source: Cancer Management: A Multidisciplinary Approach, 11th edition. Pazdur R, Wagman L, Camphausen K, et al. (Eds), Color atlas. Copyright 2008, All rights reserved.)

Multitargeted kinase inhibitors (MKIs) have been found to be associated with hand–foot skin reaction (HFSR) along with multiple other cutaneous side effects including a rash, xerosis, and pigmentary changes [3]. Both sunitinib and sorafenib have been found to be associated with significantly increased risk of HFSR in patients with multiple solid tumors. Meta-analysis demonstrated the overall incidence of HFSR with sunitinib to be 18.9% for all-grade and 5.5% for high grade. Conversely, incidence with sorafenib was 33.8% for all grade and 8.9% for high grade [3]. The loss of repair mechanisms by fibroblasts and endothelial cells in combination with repeated daily trauma can result in the characteristic palmoplantar affectation [11]. HFSR by itself is not life-threatening, but by leading to either reduction or interruption of treatment, it can potentially compromise the efficacy of the agent. Certain recommendations for treatment have been proposed. Preemptive strategy is a crucial part of the management of HFSR (Table 35.2). Certain prophylactic measures such as removing calluses and orthotics where

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E. Balagula and M.E. Lacouture

indicated, have been shown to avert the first and recurring episodes of HFSR [12]. Once HFSR develops, therapy is given based on the degree of the severity. These proposed guidelines arise from expert opinions of clinicians commonly Table. 35.2  Preemptive strategies for HFSR • Full-body exam to look for hyperkeratotic regions on palms and soles and removal of calluses • Avoiding hot water when taking shower, bath, or dishwashing • Avoidance of trauma and friction during the first 2–4 weeks • Avoidance of vigorous exercise, especially during the first month of therapy • Avoidance of tight-fitting shoes and evaluation by orthotist if necessary • Avoiding excessive pressure when applying lotions • Utilization of moisturizing creams containing keratolytics such as ammonium lactate (both prior and during therapy) or urea • Wear thick cotton gloves and/or socks and slippers Data from Lacouture et al. [3]

treating this type of skin toxicity [3] (Fig. 35.4). To diminish trauma to lesions of HFSR, cotton socks or gloves, gel inserts, and soft shoes or Tempur-Pedic® slippers can be used [12]. Urea is a keratolytic agent able to loosen up the horny layer of the skin, thereby softening the areas of thickening. Tazarotene, used in psoriasis patients, also has an effect of decreasing epidermal thickness. These agents can be used to treat hyperkeratotic lesions and should be applied to affected areas only in order to avoid irritation to normal surrounding skin [3, 11].

Hand–Foot Syndrome (Palmoplantar Erythrodysesthesia) Hand–foot syndrome (HFS), also known as palmar-plantar erythrodysesthesia, is a skin toxicity associated with several cytotoxic chemotherapeutic agents. However, common

Hand-Foot Skin Reaction and Hand Foot Syndrome Severity (CTCAE v.4)

Intervention

Grade 0

Prophylaxis with Ammonium lactate 12% cream (Amlactin®) twice daily OR heavy moisturizer (e.g. vaseline) twice daily

Grade 1

Continue treatment at current dose and monitor for change in severity Urea 20% cream twice daily AND clobetasol 0.05% cream once daily Reassess after 2 weeks (either by healthcare professional or patient selfreport); if reactions worsen or do no improve proceed to next step

Grade 2

Continue treatment at current dose and monitor for change in severity Urea 20% cream twice daily AND clobetasol 0.05% cream once daily Pain control with NSAIDs/GABA agonists/Narcotics Reassess after 2 weeks (either by healthcare professional or patient selfreport); if reactions worsen or do not improve, proceed to next step

Grade 3

Interrupt treatment until severity decreases to grade 0-1; continue treatment of skin reaction with the following Clobetasol 0.05% cream twice daily AND pain control with NSAIDs/GABA agonists/Narcotics Reassess after 2 weeks; if reactions worsen or do not improve, dose interruption or discontinuation per protocol may be necessary

Fig. 35.4  Treatment algorithm for hand–foot skin reaction and hand–foot syndrome

35  Dermatologic Toxicities

culprits include 5-Flourouracil (5-FU), its prodrug capecitabine, doxorubicin, liposomal doxorubicin, docetaxel, and cytarabine [13]. The incidence of HFS varies depending on the offending agent [13]. Pegylated liposomal doxorubicin (PLD), which is a long circulating formulation of doxorubicin, has an improved side-effect profile as compared to its predecessor, with the exception of HFS, which appears with higher frequency [14]. It should be noted that even a single drug can lead to different frequencies of HFS depending on the modality of administration. Such a case is with 5-FU, whereby continuous infusion (CI) gives rise to a higher incidence as compared to a bolus infusion. A meta-analysis revealed that 34% of patients developed HFS if the drug was administered by CI versus 13% if treated by 5-FU bolus [15]. In the case of PLD, it was shown that the reaction is more likely to occur after repeated administrations of the drug [14]. While most of the HFS cases are mild, it is the most prevalent cumulative toxicity in patients treated with PLD and is seen in up to 45% of the patients [16]. The onset of symptoms is variable and ranges anywhere from a few days to up to 10  months after the initiation of therapy [16]. The characteristic initial manifestation is with paresthesias, followed by the appearance of symmetrical painful erythema and edema involving the palms and soles after 3–4 days (Fig. 35.5). Without appropriate interventions the lesions can blister, desquamate, form crusts, ulcerate, or even progress to epidermal necrosis [14]. Extravasation with accumulation of the drug in the stratum corneum has been hypothesized as a potential mechanism of toxicity. In the case of PLD, it has been suggested that the drug is transported to the surface of the skin by the eccrine

Fig.  35.5  Hand–foot syndrome (Reprinted with permission from CMPMedica. Source: Cancer Management: A Multidisciplinary Approach, 11th edition. Pazdur R, Wagman L, Camphausen K, et  al (Eds), Color atlas. Copyright 2008, All rights reserved.)

367

sweat glands leading to the accumulation of the drug in the stratum corneum [14, 16]. One of the most important aspects in the management of these patients is their education and surveillance to assist in early detection of signs and symptoms. Certain lifestyle modifications have been recommended including avoiding hot showers and baths that lead to vasodilatation, tight-fitting clothing, and significant friction or pressure. In addition, avoidance of vigorous exercise, especially running, and keeping lower extremities elevated when appropriate is recommended as well [16]. Topical therapy using emollients, aloe vera lotions, moisturizing creams, and topical petroleum-lanolin based ointments can be used to alleviate the symptoms of HFS but have not showed benefit in RCT [14]. The data supporting the use of oral pyridoxine (vitamin B6) for the treatment and prevention of the HFS are limited and conflicting. Evidence does exist for its successful use in both treatment and prevention of HFS induced by different drugs. An RCT failed to demonstrate benefit of prophylactic pyridoxine in its ability to prevent capecitabine induced HFS [16]. Due to the lack of adequate clinical data and a recent negative trial, pyridoxine is not recommended for routine clinical use in cases of PLD or capecitabine-induced HFS [16]. Similar to oral pyridoxine, the use of corticosteroids in the management of HFS is not straightforward and no large RCTs were conducted so far to examine its use. One study examined prophylactic use of oral dexamethasone in patients with a prior history of HFS undergoing repeated treatment with PLD. It showed that patients treated with dexamethasone did not require dosage adjustment for Grade ³2 toxicity. However, treatment interruption or a dose reduction was needed for three patients with the same HFS severity who were not treated with steroids [16]. In addition, successful use of oral prednisone in alleviating patient’s pain and swelling in the setting of HFS induced by cytarabine has been described [17]. Multiple studies demonstrate the benefit of regional cooling of extremities in preventing HFS in patients being treated with PLD. Unfortunately, similar to the use of pyridoxine and steroids, the lack of adequate evidence prevents this method from being recommended for wide use [16]. Similarly, there is no substantial evidence to support the regular use of IV amifostine [16]. In the case of PLD, RCTs have been conducted in order to investigate the potential benefit of dose intensity modification to reduce the associated toxicity. The available evidence suggests that PLD treatment schedule with 40 mg/m2 every 4  weeks reduces HFS incidence without compromising efficacy [14, 16]. Overall, due to the lack of adequate supporting evidence, the recommendation for management of HFS heavily

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E. Balagula and M.E. Lacouture

relies on working closely with the patients and educating them about the importance of recognizing early signs and symptoms in order to implement individualized interventions on time. In addition, prevention and supportive measures are an integral component as well [16]. For treatment approaches and prophylactic measures, refer to Fig. 35.4.

Morbilliform Eruption (Maculopapular Rash) A rash characterized by pink to red macules and/or papules that blanch with pressure, the so-called morbilliform rash, is one of the most common skin toxicities

Severity (CTCAE v.4)

associated with drugs [18]. Some of the agents that can trigger this type of a skin rash include cytarabine, docetaxel, cladribine, gemcitabine, pemetrexed, liposomal doxorubicin, topotecan, imatinib, and dasatinib [13]. The rash typically starts on the trunk and may involve the extremities. The treatment typically includes topical and/or oral corticosteroids and antihistamines which could be used as premedication in some cases [18]. It is important to note that this type of rash needs to be carefully observed for progression to severe reactions such as SJS/TEN [19]. In cancer patients, multiple other medicines are usually being administered, therefore the culprit should be carefully investigated. Antibiotics and anticonvulsants are other frequent culprits. Treatment algorithms can be found in Fig. 35.6.

Maculopapular Rash

Intervention

Moisturizing creams; Gentle skin care instructions given

Grade 0

Continue anticancer agent at current dose and monitor for change in severity

Grade 1

Hydrocortisone 2.5% cream to face AND triamcinolone 0.1% cream to body bid Reassess after 2 weeks (either by healthcare professional or patient self-report); if reactions worsen or do not improve proceed to next step Continue anticancer agent at current dose and monitor for change in severity

Grade 2

Hydrocortisone 2.5% cream to face bid AND Fluocinonide 0.1% cream to body bid Reassess after 2 weeks (either by healthcare professional or patient self-report); if reactions worsen or do not improve, proceed to next step

Grade 3

Dose modify as per PI; obtain bacterial/viral cultures if infection is suspected and continue treatment of skin reaction with the following:

Hydrocortisone 2.5% cream to face bid AND Fluocinonide 0.1% cream to body bid AND Prednisone 0.5mg/kg for 10 days Reassess after 2 weeks; if reactions worsen or do not improve, dose interruption or discontinuation per PI may be necessary

Fig. 35.6  Treatment algorithm for maculopapular rash

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35  Dermatologic Toxicities

Stevens Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN) SJS and TEN represent rare, severe and potentially fatal mucocutaneous blistering diseases that form a spectrum sharing the same underlying disease process [20]. These two diseases are categorized according to the degree of epidermal detachment, expressed as the percentage of the total body surface area (TBSA) affected [21]. With the involvement of less than 10% of TBSA it falls into the category of SJS; greater than 30% of TBSA, TEN is used, whereas SJS/ TEN overlap affects between 10% and 30% of TBSA. It should be noted that SJS/TEN are commonly recognized as separate diseases from erythema multiforme (EM) [20]. An overwhelming majority of TEN cases are associated with drug exposure. In cases of SJS, drugs are still the predominant cause, with other triggers including infections, vaccinations, and GVHD [20, 22]. Overall, allopurinol is the most common drug to trigger SJS/TEN followed by sulfonamide antibiotics, NSAIDs, and anticonvulsants [20]. Sorell J. et al. have demonstrated that several different families of chemotherapy agents such as monoclonal antibodies, antimetabolites, and alkylating agents can be associated with both SJS and TEN [23]. Overall, the estimated incidence of SJS and TEN is 1.2–6 and 0.4–1.2 per million people, respectively. Depending on the degree of epidermal detachment, the mortality ranges between 1% and 5% in SJS and up to 35% in cases of TEN [22]. The pathophysiology underlying the development of SJS/TEN is thought to involve an immune response to drugs or drug metabolites that may be the initial trigger in the cascade of events with a variety of immune cells (cytotoxic CD8 + T, CD4 + T cells, and macrophages) that may play a role. Fas ligand and perforin/granzyme B pathways may account for keratinocyte necrosis that is seen in SJS/TEN [20]. SJS/TEN are characterized by the epidermal detachment which distinguishes them from the previously described morbilliform drug eruption. The typical skin lesions in SJS/TEN are diffuse, flat, atypical target lesions or purpuric macules, often with a necrotic center [20, 22]. There is epidermal detachment from the underlying dermis resulting in flaccid blisters. With increasing severity, the epidermis can slough off easily resulting in superficial erosions [22]. Different mucosal sites can be affected to a variable degree including the eyes, oral mucosa, tracheobronchial tree, gastrointestinal tract, and genitalia [20]. Although the diagnosis heavily relies on the clinical presentation, it should be confirmed with the biopsy that typically shows diffuse keratinocyte apoptosis and full-thickness epidermal necrosis [20].

There are several aspects that need to be considered for optimal management of SJS/TEN. Since a variety of medications appear to be a culprit, early recognition of these entities is essential for timely removal of the offending drug which has been shown to improve the prognosis [24]. Furthermore, the treatment can be divided into supportive care and specific treatments. Corticosteroid use is controversial with some studies reporting increased risk of infection and mortality. Despite the existing evidence that early administration of corticosteroids may be beneficial, corticosteroid use needs to be further examined [20]. There have been multiple studies examining the use of Intravenous Immunoglobulin (IVIG) in both SJS and TEN with conflicting results demonstrating variable effects on mortality. However, it is often considered for treatment due to available data, clinical experience, and relatively minimal toxicities. Overall, decreased mortality is seen when the total dose of IVIG is greater than 2 g/kg [22]. According to recent guidelines from the European Journal of Dermatology, IVIG should be administered as soon as possible after confirming the diagnosis of TEN at a recommended total dose of 3 g/kg of the body weight over the period of 3–5 days [25].

Seborrheic Dermatitis-Like Rash Both sorafenib and sunitinib, novel multikinase inhibitors (MKIs), have been associated with a rash closely resembling seborrheic dermatitis (a.k.a. dandruff) [3]. Scalp dysesthesia may occur simultaneously or prior to the onset of the rash [26]. The rash affecting the scalp and the medial aspect of the face is usually seen a couple weeks after initiation of treatment. For symptomatic patients, treatment with 2% ketoconazole or topical steroids (hydrocortisone 2.5% cream) can be attempted [26].

Intertrigo-Like Rash An intertriginous (intertrigo-like) eruption, characterized by erythematous patches that may be painful or pruritic and involve areas of skin folds such as an axillae and groin or regions that are exposed to friction like under bra areas, can be seen with pegylated doxorubicin (PDL) [19, 27]. Topical corticosteroids may be useful in diminishing the rash and frequently occurring secondary infections require therapy with antibiotics. Maintaining good hygiene and keeping the involved areas dry may be of benefit. Thick barrier creams (zinc oxide 20–30%) can be used to diminish the friction [19]. A treatment algorithm can be found in Fig. 35.7.

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E. Balagula and M.E. Lacouture

Severity (CTCAE v.4)

Intertriginous Rash

Intervention

Grade 0

Prophylaxis with zinc oxide cream bid to perianal areas and after bowel movement; Gentle skin care instructions given

Grade 1

Continue treatment at current dose and monitor for change in severity Silvadene 1% cream applied bid to affected areas Reassess after 2 weeks (either by healthcare professional or patient self-report); if reactions worsen or do not improve proceed to next step

Grade 2

Continue treatment at current dose and monitor for change in severity Silvadene 1% cream AND triamcinolone 0.1% cream bid Reassess after 2 weeks (either by healthcare professional or patient self-report); if reactions worsen or do not improve, proceed to next step

Grade 3

Interrupt until severity decreases to grade 0-1; obtain bacterial/viral cultures if infection is suspected and continue treatment of skin reaction with the following: Silvadene 1% cream bid and triamcinolone 0.1% cream Reassess after 2 weeks; if reactions worsen or do not improve, dose interruption or discontinuation per protocol may be necessary

Fig. 35.7  Treatment algorithm for intertrigo-like rash

Eccrine Squamous Syringometaplasia

Neutrophilic Eccrine Hydradenitis

A variety of agents including but not limited to cytarabine, anthracyclines, cisplatin, cyclophosphamide, carmustine, methotrexate, melphalan, and busulphan have been associated with the condition, eccrine squamous syringometaplasia (ESS) [28]. The manifestation of the ESS may be characterized by the erythematous macules, papules, vesicles, or plaques that are either generalized or localized in distribution [29]. The onset of the lesions may occur several days to 5 weeks following the initiation of therapy and the resolution is spontaneous within approximately 4 weeks without scarring (28–29). The histopathological findings include squamous metaplasia of the eccrine gland with some areas of necrosis of the eccrine ductal epithelium [28]. It is hypothesized to be due to a direct toxicity of a chemotherapeutic agent on the eccrine (sweat) glands [29].

Neutrophilic eccrine hidradenitis (NEH) may present similar to ESS with erythematous maculopapules or plaques involving the head, neck, trunk, and the extremities with the usual onset approximately within 1–2 weeks after initiation of the chemotherapy. Pustules may be seen as well. Fever usually accompanies the rash [29]. The periorbital area or the ear may be potentially affected, clinically resembling cellulitis [28]. Similar to ESS, disappearance of the rash is expected without a specific treatment or subsequent hyperpigmentation and scarring (28–29). The pathological examination reveals neutrophils both around and within the eccrine sweat glands with necrosis of the eccrine epithelial cells. The drugs most commonly associated with NEH include chlorambucil, lomustine, daunorubicin, doxorubicin, cytarabine, cisplatin, vincristine, bleomycin, and mitoxantrone. The removal of

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35  Dermatologic Toxicities

the offending drug will result in self-resolution. To alleviate the pain that may accompany the rash, corticosteroids may be attempted [29]. Reexposure to the drug may induce the same rash [28].

Cutaneous Eruption of Lymphocyte Recovery Eruption of lymphocyte recovery (ELR) is thought to occur in response to autologous hematopoietic stem cell transplants (HSCT) and is limited to skin. It is considered by some authorities to represent a variant of autologous graft versus host disease (GVHD) that lacks involvement of other system organs which may not have been reported or recognized [30]. The typical manifestation of the lesions takes place approximately within 3  weeks post-transplant. It presents with an erythematous maculopapular rash which may lead to erythroderma. Patients may commonly complain of pruritus with occasional eczematous lesions. Fever may follow the eruption of the rash [28].

Graft Versus Host Disease Multiple organ systems can be affected by graft versus host disease (GVHD) but skin is typically the first and most commonly involved organ [31]. As opposed to a previously used scheme of categorizing GVHD into acute (<100 days) and chronic (>100 days) diseases, the US National Institutes of Health (NIH) modified the classification by adding a late onset acute GVHD in which symptoms appear after 100 days post-transplant. Similarly, a category of an overlap syndrome was created with features of both acute and chronic GVHD regardless of time of onset [31]. The underlying pathophysiology of acute GVHD is believed to result from activation of antigen presenting cells (APC) by pre-transplant treatments such as total body irradiation, followed by activation of donor T-cells with their proliferation and migration resulting in subsequent organ tissue damage [31, 32]. The etiology of chronic GVHD is less understood but appears to be related to an immune-mediated process [32]. Prior to detection of peripheral lymphocytes, a maculopapular rash accompanied by fever and occurring within 2 weeks of transplant is referred to by some authorities as a hyperacute stage of acute GVHD [32]. The typical acute GVHD manifests between the second and sixth week, with an abrupt onset of pruritic, symmetric morbilliform rash that can become diffuse. Palms and soles may be the initially affected site, presenting with pronounced erythema and subsequent spread to the rest of the body. With progression,

bullae and desquamation can occur, mimicking TEN [32]. Chronic GVHD has various manifestations and can result in dyspigmentation, new onset  alopecia, poikiloderma, lichen planus-like lesions, or sclerodermoid changes [31]. Calcineurin inhibitors, cyclosporine or tacrolimus, serve as the predominant method in prevention of GVHD [31]. Various methods to achieve T-cell depletion such as ex vivo T-cell depletion do achieve lower frequency of end-organ damage but at the expense of higher risk of graft failure or rejection, and post-transplant lymphoproliferative disease (PTLD) [32]. Prophylactic in  vivo use of alemtuzumab, a monoclonal antibody that binds to leukocytes, is able to diminish the incidence of acute and chronic GVHD but at the expense of increased infections and relapse and no survival benefit [31]. Anti-thymocyte and anti-lymphocyte antibodies may decrease GVHD but result in increased infections and no survival benefit [31]. Topical emollients should be used in both acute and chronic xerotic GVHD. With acute GVHD affecting less than 50% of BSA, topical potent corticosteroids or tacrolimus should be employed. With more severe skin and other organ involvement, high doses of systemic corticosteroids and other immunosuppressives are the primary therapy [32]. Steroid-resistant acute GVHD is challenging to treat. Extracorporeal photopheresis has been shown in a phase II study to enhance the recovery from a steroid refractory GVHD [31]. Chronic GVHD is also more difficult to manage and a combination of systemic corticosteroids with or without calcineurin inhibitors remains the primary strategy [31]. The use of topical steroids and tacrolimus in chronic GVHD is not well-established [32]. Utilization of extracorporeal photopheresis, especially in cutaneous GVHD, has been found to be beneficial in chronic GVHD [32]. Resistant chronic GVHD limited to skin can be attempted to be managed with PUVA therapy [32]. A review conducted by Bates et  al. described both retrospective and prospective studies that suggest that Rituximab, a monoclonal antibody targeting the CD20 molecule on B cells, may be a useful alternative option in the treatment of steroid refractory chronic GVHD, by targeting various antibodies thought to play a role in pathogenesis of chronic GVHD [33].

Sclerodermiform Dermatitis A sclerodermiform dermatitis predominately involving the lower extremities is a rare skin toxicity in which the taxanes (docetaxel, paclitaxel) appear to be the main culprit, with some reported cases induced by gemcitabine [28, 34]. The rash manifests as flesh-colored to brown plaques that

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E. Balagula and M.E. Lacouture

may have a shiny appearance. Swelling and edema of the lower extremities precedes the onset of the skin induration and fibrosis. Usually, the serologies are negative for connective tissue disease [19, 34]. Skin induration is seen after several cycles of chemotherapy but the reversal of the fibrosis can be expected after the discontinuation of the offending drug or use of high-potency topical corticosteroids [13, 19].

lack of cells that express EGFRs as a result of prior radiation treatment. On the other hand, EGFRI can behave as sensitizers, leading to a more pronounced skin reaction in cases where radiation treatment is administered simultaneously [35]. Topical corticosteroids may be used to diminish the inflammation. Overall, termination of therapy and wound care is helpful in healing the area of involvement [19].

Radiation Dermatitis and Enhancement Dermatomyositis-Like Rash Hydroxyurea has been associated with the dermatomyositislike rash which is characterized by the erythematous to violaceous periorbital plaques. Additionally, scaly plaques involving the chest, arms, metacarpophalangeal, and interphalangeal joints are seen. An important distinction should be made from dermatomyositis in that there is no involvement of the muscles and thus no markers of muscle damage are present. There is a tendency for the rash to be distributed in the sun-exposed areas. The removal of the offending agent is followed by resolution in anywhere between 10 and 18 months [19]. Sun avoidance and sunscreen use are recommended, along with topical or oral corticosteroids [19].

Radiation Recall Radiation recall is characterized by a rash that is caused by chemotherapy and manifests itself in the areas of pre­vious radiotherapy. The underlying etiology is unclear and some propose that it may be the result of the combination of chemotherapy-induced free radicals and the genetic defects induced by prior radiation treatments [19, 29]. A variety of drugs have been associated with these reactions (Table 35.3). The latency period for the radiation recall is wide and ranges anywhere from a period of several months to years [19]. Conversely, EGFRI induced rash may be absent in the areas of previous irradiation, which may be explained by the Table 35.3  Chemotherapeutic agents associated with radiation recall Methotrexate Hydroxyurea Etoposide Melphalan Doxorubicin Capecitabine Cytarabine Cyclophosphamide Dactonimycin Gemcitabine Bleomycin Pemetrexed Etoposide Oxaliplatin Paclitaxel Vinblastine 5-Fluorouracil Docetaxel Lomustine Idarubicin Payne et al. [34] and Heidary et al. [13]

One of the most prevalent adverse effects of radiotherapy is an acute skin reaction, defined as manifesting itself within the first 6 months [36]. The underlying pathophysiology is due to direct tissue toxicity and involvement of inflammatory cells [37]. The presentation of radiation dermatitis ranges from erythema and dry desquamation to moist desquamation and ulceration with increasing severity [36]. Typically presenting within the first several weeks, it is mild to moderate in intensity in the majority of patients [37]. Two prospective double-blind RCTs demonstrated the potential beneficial effect of high-potency topically applied corticosteroids when used in a prophylactic manner. Both studies utilized the topical steroids starting at the beginning of radiotherapy until 2–3 weeks after the completion of treatment and resulting in diminished clinical manifestation of radiation dermatitis [38, 39]. The use of topical antibiotics should be restricted to cases of skin breakdown or suspected superinfection. The severity of rare grade 4 reactions mandates specialized wound care and requires attention from a wound specialist [37]. For a treatment algorithm refer to Fig. 35.8. When chemotherapy agents are administered either at the same time or within 1 week, they can potentiate the toxicity of the radiation therapy. This phenomenon is called radiation enhancement and can be induced by methotrexate, hydroxyurea, fluorouracil, doxorubicin, dactinomycin, bleomycin, and cisplatin [28]. In addition to conventional cytotoxic agents, there appears to be a synergistic effect of EGFRI and radiation with an increased risk of high-grade radiation dermatitis and a rash [40].

Photosensitivity A variety of chemotherapy agents have been associated with photosensitive reactions upon exposure to ultraviolet light. These broadly can be divided into a photoallergic and phototoxic reactions. Photoallergic reactions are less common, require prior sensitization, and are immunologically mediated. On the other hand, phototoxicity is much more common and is not immunologically mediated. Photoallergy shares similarities with eczematous dermatitis and is predominately limited to sun-exposed skin. The lesions can evolve from erythema and vesiculation to scaling and lichenification.

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35  Dermatologic Toxicities

Radiation Dermatitis Intervention

Severity (CTCAE v.4) Grade 0

Prophylaxis with mometasone 0.1% cream bid throughout therapy

Grade 1

Continue treatment at current dose and monitor for change in severity mometasone 0.1% cream bid Reassess after 2 weeks (either by healthcare professional or patient selfreport); if reactions worsen or do not improve proceed to next step

Grade 2

Continue treatment at current dose and monitor for change in severity mometasone 0.1% cream bid AND silver sulfadiazine 1% cream bid to open areas Reassess after 2 weeks (either by healthcare professional or patient selfreport); if reactions worsen or do not improve, proceed to next step

Grade 3

Interrupt treatment until severity decreases to grade 0-1; continue treatment of skin reaction with the following mometasone 0.1% cream bid AND silver sulfadiazine 1% cream bid to open areas AND pain control with NSAIDs/GABA agonists/Narcotics Reassess after 2 weeks; if reactions worsen or do not improve, dose interruption or discontinuation per protocol may be necessary

Fig. 35.8  Treatment algorithm for radiation dermatitis

Phototoxic lesions in sun-exposed areas are similar to a more severe sunburn, characterized by erythema and edema that with increasing severity can progress to vesicles, desquamation, and blistering. Patients may experience pain and burning sensations [41] (Fig. 35.9). Photosensitive reactions have been seen with a variety of agents (Table  35.4). In general, these reactions are phototoxic in nature [28]. Patients should be educated about the potential sensitivity to sun and encouraged to avoid exposure. In addition, photoprotective methods should be utilized such as protective clothing and broad-spectrum sunscreens (containing zinc or titanium dioxide). Sunscreens with inorganic ingredients such as titanium oxide and zinc oxide should be recommended over organic ingredients, which are associated with these types of reactions as well. Only anecdotal evidence supports the use of topical corticosteroids to relieve the inflammation, but they are broadly employed [19, 41]. In addition, cold compresses and lotions can be employed to alleviate the symptoms [41].

Fig.  35.9  Photosensitivity rash (Reprinted with permission from CMPMedica. Source: Cancer Management: A Multidisciplinary Approach, 11th edition. Pazdur R, Wagman L, Camphausen K, et al. (Eds), Color atlas. Copyright 2008, All rights reserved.)

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E. Balagula and M.E. Lacouture Table 35.4  Chemotherapeutic agents associated with photosensitive reactions 5-FU Dasatinib Dacarbazine Fotemustine Hydroxyurea Taxanes Imatinib Tegafur Doxorubicin Heidary et al. [13] and Guillot et al. [28]

UV recall can be seen with chemotherapy agents as well. It is similar to radiation recall, whereby administered medication induces a rash in the distribution of a previous sunburn. It has been proposed to categorize these skin reactions based on the time period elapsed after UV exposure. The rash induced by medication given within 1 week of exposure is termed UV enhancement. UV recall refers to reactions occurring weeks to months following UV exposure. Multiple agents have been observed to induce these reactions including methotrexate, paclitaxel, suramin, and etoposide [19, 42].

Skin Changes Xerosis and Pruritis Multiple agents can induce xerosis (dry skin), and pruritus. Both sorafenib and sunitinib can lead to xerosis seen in up to 31% of patients [3]. Similarly, EGFRI and cytotoxic agents are commonly associated with xerosis as well. It is seen in up to 35% of patients being treated with EGFRIs, gradually developing over weeks and presents with dry, scaly, and itchy skin [43] (Fig. 35.10). Patients that are older and with history

Fig. 35.11  EGFR inhibitor fissures (Reprinted with permission from CMPMedica. Source: Cancer Management: A Multidisciplinary Approach, 11th edition. Pazdur R, Wagman L, Camphausen K, et al. (Eds), Color atlas. Copyright 2008, All rights reserved.)

of atopic eczema tend to have a more pronounced xerosis [43]. This may progress into chronic xerotic dermatitis with a risk of being secondarily infected with Staphylococcus aureus or Herpes simplex virus. Xerosis involving hands or feet can potentially lead to painful fissures in the tips of fingers and/or toes [44] (Fig. 35.11). Tepid water, minimizing showering, and avoiding using soap should be advised to patients to diminish xerosis of the skin. With development of eczema, treatment can be conducted with a short course (1–2  weeks) of topical steroids [44]. Oral antihistamines, and the gamma-aminobutyric acid analogues gabapentin and pregabalin can be utilized to decrease pruritus. For a treatment algorithm refer to Fig. 35.12.

Pigmentary Changes

Fig. 35.10  EGFR inhibitor xerosis (Reprinted with permission from CMPMedica. Source: Cancer Management: A Multidisciplinary Approach, 11th edition. Pazdur R, Wagman L, Camphausen K, et al. (Eds), Color atlas. Copyright 2008, All rights reserved.)

A variety of chemotherapeutic agents have been associated with a range of pigmentary changes. Both hyperpigmentation and hypopigmentation of the skin can be seen. Depending on the agent, different patterns of hyperpigmentation can be observed with various underlying mechanisms (Table 35.5). Various anatomical sites can be affected including palms and soles as in the case with cyclophosphamide [19]. In addition to the ability of capecitabine to induce hyperpigmentation, it may also stimulate development of normal and dysplastic melanocytic nevi [45]. Sun avoidance is critical and frequent use of sunscreens is recommended. Topical application of retinoids may be of benefit by facilitating rapid loss of keratinocytes along with their pigment. Formulations with hydroquinone or retinoids may diminish synthesis of melanin and diminish the degree of pigmentation [19]. Pigmentary changes can be diminished or prevented by trying to avert or

375

35  Dermatologic Toxicities

Severity (CTCAE v.4)

Xerosis

Intervention

Grade 0

Prophylactic therapy with sunscreen SPF≥30; Moisturizing creams; Gentle skin care instructions given

Grade 1

Continue anticancer agent at current dose and monitor for change in severity OTC Moisturizing cream or ointment to face bid AND Ammonium lactate 12% cream to body bid Reassess after 2 weeks (either by healthcare professional or patient self-report); if reactions worsen or do not improve proceed to next step

Grade 2

Continue anticancer agent at current dose and monitor for change in severity OTC Moisturizing cream or ointment to face bid AND Ammonium lactate 12% cream OR salicylic acid 6% cream to body bid Reassess after 2 weeks (either by healthcare professional or patient self-report); if reactions worsen or do not improve proceed to next step

Grade 3

Dose modify as per PI; obtain bacterial/viral cultures if infection is suspected and continue treatment of skin reaction with the following: OTC Moisturizing cream or ointment to face bid AND Ammonium lactate 12% cream OR salicylic acid 6% cream to body bid AND triamcinolone 0.25% cream to eczematous areas bid Reassess after 2 weeks; if reactions worsen or do not improve, dose interruption or discontinuation per PImay be necessary

Fig. 35.12  Treatment algorithm for xerosis

Table 35.5  Chemotherapy agents associated with pigmentary changes Pattern of pigmentary changes Drugs Hyperpigmentation Acral Diffuse

Irregular, patchy Flagellate Supravenous serpentine

Tegafur Capecitabine Busulfan Cyclophosphamide Hydroxyurea Methotrexate Fluorouracil (5-FU) Bleomycin Docetaxel Paclitaxel Fotemustine Vinorelbine Vincristine Cyclophosphamide

Transverse bands Hypopigmentation Localized, patchy, diffuse Imatinib Data from Wyatt et al. [19]; Payne et al. [34]; and Heidary et al. [13]

aggressively treat rashes and eczema [44]. Refer to Fig. 35.13 for treatment of hyperpigmentation. A range of pigmentary changes have been seen with imatinib including hypopigmentation and hyperpigmentation. Hypopigmentation tends to resolve upon reduction of the dose or discontinuation of therapy [13].

Inflammation of Actinic (Solar) Keratoses/ Accelerated Growth of Skin Carcinoma Inflammation of actinic keratoses (AK), leading to pronounced erythema and scaling papules in photodistributed areas, is seen with multiple agents such as cytarabine, fluorouracil, vincristine, doxorubicin, and capecitabine [19, 34]. Moreover, inflammation can actually be followed by clearing and resolution of AKs. Thus, this drug side effect can be thought of as being beneficial since it leads to destruction of

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E. Balagula and M.E. Lacouture

Hyperpigmentation Severity (CTCAE v.4)

Intervention

Grade 0

Prophylaxis with sunscreen SPF≥ 30 to face, ears, neck, arms and hands when exposed to sun, use of hats and protective clothing

Grade 1

Continue treatment at current dose and monitor for change in severity

Ensure that there is no associated dermatitis (erythema, rash, edema) that should be treated with triamcinolone 0.1% cream; treat with hydroquinone 4% cream bid AND use sunscreen Reassess after 2 weeks (either by healthcare professional or patient selfreport); if reactions worsen or do not improve proceed to next step

Grade 2

Interrupt treatment until severity decreases to grade 0-1; continue treatment of skin reaction with the following: Hydroquinone 4% cream bid to affected areas AND strict sun protection Reassess after 2 weeks; if reactions worsen or do not improve, dose interruption or discontinuation per protocol may be necessary

Fig. 35.13  Treatment algorithm for hyperpigmentation

premalignant lesions [19]. Chemotherapy should not be discontinued in a setting of this reaction and topical application of corticosteroids can be used to ameliorate inflammation when it is severe [19]. Recently, sorafenib has been found to be associated with the development of AKs and invasive cutaneous squamous cell carcinomas (SCCs). It is possible that sorafenib can induce keratinocyte proliferation and lead to de novo formation of AKs and SCC’s. These tend to regress after discontinuation of therapy but may recur with repeated treatments even with reduced doses [46]. In addition, long-term use of hydroxyurea has been linked to development of AKs and skin carcinoma including basal cell or squamous cell carcinomas that are photodistributed [28].

Nail Toxicity Various agents have been associated with nail toxicity but taxanes are thought to be the most common culprits [47]. In general, one can categorize nail toxicity as caused by damage to the nail bed (onycholysis, subungual hemorrhage),

nail plate (pigmentary changes, grooves, brittle nails), or nail fold (paronychia).

Paronychia All EGFRI presently in use have been associated with this type of nail toxicity. Paronychia (periungual inflammation), seen in up to approximately 15% of patients, can affect any finger or toe nail. It initially presents as erythematous inflammation of the lateral nail fold that can potentially progress into lateral nail fold pyogenic granuloma-like lesions which are very painful and can mimic an ingrown nail. This nail toxicity tends to manifest later in the treatment with EGFRI, usually occurring after 1–2  months of therapy [43]. Infection is not the primary event but secondary impetiginization with Staphylococcus aureus or Grambacteria can occur [44]. Treatment with taxanes is also associated with acute exudative paronychia that may potentially progress to subungual abscess. Capecitabine has been known to induce periungual pyogenic granuloma-like lesions that spontaneously resolve with treatment ­interruption [34].

377

35  Dermatologic Toxicities

Severity (CTCAE v.4)

Paronychia

Intervention

Grade 0

Moisturizing creams; Gentle skin care instructions given

Grade 1

Continue anticancer agent at current dose and monitor for change in severity Topical antibiotics AND vinegar soaks* Reassess after 2 weeks (either by healthcare professional or patient self-report); if reactions worsen or do not improve proceed to next step

Grade 2

Continue anticancer agent at current dose and monitor for change in severity Topical antibiotics AND vinegar soaks* AND Silver nitrate application weekly Reassess after 2 weeks (either by healthcare professional or patient self-report); if reactions worsen or do not improve proceed to next step

Grade 3

Dose modify as per PI; obtain bacterial/viral cultures if infection is suspected and continue treatment of skin reaction with the following: Systemic antibiotics AND vinegar soaks* AND Silver nitrate application weekly

*Vinegar soaks consist of soaking fingers or toes in a solution of white vinegar in water 1:1 for 15 minutes every day

Reassess after 2 weeks; if reactions worsen or do not improve, dose interruption or discontinuation per PI may be necessary

Fig. 35.14  Treatment algorithm for paronychia

Treatment of the nail toxicity depends on the severity of the toxicity (Fig. 35.14). Overall, therapy with cytotoxic agents and EGFRIs leads to slow growth of nails and brittleness [43]. Use of biotin 2.5  mg a day has been shown to strengthen nails, and is recommended for patients affected with this disorder [48].

Subungual Hemorrhage MKIs such as sorafenib and sunitinib have been associated with subungual splinter hemorrhages that more commonly affect fingernails as compared to toenails. They typically present as painless straight black or red lines, but their pattern and location (distal or proximal) can vary [43, 49]. Seen in approximately 30% of patients with sunitinib and 60% with sorafenib, they usually manifest within 2–4  weeks of treatment [49]. It is important to note that they are not related to thrombotic or embolic phenomena and are thought to arise due to VEGFR inhibition resulting in disrupted repair of tiny

capillaries in the nail bed [49]. These do not warrant interruption or reduction of therapy and resolve spontaneously without any specific treatments [43, 49]. Both docetaxel and paclitaxel have been associated with painful subungual hemorrhage that can secondarily be infected leading to subungual abscess and hemopurulent drainage [19, 50]. These changes lead to onycholysis. Broadspectrum antibiotics and white vinegar in water 1:1 soaks can be employed in the case of subungual abscess formation. In addition, for large-size abscesses, nail plate avulsion or fenestration can be attempted to drain the collection [19]. After termination of the offending agent, normal regrowth of the nail should be expected [19].

Onycholysis Onycholysis, which is a separation of the nail plate from the underlying nail bed, occurs secondary to acute toxicity to the nail bed epithelium from a chemotherapy agent. Pain can

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often precede or occur simultaneously with nail plate separation. This toxicity has been observed with taxanes (paclitaxel and docetaxel), bleomycin, capecitabine, doxorubicin, fluorouracil, methotrexate, and etoposide [47]. Cutting the nails short, using topical antimicrobials, and minimizing exposure to irritants can be employed in treatment of onycholysis [47]. Onycholysis along with other nail toxicities induced by docetaxel has been shown to be diminished by the use of frozen gloves and slippers, worn 15 min prior to, during the infusion, and 15 min post-infusion [51]. Frozen socks have also been shown to decrease docetaxel associated nail toxicity including onycholysis [47]. This cryotherapy may potentially be of benefit in nail toxicity due to other agents as well, which share a similar half-life to docetaxel.

Beau’s Lines Multiple chemotherapy agents result in a reduced or termination of nail plate synthesis, leading to horizontally oriented depressions called Beau’s lines. No intervention is needed as depressions gradually move forward and resolve with growth of the nail [47].

E. Balagula and M.E. Lacouture

applied but pigmentary changes can remain for several years despite discontinuation of therapy [47].

Summary Despite the fact that most of the skin toxicities associated with chemotherapy are not life-threatening, their manifestation can result in significant discomfort to the patient and decreased quality of life, necessitating either dose reduction or termination of therapy. Subsequently, the optimal benefit of chemotherapy treatment is compromised with a negative impact on mortality and morbidity. Many treatment algorithms have not been validated by RCTs but proposed guidelines exist. One critical aspect in management of several toxicities described in this chapter is active patient involvement and education prior to initiation of treatment. Multiple preemptive strategies can be employed as well. These approaches along with careful monitoring of patients can facilitate early recognition of symptoms allowing for appropriate therapies to be employed. The ultimate goal of managing these patients is avoiding treatment modifications or interruptions to attain a maximum benefit from the anticancer agents and the most optimal quality of life.

Leukonychia An apparent and not true leukonychia is seen with various chemotherapy drugs and is secondary to damage to the nail bed. Apparent leukonychia manifests as horizontally oriented white lines with normal colored nail bed (Muehrcke’s lines) interspersed in between. No intervention is required and spontaneous resolution is seen upon treatment discontinuation [47]. True leukonychia arises from damage to the nail matrix and gives rise to transverse opaque lines (Mees’ lines) in the nail plate which move as the nail grows [47]. Leukonychia can be associated with cisplatin, anthracyclines, vincristine, and cyclophosphamide [28].

Pigmentary Changes Different patterns of hyperpigmentation are seen depending on the agent. Diffuse nail hyperpigmentation can be seen with cyclophosphamide, fluorouracil, and cisplatin [28, 47]. Partial hyperpigmentation with longitudinal bands is more common and is associated with cyclophosphamide, hydroxyurea, melphalan, busulphan, and doxorubicin. Anthracyclines, fluorouracil, hydroxyurea, and idarubicin have been linked to less common horizontal bands of hyperpigmentation [28, 47]. To improve cosmetic appearance colored nail varnish can be

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35  Dermatologic Toxicities FOLFIRI or irinotecan-only chemotherapy (CT as 2nd-line ­treatment (tx): Interim analysis. J Clin Oncol 2008; (abstract 15007): 644s. 8. Scope A, Agero AL, Dusza SW, Myskowski PL, Lieb JA, Saltz L, Kemeny NE, Halpern AC. Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol 2007; 25: 5390–5396. 9. Jatoi A, Rowland K, Sloan JA, Gross HM, Fishkin PA, Kahanic SP, Novotny PJ, Schaefer PL, Johnson DB, Tschetter LK, Loprinzi CL. Tetracycline to prevent epidermal growth factor receptor inhibitorinduced skin rashes: results of a placebo-controlled trial from the North Central Cancer Treatment Group (N03CB). Cancer 2008; 113: 847–853. 10. Lacouture ME, Basti S, Patel J, Benson A, 3rd. The SERIES clinic: an interdisciplinary approach to the management of toxicities of EGFR inhibitors. J Support Oncol 2006; 4: 236–238. 11. Lacouture ME, Reilly LM, Gerami P, Guitart J. Hand foot skin reaction in cancer patients treated with the multikinase inhibitors sorafenib and sunitinib. Ann Oncol 2008; 19: 1955–1961. 12. Chu D, Lacouture ME, Fillos T, Wu S. Risk of hand-foot skin reaction with sorafenib: a systematic review and meta-analysis. Acta Oncol 2008; 47: 176–186. 13. Heidary N, Naik H, Burgin S. Chemotherapeutic agents and the skin: An update. J Am Acad Dermatol 2008; 58: 545–570. 14. Lorusso D, Di Stefano A, Carone V, Fagotti A, Pisconti S, Scambia G. Pegylated liposomal doxorubicin-related palmar-plantar erythrodysesthesia ('hand-foot' syndrome). Ann Oncol 2007; 18: 1159–1164. 15. Janusch M, Fischer M, Marsch W, Holzhausen HJ, Kegel T, Helmbold P. The hand-foot syndrome – a frequent secondary manifestation in antineoplastic chemotherapy. Eur J Dermatol 2006; 16: 494–499. 16. von Moos R, Thuerlimann BJ, Aapro M, Rayson D, Harrold K, Sehouli J, Scotte F, Lorusso D, Dummer R, Lacouture ME, Lademann J, Hauschild A. Pegylated liposomal doxorubicin-­ associated hand-foot syndrome: recommendations of an international panel of experts. Eur J Cancer 2008; 44: 781–790. 17. Brown J, Burck K, Black D, Collins C. Treatment of cytarabine acral erythema with corticosteroids. J Am Acad Dermatol 1991; 24: 1023–1025. 18. Agha R, Kinahan K, Bennett CL, Lacouture ME. Dermatologic challenges in cancer patients and survivors. Oncology (Williston Park) 2007; 21: 1462–1472; discussion 1473, 1476, 1481 passim. 19. Wyatt AJ, Leonard GD, Sachs DL. Cutaneous reactions to chemotherapy and their management. Am J Clin Dermatol 2006; 7: 45–63. 20. Borchers AT, Lee JL, Naguwa SM, Cheema GS, Gershwin ME. Stevens-Johnson syndrome and toxic epidermal necrolysis. Autoimmun Rev 2008; 7: 598–605. 21. Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 1993; 129: 92–96. 22. French LE. Toxic epidermal necrolysis and Stevens Johnson syndrome: our current understanding. Allergol Int 2006; 55: 9–16. 23. J. Sorrell, D. P. West, C. L. Bennett, D. W. Raisch, Lacouture ME. Life-threatening dermatologic toxicities to cancer drug therapy: An assessment of the published peer-reviewed literature. J Clin Oncol 2009; 27: (suppl; abstr e20592). 24. Hazin R, Ibrahimi OA, Hazin MI, Kimyai-Asadi A. StevensJohnson syndrome: pathogenesis, diagnosis, and management. Ann Med 2008; 40: 129–138. 25. Enk A. Guidelines on the use of high-dose intravenous immunoglobulin in dermatology. Eur J Dermatol 2009; 19: 90–98.

379 26. Robert C, Soria JC, Spatz A, Le Cesne A, Malka D, Pautier P, Wechsler J, Lhomme C, Escudier B, Boige V, Armand JP, Le Chevalier T. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 2005; 6: 491–500. 27. Kim RJ, Peterson G, Kulp B, Zanotti KM, Markman M. Skin toxicity associated with pegylated liposomal doxorubicin (40 mg/m2) in the treatment of gynecologic cancers. Gynecol Oncol 2005; 97: 374–378. 28. Guillot B, Bessis D, Dereure O. Mucocutaneous side effects of antineoplastic chemotherapy. Expert Opin Drug Saf 2004; 3: 579–587. 29. Sanborn RE, Sauer DA. Cutaneous reactions to chemotherapy: commonly seen, less described, little understood. Dermatol Clin 2008; 26: 103–119, ix. 30. Nellen RG, van Marion AM, Frank J, Poblete-Gutierrez P, Steijlen PM. Eruption of lymphocyte recovery or autologous graft-versushost disease? Int J Dermatol 2008; 47 Suppl 1: 32–34. 31. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet 2009; 373: 1550–1561. 32. Hausermann P, Walter RB, Halter J, Biedermann BC, Tichelli A, Itin P, Gratwohl A. Cutaneous graft-versus-host disease: a guide for the dermatologist. Dermatology 2008; 216: 287–304. 33. Bates JS, Engemann AM, Hammond JM. Clinical utility of rituximab in chronic graft-versus-host disease. Ann Pharmacother 2009; 43: 316–321. 34. Payne AS, James WD, Weiss RB. Dermatologic toxicity of chemotherapeutic agents. Semin Oncol 2006; 33: 86–97. 35. Lacouture ME, Hwang C, Marymont MH, Patel J. Temporal dependence of the effect of radiation on erlotinib-induced skin rash. J Clin Oncol 2007; 25: 2140; author reply 2141. 36. Bolderston A, Lloyd NS, Wong RK, Holden L, Robb-Blenderman L. The prevention and management of acute skin reactions related to radiation therapy: a systematic review and practice guideline. Support Care Cancer 2006; 14: 802–817. 37. Bernier J, Bonner J, Vermorken JB, Bensadoun RJ, Dummer R, Giralt J, Kornek G, Hartley A, Mesia R, Robert C, Segaert S, Ang KK. Consensus guidelines for the management of radiation dermatitis and coexisting acne-like rash in patients receiving radiotherapy plus EGFR inhibitors for the treatment of squamous cell carcinoma of the head and neck. Ann Oncol 2008; 19: 142–149. 38. Schmuth M, Wimmer MA, Hofer S, Sztankay A, Weinlich G, Linder DM, Elias PM, Fritsch PO, Fritsch E. Topical corticosteroid therapy for acute radiation dermatitis: a prospective, randomized, double-blind study. Br J Dermatol 2002; 146: 983–991. 39. Bostrom A, Lindman H, Swartling C, Berne B, Bergh J. Potent corticosteroid cream (mometasone furoate) significantly reduces acute radiation dermatitis: results from a double-blind, randomized study. Radiother Oncol 2001; 59: 257–265. 40. Tejwani A, Wu S, Jia Y, Agulnik M, Millender L, Lacouture ME. Increased risk of high-grade dermatologic toxicities with radiation plus epidermal growth factor receptor inhibitor therapy. Cancer 2009; 115: 1286–1299. 41. Stein KR, Scheinfeld NS. Drug-induced photoallergic and phototoxic reactions. Expert Opin Drug Saf 2007; 6: 431–443. 42. Goldfeder KL, Levin JM, Katz KA, Clarke LE, Loren AW, James WD. Ultraviolet recall reaction after total body irradiation, etoposide, and methotrexate therapy. J Am Acad Dermatol 2007; 56: 494–499. 43. Lacouture ME, Boerner SA, Lorusso PM. Non-rash skin toxicities associated with novel targeted therapies. Clin Lung Cancer 2006; 8 Suppl 1: S36–42. 44. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 2005; 16: 1425–1433.

380 45. Villalon G, Martin JM, Pinazo MI, Calduch L, Alonso V, Jorda E. Focal acral hyperpigmentation in a patient undergoing chemotherapy with capecitabine. Am J Clin Dermatol 2009; 10: 261–263. 46. Dubauskas Z, Kunishige J, Prieto VG, Jonasch E, Hwu P, Tannir NM. Cutaneous squamous cell carcinoma and inflammation of actinic keratoses associated with sorafenib. Clin Genitourin Cancer 2009; 7: 20–23. 47. Gilbar P, Hain A, Peereboom VM. Nail toxicity induced by cancer chemotherapy. J Oncol Pharm Pract 2009; 15: 143–155. 48. Hochman LG, Scher RK, Meyerson MS. Brittle nails: response to daily biotin supplementation. Cutis 1993; 51: 303–305.

E. Balagula and M.E. Lacouture 49. Hammond-Thelin LA. Cutaneous reactions related to systemic immunomodulators and targeted therapeutics. Dermatol Clin 2008; 26: 121–159, ix. 50. Roh MR, Cho JY, Lew W. Docetaxel-induced onycholysis: the role of subungual hemorrhage and suppuration. Yonsei Med J 2007; 48: 124–126. 51. Scotte F, Tourani JM, Banu E, Peyromaure M, Levy E, Marsan S, Magherini E, Fabre-Guillevin E, Andrieu JM, Oudard S. Multicenter study of a frozen glove to prevent docetaxel-induced onycholysis and cutaneous toxicity of the hand. J Clin Oncol 2005; 23: 4424–4429.

Chapter 36

Chemotherapy-Induced Alopecia: Overview and Methodology for Characterizing Hair Changes and Regrowth Elise A. Olsen

Introduction Chemotherapy-induced alopecia (CIA) is a common adverse effect of many chemotherapeutic agents. For each agent or combination of agents, the hair loss may be of different types, assume a different final degree of hair loss and a ­different potential/time course for full regrowth after the conclusion of therapy. Previously, oncologists have characterized hair loss according to the version 3.0 of the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE v3.0) [1, 2] and/or the World Health Organization (WHO) grading scale [3] which have not fully characterized the amount of hair loss. More recently, the author has been involved in modifying the hair-related adverse effect (AE) definitions for the NCI-CTCAE v4.0, developing guidelines for hair changes from epidermal growth factor inhibitors (EGFRIs) for the Multinational Association of Supportive Care in Cancer (MASCC) [4] and creating a grading tool that would allow more precise definition of independent assessment of hair loss and regrowth for usage in clinical trials. These are all discussed in this brief review of CIA.

very fine and less than 2 cm in length but provides a reservoir of hair follicles that can, under appropriate circumstances, be stimulated to become terminal hair. Ninety percent of scalp hair is in anagen (growth phase) at any given time and all hair goes through an obligatory period of telogen (rest phase) which normally lasts approximately 3–4 months. The duration of anagen, and the related length of hair, varies with age and whether there is an underlying condition, such as male or female pattern hair loss, which can shorten the anagen phase in affected scalp hairs. Hair anywhere else on the body has its own normal duration of anagen and telogen but in general, all have a much lower percentage of hair in anagen than scalp hair. When hair is in the anagen phase, there is a high mitotic rate in the proximal bulbar portion which makes growing hair vulnerable to agents that affect rapidly growing cells. Agents used to treat cancer are, by nature, antiproliferative and can have multiple effects on hair including accelerating the transition of hairs from anagen to telogen or disruption of normal anagen. These effects on the hair and hair cycle result in different rates and amount of scalp hair loss but can be generalized into the following categories.

Background

Types of Cia

When one is discussing scalp hair loss, the focus is on ­terminal and not vellus hair. Terminal hair populates the majority of the scalp, eyebrows, eyelashes, and areas where hair growth is stimulated by androgens, that is, hair in the beard, axilla, or groin area in either men or women. Terminal hair typically have diameters >60 mm and with an ultimate potential length of ³100 cm on the scalp [5]. Telogen hair is

Telogen Effluvium

E.A. Olsen (*) Duke University Medical Center, Box 3294, Durham, NC 27710, USA e-mail: [email protected]

In this scenario, a larger proportion than normal of anagen hair on the scalp moves into telogen. The result is an increase in shedding diffusely over the scalp and a corresponding decrease in hair density (Fig. 36.1a). Usually the shedding begins at the end of the normal telogen period so that the loss is most profound at about 3–4 months after drug exposure. Telogen hair loss may be confirmed by evaluation of the proximal ends of the hair extracted by pulling on a group of 50–100 scalp hairs (the standard “hair pull”) under a 10 × microscope [6] (Fig. 36.1b). A telogen effluvium rarely goes beyond involving approximately 50% of scalp hair so it never

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_36, © Multinational Association for Supportive Care in Cancer Society 2011

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E.A. Olsen

Fig. 36.1  (a) Clinical picture of telogen effluvium (b) Telogen hairs on microscopic examination of proximal hairs obtained by hair pull

Fig. 36.2  (a) Clinical picture of anagen effluvium (b) Bayonet hair. The bayonet is caused by breakage of the hair at the weakest point with the narrowing of the shaft prior to the actual break caused by acute damage to the matrix of the anagen hair

leads to baldness. The process resolves spontaneously once the inciting agent is stopped and its effect dissipates but it may take at least 6  months for the new anagen growth to achieve significant length. Anticancer agents that frequently lead to telogen effluvium include methotrexate, ­5-fluorouracil, and retinoids.

Anagen Effluvium Cancer chemotherapy targets rapidly growing populations of neoplastic cells but other normal cells with a high proliferation rate, such as hair matrix cells in anagen, are often affected as well. Anagen effluvium is also characterized by diffuse scalp hair shedding but the time course is earlier (most are apparent at 1–2 months after initiation of therapy) and the extent of loss potentially much greater than that seen in a telogen effluvium (Fig.  36.2a). In anagen effluvium, there is acute disruption of cellular proliferation in the proximal hair with an abnormal hair produced. This affected hair may only have abnormal anchoring secondary to a toxic effect on the inner root sheath cells or the hair shaft integrity may be affected leading to an abnormally weak section of hair. The result is either hair that falls out with mild pressure or hair that breaks off on reaching the scalp surface. Performing a hair pull and examining the proximal ends of the hairs so removed will show either abnormal anagen bulbs

or bayonet hairs (Fig. 36.2b) at the point the weak hair breaks off. Once lost, the anagen hairs remain in telogen for as long as the effect of the treatment is ongoing. Since an anagen effluvium obviously affects the majority of scalp hairs, the hair loss can be profound and nearly ­complete in a short period of time. Well-known examples of chemotherapeutic agents that cause anagen effluvium include cyclophosphamide, etoposide, topotecan, and paclitaxel. Unless there is some damage to the hair stem cells, which reside at the level of the sebaceous gland in the outer root sheath area of the hair structure during telogen, the hairs will be able to start regrowing at the conclusion of the treatment process once the biological effect of the treatment is removed. The hair that regrows may be different in color or texture but ­generally grows back fully with time. Certain mono- or combination chemotherapy, however, may cause a permanent decrease in hair density. Busulphan/cyclophosphamide [7, 8] and high-dose cyclophosphamide/thiotepa/carboplatin [9] before bone marrow transplant may cause a prolonged or permanent alopecia.

Disruption of Hair Growth The EGFRIs are notable for the effects on the disruption of hair growth [10–13]. The time to presentation is variable and the effect on scalp hair loss ranges from a patchy or diffuse

36  Chemotherapy-Induced Alopecia: Overview and Methodology for Characterizing Hair Changes and Regrowth

383

Table 36.1  Comparison of WHO and Olsen CIA Scales for determining gradation of severity of chemotherapy-related hair loss WHO No hair loss Minimal hair loss Moderate patchy hair loss Complete but reversible hair loss Classification Grade 0 Grade 1 Grade 2 Grade 3 Olsen CIA Scale

No scalp hair loss 0% loss

Minimal scalp hair loss 1–24% loss

Moderate scalp hair loss

Extensive scalp hair loss

Complete scalp hair loss

25–49% loss

75–95% loss

100% loss

Grade 0

Grade 1

Grade 2

50–74% loss Grade 3

Grade 4a

96–99% loss Grade 4b

Grade 5

nonscarring hair loss to textural changes to changes in growth rate. Increases in the size and/or length of eyelashes, eyebrows, facial, and chest hair have been reported. The changes appear to be reversible off the drug.

Methodology for Assessing Degree of Hair Loss The WHO method of qualifying hair loss has been a ­commonly used grading scale [3] (Table 36.1). However, this scale imbeds the potential for regrowth into the hair loss grading tool, thus making it inappropriate to use in acute hair loss situations. The Olsen CIA grading scale (Table  36.1) uses the principle developed in assessing hair loss in alopecia areata. The Severity Weighted Alopecia Tool or SALT [14] was developed to enable tracking the quantity of hair loss on the scalp in alopecia areata (another cause of anagen effluvium) by assessing the percentage of overall hair growth (or loss) over the entire scalp. To facilitate this assessment, the actual percentage of scalp surface are on the top, sides, and back of the scalp was determined and a visual tool developed (Fig. 36.3). The SALT can be utilized to help determine the gradations of hair loss in the Olsen CIA grading scale for both hair loss in the acute setting or regrowth in the recovery phase after CIA. The determination of the percentage of scalp hair loss can also be used to help place the hair loss into the new AE categories in the CTCAE v4.0 and MASCC grading scales [4] (Table 36.2). The CTCAE v3.0 did not specifically address abnormal hair growth that may occur with some agents used to treat cancer including the EGFRIs. This type of hair loss is now covered in the MASCC adverse event grading scale (Table 36.3).

Treatment of Cia There have been several treatments used to prevent CIA including, most prominently, the use of cooling caps in an effort to decrease blood flow to the scalp during chemother-

Fig. 36.3  Visual aid (Olsen/Canfield) for estimating percentage scalp hair loss, “x” score and percent regrowth. Using this diagram, one can determine the percent scalp hair loss in a given quadrant and multiply this by the total scalp area delineated by that quadrant and sum the resultant numbers for each quadrant to give the total percent scalp hair loss. This diagram also allows the evaluator to graph the area(s) of alopecia, if desired, in order to facilitate the estimate of percent scalp hair loss and to compare the hair loss on subsequent evaluations. This percent hair loss can later be corroborated by image analysis if desired (From Olsen EA, et  al. Alopecia areata investigational assessment guidelines – Part II. National Alopecia Areata Foundation. J Am Acad Dermatol 2004;51:440–447.)

apy [15, 16]. However, concerns regarding their lack of ability to fully prevent hair loss, the risk of creating a privileged site protected from the effects of chemotherapy and hence subject to an incomplete remission or early relapse and the safety to the skull circulation have curtailed their use. Instead,

2a. Hair loss associated with marked increase in shedding and 50–74% loss compared to normal for that individual. Hair loss is apparent to others, may be difficult to camouflage with change in hairstyle and may require hairpiece

2b. Marked loss of at least 75% hair compared to normal for that individual with inability to camouflage except with a full wig OR new cicatricial hair loss documented by biopsy that covers at least 5% scalp surface area. May impact on functioning in social, personal, or professional situations

CTCAE v4.0 Grade of Alopecia Hair loss of ³50% normal for that individual that is readily Alopecia Hair loss of up to 50% of apparent to others; a wig or hairpiece is necessary if the normal for that patient desires to completely camouflage the hair loss; individual that is not associated with psychosocial impact obvious from a distance but only on close inspection: a different hairstyle may be required to cover the hair loss, but it does not require a wig or hairpiece to camouflage Source: Reprinted with permission from Lacouture ME, et al. [4]

MASCC Grades of Alopecia Hair loss <50% of normal Hair changes: Scalp for that individual that hair loss or may or may not be alopecia) noticeable to others but is associated with increased shedding and overall feeling of less volume. May require different hairstyle to cover but does not require hairpiece to camouflage

Table 36.2  CTCAE v4.0 and MASCC scalp hair loss grading scales Grading of Adverse Effects According to CTCAE v4.0 1 2 Moderate: minimal, local or noninvasive intervention Description of Mild: asymptomatic or mild indicated; limiting age-appropriate instrumental ADL* severity of AE symptoms; clinical or diagnostic observation only; intervention not indicated 3 Severe or moderately significant but not immediately life-threatening; hospitalization or prolongation of hospital-ization indi-cated; dis-abling limiting self-care ADL*

4 Life-threaten-ing conse-quences; urgent intervention indicated

5 Death related to AE

384 E.A. Olsen

Some distortion of hair growth 2a. Distortion of hair Hair changes: disruption growth in many but does not cause of normal hair growth hairs in a given area symptoms or require (specify all areas that that causes intervention apply): discomfort or – Facial hair (diffuse, not symptoms that may just in male beard/ require individual mustache areas) hairs to be removed – Eyelashes – Eyebrows – Body hair – Moustache and/or beard areas only Source: Reprinted with permission from Lacouture ME, et al. [4]

2b. Distortion of hair growth of most hairs in a given area with symptoms or resultant problems requiring removal of multiple hairs

Table 36.3  MASCC grading scale for disruption of hair growth from EGFRIs or other cancer treatments Grading of adverse effects 1 2 Moderate: minimal, local or noninvasive Mild: asymptomatic or mild Description of severity of intervention indicated; limiting age-appropriate symptoms; clinical or AE according to CTCAE instrumental ADL* diagnostic observation only; v4.0 intervention not indicated 3 Severe or moderately significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling limiting self-care ADL*

4 Life-threatening consequences; urgent intervention indicated

5 Death related to AE

36  Chemotherapy-Induced Alopecia: Overview and Methodology for Characterizing Hair Changes and Regrowth 385

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a more effective and safe approach today is to focus on hastening regrowth post-CIA. The agent topical minoxidil has been proven to shorten the duration of chemotherapy-induced hair loss [17]. Hats, scarves, and wigs remain the mainstay of approaches to dealing with extensive hair loss from CIA in either the workplace, social situations, and even at home.

Conclusions CIA is a common adverse effect of various mono- and ­combination chemotherapeutic agents. The hair loss may be secondary to premature anagen-to-telogen transformation leading to a telogen effluvium or a direct toxic effect on the hair matrix or root sheath leading to an anagen effluvium. New methods of quantifying the hair loss are now available and will help in determining the time course and extent of this AE with various agents. Currently, there is at least one topical agent that can enhance the regrowth from CIA. However, agents that enable sparing of the scalp terminal hair follicles while permitting the effect of cytotoxic chemotherapy on the rapidly growing population of neoplastic cells is still needed.

References 1. Trotti A, Colevas A, Setser A, Rusch V, Jaques D, BudachV, Langer C, Murphy B, Cumberlin R, Coleman B. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Seminars in Radiation Oncology. 2003;13:176–181. 2. Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS, http://ctep.cancer.gov, Publish Date: August 9, 2006. 3. Miller AB, Hoogstraten B, Staquel M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207–214.

E.A. Olsen 4. Lacouture ME, Maitland ML, Degaert S, Setser A, Baran R, Fox LP et al. A proposed EGFR inhibitor dermatologic adverse event-­specific grading scale from the MASCC skin toxicity study group. Support Care Cancer. 2010 Apr;18(4):509–522. Epub 2010 Feb 10. 5. Cotsarelis G, Millar SE and Chan EF. Embryology and Anatomy of the Hair Follicle. In Olsen EA Editor, Disorders of Hair Growth: Diagnosis and Treatment. McGraw-Hill, New York, 2004. 6. Olsen EA. Clinical Tools for Assessing Hair Loss. In Olsen EA Editor, Disorders of Hair Growth: Diagnosis and Treatment. McGraw-Hill, New York, 2004. 7. Baker BW et al. Busulfan/cyclophosphamide conditioning for bone marrow transplantation may lead to failure of regrowth. Bone Marrow Transplant 1991;7:43–47. 8. Tran D, Sinclair R, Schwater A. Permanent alopecia following chemotherapy and bone marrow transplantation. Aust J Dermatol 2000;41:106–108. 9. de Jonge ME, Mathôt RAA, Dalesio O, Huitema ADR, Rodenhuis S, Beijnen JH. Relationship between irreversible alopecia and ­exposure to cyclophosphamide, thiotepa and carboplatin (CTC) in high-dose chemotherapy. Bone Marrow Transplantation 2002;30: 593–597. 10. Dueland S, Sauer T, Lund-johansen F, Ostenstad F, Kjell MT. Epidermal growth factor receptor inhibition induces trichomegaly. Acta Oncologica 2003;42: 345–346. 11. Van Doorn R, Kirtschig G, Scheffer E, et al. Follicular and epidermal alterations in patients treated with ZD1839 (Iressa), an inhibitor of the epidermal growth factor receptor. Br J Dermatol 2002; 147:598–601. 12. Robert C, Soria J-C, Spatz A, LeCesne A, Malka D, Paturier P et al. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 2005;6:491–500. 13. Lacoutoure ME, Basti S, Patel J, Benson A 3rd. The SERIES clinic: an interdisciplinary approach to the management of toxicities of EGFR inhibitors. J Support Oncol 2006;4:236–239. 14. Olsen E, Hordinsky M, McDonald-Hull S, Price V, Roberts J, Shapiro J, Stenn K. Alopecia areata investigational assessment guidelines. J Am Acad Dermatol 1999;40:242–246. 15. Perlin E, Amin D. Protection from chemotherapy induced alopecia. Med Pediatr Oncol 1991;19:129–130. 16. Grevelman EG, Breed WPM. Prevention of chemotherapy-induced hair loss by scalp cooling. Ann Oncol 2005;16:352–358. 17. Duvic M, Lemak NA, Valero V. A randomized trial of minoxidil in chemotherapy induced alopecia. J Am Acad Dermatol 1996;35: 74–78.

Part XIII

Rehabilitation

Chapter 37

Rehabilitation in Cancer Martin R. Chasen and Paul B. Jacobsen

Rehabilitation in Cancer History of Rehabilitation Rehabilitation derives from the Latin “rehabilitare” meaning to make fit again. Cancer rehabilitation, as defined by Cromes, involves helping a person with cancer to help himself or herself to reach the maximum physical, social, psychological, and vocational functioning within the limits imposed by the disease and its treatment [1]. In 1969, Dietz introduced the first conceptual framework for designing a successful rehabilitation program triaging the patients based on their rehabilitation goals and needs [2]. These specific rehabilitation needs of patients with cancer were further defined by other practitioners such as Rusk, DeLisa, and deLateur. Historically, the concept of cancer rehabilitation stems from an integral component of The [US] National Cancer Act of 1971. That legislation declared cancer rehabilitation to be an objective, and it directed funds toward the development of training programs and research projects. In 1972, the US National Cancer Institute sponsored the National Cancer Rehabilitation Planning Conference, which identified four objectives for the rehabilitation of cancer patients, viz., (1) optimization of physical functioning, (2) psychosocial support, (3) vocational counseling, and (4) optimization of social functioning.

Population Each year, there are more than 10 million new patients diagnosed with cancer worldwide. In the USA, an estimated 1,479,350 new cancer cases are forecast for 2009. The recent M.R. Chasen (*) Division of Palliative Care, University of Ottawa; Palliative Rehabilitation, Élisabeth Bruyère Hospital, Ottawa, ON, Canada e-mail: [email protected]

statistical data shows that there are approximately 22 million people living worldwide with a diagnosis of cancer [3]. It is estimated that 70% of all the patients with cancer survive for more then 5 years after the date of diagnosis and the majority of the cancer survivors are of working age (<55 years) [4]. Improved outcomes have, therefore, created a constantly growing population of patients living with a cancer diagnosis. In 2006, there were 11.4 million cancer survivors in the USA (Fig. 37.1) [5]. Breast cancer survivors continue to represent the largest segment of the survivor population (23%), followed by prostate cancer survivors (20%) and colorectal cancer survivors (10%) [6]. Reasons for increases in long-term survival rates in the last decades of the twentieth century are probably manifold and vary between cancer sites. These include: 1. Improvements in and broader use of newer cancer screening technologies, such as HPV-DNA in cervical cancer screening. In breast cancer, early detection has probably made the largest contribution. 2. Progress in the discovery, development, and delivery of more effective multimodal and multi-agent combination therapies, such as tyrosine-kinase inhibitors and monoclonal antibodies. For cancers, such as testicular, childhood cancers, and Hodgkin disease, improvement is mainly attributable to breakthroughs in treatment. 3. Greater application of adjuvant treatments for very early breast, lung, and colon cancer. 4. Better supportive care, such as growth factors. 5. Attention to posttreatment surveillance for early detection of recurrence and second primaries.

Impact of Cancer The functional autonomy of patients with cancer is compromised throughout the trajectory of illness in different ways and influenced by different factors. The severity of

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Fig. 37.1  Estimated Number of Cancer Survivors in the USA from 1971 to 2006 (Data from [5], http://seer.cancer.gov/ csr/1975_2006/, based on November 2008 SEER data submission, posted to the SEER web site, 2009)

this compromise ranges from negligible to profound at the extremes. The extent of the impact on the individual is influenced by: 1 . Location and stage of the disease 2. Treatment modalities used 3. Duration of treatment 4. Disease response 5. Time elapse since last treatment 6. Psychosocial environment 7. Patient co-morbidities Whilst some patients experience symptoms during the initial phases of diagnosis and treatment, others experience treatment related, long term, debilitating, side effects. Patients progress through different phases and experience different reactions after being given the diagnosis of cancer. Each phase is characterized by specific symptoms which affect specific functional domains of the patients, which req­ uire specific rehabilitation interventions. The initial phase of the post-diagnosis disease trajectory is the staging and pretreatment phase. Symptoms experienced by the patients include anxiety, fatigue, and pain. During this phase, patients may be preoccupied with the diagnosis and consequences thereof. A drastic change in the patients’ daily routine, sleep pattern, and social interaction is usually evident. The second phase is the primary treatment phase, during which time patients experience, in addition to the above mentioned symptoms, other disease-specific symptoms such as impaired speech with head and neck surgery or change in body image post-mastectomy. Acute effects of chemotherapy and/or radiation therapy such as nausea, vomiting, and infections are also prominent [already mentioned fatigue]. Aspects of the daily routine, such as self-care, cosmesis, and social interaction,

such as eating together at meal times, are frequently interrupted. The third Phase is the posttreatment phase. In this phase, patients often experience treatment-related symptoms such as pain after surgery or lymphedema post-mastectomy. Decreased movement, loss of strength, anxiety, and depression are also reported. Problems with interpersonal relationships and economic hardship related to the cost of care and job losses often encountered. Activities of daily living and cosmesis are affected. The fourth phase is the recurrence phase. Shock, disbelief, anxiety, fear, grief, and a feeling of betrayal and anger are common. Patients feel weak both physically and psychologically, they lose their appetite and are depressed. Symptoms related to local growth of tumor which cause pain, for example, may predominate. The activities of daily routine are disrupted and patients are usually preoccupied with negative thoughts and emotions about their existing condition and their future. The fifth and final phase is the end-of-life phase. During this phase there may be a feeling of alienation or isolation. Fear of impending death and concern over the events preceding death. The most common complaints during this phase are anasarca (generalized edema), pain, fatigue, crumbling autonomy, and lack of appetite. Patients are usually bedridden and there is an obvious dependency on others for their activities of daily living.

Caregivers Cancer affects the quality of life (QOL) of individuals with the disease and also that of their family members and close friends. This is significant throughout the

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trajectory of the illness: Informal care provided by family caregivers includes: 1. Treatment monitoring for side effects and help with reporting them to the physician 2. Treatment-related symptom management 3. Emotional, financial, and spiritual support 4. Assistance with personal and prosthetic care Family caregivers experience problems from their caregiving experiences, including conflict about their social roles, restrictions of activities, strain in marital and family relationships, psychological distress, and diminished physical health [7]. The degree to which family caregivers have negative and positive experiences in caregiving may affect their ability to care for the patient. This ability also relates to their own QOL, which includes psychological, mental, social, physical, spiritual, and behavioral components, not only during the time that they are providing care but also throughout the trajectory of the illness. Follow-up studies of caregivers show increased morbidity after a patient’s death [8].

Classification of Rehabilitation According to Dietz Owing to the nature of the cancer trajectory, rehabilitative goals have been divided into preventive, restorative, supportive, and palliative [2]. I. Preventive rehabilitation aims at reducing the burden of mortality or morbidity of the disease and/or treatment. Interventions could include preoperative education to maintain strength and range of motion in the upper extremity following breast surgery. The education of caregivers can help reduce predictable complications such as skin ulcers that result from immobility and chemotherapeutic neuropathies. Rehabilitation interventions include the education concerning the functional impact of the treatment with focus on the method to preserve social function and activities of daily living. II. Restorative care aims to return the individual with minimum functional impairments to their premorbid state. For example, after mastectomy, restorative approaches can restore shoulder range of motion and upper extremity strength. Structured progressive aerobic conditioning represents a very effective restorative technique for patients undergoing bone marrow transplantation. It can allow them to recover their premorbid fitness levels. Psychological interventions and social approaches help to allow families to reach their previous equilibrium. Issues requiring attention during this phase include

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adequate control of symptoms with appropriate medications. Management of pain, sleep hygiene, and the evaluation of the effects of treatments are required. III. Supportive efforts seek to reduce functional difficulties and compensate for permanent deficits. An example of this approach would include the multimodal techniques used to rehabilitate patients after amputation. Teamwork includes reeducating the person regarding care of the prosthesis, learning to walk again, interacting with peers, and returning to work. Rehabilitation intervention aims at developing a program to restore mobility and management of symptoms that occur as a result of treatment. Equipping patients with education for self-monitoring of possible side effects of treatment, and maintaining a healthy lifestyle is addressed. IV. Palliative treatment aims to eliminate or reduce complications, especially pain and any other symptoms. Emotional support is also important. Prevention of bedsores can be achieved by education of caregivers. Existential issues can also be addressed by clergy. Rehabilitation intervention for this phase is to educate the patient and their caregivers on how to conserve energy. Training about body mechanics; educating the patients about the use of assistive devices to minimize energy expenditure while maintaining independence; pharmacological treatment of symptoms such as pain, delirium, and constipation; and education to prevent bedsores are addressed.

Psychosocial Rehabilitation As noted previously, psychosocial problems and psychological distress are common consequences of cancer and its treatment. Accordingly, there is growing recognition that psychosocial care is an essential component of a comprehensive approach to the treatment and rehabilitation of people with cancer [9]. A consensus report recently issued by the US Institute of Medicine (IOM) described a model for the effective delivery of psychosocial services to cancer patients [9]. As specified in the model, processes need to be in place to (a) identify distressed patients; (b) link patients and families to needed psychosocial services; (c) support patients and families in managing the illness; (d) coordinate psychosocial and biomedical care; and (e) follow-up on care delivery to monitor the effectiveness of services provided and make modifications if needed. These recommendations are similar to those contained in the Clinical Practice Guidelines for Management of Distress developed by the US National Comprehensive Cancer

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Network (NCCN) [10]. The NCCN guidelines were developed based on the recognized need for better management of distress and with the intent of promoting best practice for the psychosocial care of cancer patients. Although too detailed to be fully summarized here, the NCCN guidelines are presented in the form of clinical pathways that describe recommended procedures for evaluating patients and recommended uses of psychological, psychiatric, social work, and pastoral care services to treat a wide range of psychosocial problems. Similar to the IOM report, the NCCN guidelines recommend that all patients be routinely screened to identify the level and sources of their distress. This could be accomplished using the single-item Distress Thermometer and the accompanying problem list described in the guidelines. The specific services and resources subsequently recommended are designed to be appropriate to the nature and severity of the problems identified through the initial screening and a further evaluation. For example, a patient found to be distressed on screening may undergo further evaluation that reveals the presence of a mood disorder characterized by loss of interest in usual activities, depressed mood, loss of appetite, fatigue, and insomnia. For patients with a mood disorder, the initial recommendation in the guidelines is for evaluation, diagnostic studies, and modification of factors potentially contributing to mood disorder symptoms (e.g., pain and concurrent medications). Based on findings, the subsequent recommendations may include initiation of antidepressant medication, psychotherapy, and/or referral for social work services or pastoral care services. A recently published study demonstrated the benefits of an approach to psychosocial care similar to that described in the NCCN guidelines. In this study [11], cancer patients found to have major depressive disorder through screening were randomly assigned to usual care or usual care plus a collaborative care intervention. The intervention consisted of up to ten sessions with a cancer nurse who provided education about depression and its treatment (including antidepressant medication) and problem-solving therapy to overcome feelings of helplessness. In addition, the nurse communicated with each patient’s oncologist and primary care doctor about the management of major depressive disorder. Findings showed significantly lower scores on a measure of depression three months post-randomization for patients who received the collaborative care intervention. These differences are reflected in the percentages of usual care patients (45%) versus collaborative care patients (68%) whose major depressive disorder had remitted in the 3-month period. The beneficial effects of collaborative care observed at 3  months were still evident at 6-month and 12-month follow-up assessments.

M.R. Chasen and P.B. Jacobsen

Approach to Identification and Management of Specific Patient Groups Requiring Rehabilitation Specific Rehabilitation Situations in Patients with Breast Cancer Physical Impairments Treatment for breast cancer can be associated with a number of localized physical sequelae including arm edema (AE), impaired shoulder mobility, chronic pain, neurologic deficits, and reduced upper body function. Psychologic, social, and sexual dysfunctions are also prevalent.

Menopause Women with breast cancer can experience early menopause as a result of their treatment. A higher frequency of menopausal symptoms than women in the general population is reported [12], including hot flashes, night sweats, vaginal dryness, difficulty sleeping, depression, and dyspareunia. Hot flashes (HF) are more frequent, severe, distressing, and of greater duration in breast cancer survivors compared with controls without breast cancer [12]. Fatigue Severe persistent fatigue is experienced during, and shortly after breast cancer treatment and is often related to depression and pain.

Sexual Functioning Female breast cancer patients often avoid sexual intercourse especially due to negative emotional effects, changes of female body image, and fear of partner rejection. Cervical cancer patients often show fibrosis, pain with penetration due to stenosis, and decreased lubrication.

Specific Rehabilitation Situations in Patients with Colorectal Cancer Bowel Changes/Dysfunction Following rectal resection common symptoms include increased frequency of bowel motion, urgency, fecal leakage, and incontinence. Diarrhea, constipation, and excessive flatus

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have also been reported in many patients. These are important issues for survivors because even though their cancer may be cured, their function and quality of life may be severely diminished as a result of bowel-related symptoms, which impact heavily on the QOL of patients with colorectal cancer.

Ostomy Issues In patients who undergo abdominoperineal resection, the presence of a permanent colostomy has strong influence on the various domains of QOL. In a series of 203 patients with end sigmoid colostomies, paracolostomy hernia was the most common complication (36% at 10 years) [13]. In a survey study of almost 400 ostomates, 51% had skin problems (e.g., rashes) and 36% had leakage; 80% reported a change in lifestyle [14].

Neurotoxicity Women with advanced gynecologic cancer receive neurotoxic chemotherapy regimens. A study of 49 patients with ovarian cancer who were between 5 and 10 years after diagnosis found that a significant proportion still reported symptoms of neurotoxicity: numbness in the hands was reported by 10%; trouble walking, 16%, discomfort in hands, 23%; ringing in ears, 29%, discomfort in feet, 29%; trouble hearing, 35%; and muscle cramps, 39% [17]. Neurotoxicity symptoms were associated with poor physical and psychologic well-being, depression, sexual discomfort, and low confidence for managing cancer.

Pain Approximately half of the 200 ovarian cancer survivors in one study reported pain or discomfort in the bowel, pelvis, bladder, or groin [18].

Sexual Dysfunction Sexual problems are associated with surgical and radiation therapies that affect the tissues/organs of the pelvis and the nerves that innervate them. A conventional rectal cancer resection in men is associated with postoperative impotence and retrograde ejaculation or both in 25–100% of cases [15]. In females, the most common postoperative sexual complaint is dyspareunia, which may include loss of vaginal lubrication and inability to achieve orgasm.

Urologic Dysfunction Urologic dysfunction includes problems such as incomplete emptying, urgency, overflow or stress incontinence, loss of bladder sensation, dysuria, and chronic urinary tract infections occur in 7–68% of patients following low rectal resection [16].

Specific Rehabilitation Situations in Patients with Gynaecologic Cancer

Menopausal Symptoms Patients alive after the diagnosis of endometrial/cervical cancer have noted significant problems with menopausal symptoms (e.g., hot flashes, vaginal dryness/irritation). Another implication of early ovarian failure, especially for younger survivors, is the increased risk of osteoporosis.

Psychologic Distress Survivors, who are at increased risk of recurrent or persistent disease, have been reported to experience higher levels of anxiety and depression.

Sexual Functioning Patients report greater difficulty with sexual desire, excitement, orgasm, and resolution.

Specific Challenges Facing Patients with Head and Neck Cancer

Gastrointestinal Symptoms These patients report more stomachache diarrhea, and nausea. Frequent diarrhea is associated with higher fatigue and poorer social functioning.

Head and neck cancers and their treatments contribute to changes in eating, breathing, speaking, and the physical appearance of patients. Although reconstructive surgeries restore contour and functioning, patients often experience

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residual cosmetic and/or functional alterations. Facial disfigurement is a major concern for patients and family caregivers particularly in relation to the patient’s diminished selfesteem, the effect on family relationships, and the ability to work. Ongoing protective care is important to minimize skin breakdown and infections. Some disfigured individuals report feeling physically changed and that treatment damaged their appearance, thus increasing their feelings of distress, self-awareness, and social anxiety.

Changes in Eating, Saliva, Taste, Chewing, Swallowing, and Sense of Smell and Drooling Difficulties with eating, chewing, swallowing as well as changes in taste and smell and drooling are commonly reported. They contribute to eating problems and weight loss. Dysphagia or difficulty swallowing is considered to be the most common nutrition-related problem resulting from head and neck cancer. Long-term side effects and symptoms of radiation therapy include xerostomia (dryness of mouth due to dysfunction of the salivary gland), mucositis, and anorexia.

Changes in Speech and Voice Loss of a voice or intelligible speech is distressing, isolating, and creates major difficulties for individuals in their interpersonal communications.

Shoulder Dysfunction Shoulder dysfunction and pain after radical neck dissection are reported as activity-limiting and interferes with performing daily activities and ability to return to work.

Specific Challenges Facing Patients with Lung Cancer

M.R. Chasen and P.B. Jacobsen

Pain Frozen shoulder, a potential postsurgical risk, affects lung cancer survivors [20]. Rib fractures and bony metastasis cause pain as well. Altered Functional Status/Fatigue In the above study of lung cancer survivors, almost all the survivors reported significant decreases in their energy (84%). Fatigue was the most commonly reported symptom more than one year after surgery for patients undergoing thoracotomy, as was the case with long-term survivors of smallcell lung cancer [21]. Emotional Distress and Depression Depression and emotional distress are seen more often among people with lung cancer than people with other cancers (15–44%) [22]. In a qualitative study, survivors described existential changes prompting them to “seeing life as a gift,” “appreciating the little things in life,” and “trying to live life to its fullest.” Many express that life after lung cancer is not normal and feels more uncertain [23].

Teamwork The different disciplines involved in the care of patients with cancer constitute the team. These include nurses, occupational therapists, physiotherapists, psychologists, dieticians, etc. It is vital that the communication within the team is open, direct, and supportive. Herein lies the strength of collaboration between team members: They will learn of the different assessment approaches, the importance that patients place on various symptoms and the effects these symptoms have on the domains of the patient’s quality of life. With the patient and caregivers being placed as the end target of all therapeutic interventions, the combined collaborative efforts of the team are synergistic in their effect. Regular roundtable discussions are a key component of this teamwork.

Dyspnea

Rehabilitation – Using the McGill Cancer Nutrition and Rehabilitation The loss of functional lung tissue as a result of lung cancer surgery may result in transitory and permanent reductions in Program – an Innovative Team pulmonary function and, for some, physical disability. In addition to dyspnea, respiratory symptoms such as cough, phlegm, and wheezing also affect long-term survivors and diminish health-related quality of life [19].

The McGill Cancer Nutrition-Rehabilitation (CNR) Program was set up to provide treatment and lifestyle interventions targeting the population of cancer survivors [24].The global

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objective of the McGill CNR program is to use an interdisciplinary approach to empower individuals who are experiencing loss of function, fatigue, malnutrition, psychological distress, and other symptoms as a result of cancer or its treatment to improve their own quality of life. An imperative in accomplishing these goals is a coordinated multidisciplinary team approach that addresses the potential rehabilitation needs of the individual from the time of the cancer diagnosis onward. The CNR assumes that the patient and the patient’s environment are the center toward which all interventions are directed. The program recognizes that each patient is an individual and therefore requires different types and levels of intervention. Depending on the needs of the individual patient and family, members of the rehabilitation team may include the services of any or all of the following: physicians, oncology nurses, dieticians, physical and occupational therapists, social workers, psychologists, recreational therapists, vocational therapists, case managers, patient coordinators, chaplains, and relevant volunteers. Patients that are referred are those who, as compared with their level before diagnosis, are experiencing changes in appetite (with or without associated weight loss); physical functioning, such as walking; fatigue; and coping with the consequences of their disease. All new-patient visits begin in the morning. On arrival, patients complete the following questionnaires: the Edmonton Symptom Assessment Scale (ESAS) [25]; the Patient-Generated Subjective Global Assessment (PGSGA) [26]; the Brief Fatigue Inventory (BFI) [27]; and the Distress Thermometer (DT) [28]. The various professionals see each patient during this first visit. Each member of the team evaluates the patient individually for 30 min with their own set of evaluations. The dietician evaluates the patients current nutrition status and provides recommendations regarding specific dietary needs. Dietary supplements and alternative foods are discussed and prescribed. The dietician also teaches the family members about the importance of appropriate diet in successful rehabilitation. The physical therapist evaluates the patients muscle strength, mobility, and joint range of motion, conducts the 6 min walk test, gait speed test, timed two times sit to stand, Berg balance test, and if warranted performs assessment of arm girth and assessment of the scar. The treatment interventions provided include therapeutic exercises to maintain or increase range of motion, endurance, and mobility training (e.g., transfers gait, stair climbing). The occupational therapist conducts an activity interview and evaluates a patient’s ability to carry out activities of daily living such as washing, dressing, preparing meals, working, driving, or performing leisure activities. A Simmonds Functional Scale Assessment, which allows for a better understanding of the day-to-day functional ability of the patient, dysphagia assessment, pinch and grip strength test, dexterity and sensation test to assess

neuropathies, and cognitive assessment test for the elderly is also performed [29]. Education on energy conservation, including the use of compensatory techniques, how to plan and set priorities, and the use of adaptive equipment are part of the therapeutic armamentarium. The psychologist assesses and treats social, emotional, and mental functioning through patient and family education and counseling for stress, anxiety, and depression management. Using cognitive behavioral therapy, mindfulness-based cognitive therapy, existential psychotherapy, couples therapy, and support groups, the psychologist helps the patient to adjust to actual, perceived, and potential losses. The social worker provides counseling to patients and families regarding emotional support, community resources, finances, lifestyle changes, and their participation in treatment. During all this time, the patient remains in a single location, and team members move between patients. Once accepted into the program, patients have biweekly exercise sessions with the physiotherapist. A fortnightly (or more frequent, if needed) visit to the dietician, occupational therapist, nurse, physician, and other relevant team members is scheduled. If judged necessary, or if specifically requested by the patient, a detailed psychological assessment is undertaken, and specific therapy is given. At the end of the 8 weeks, a full repeat of the baseline assessment is conducted. For patients that require still more formal supervision in any component of the CNR program, a personal referral to other rehabilitation units is made. All patients are referred back to their original physician with a full follow-up summary and recommendation.

Future Directions in Cancer Rehabilitation As more physicians and other health caregivers become more aware of the additional benefits awarded to patients by rehabilitation, more research questions will be posed such as 1. Research on the causative factors of weight, appetite, and function loss 2. Importance of regular physical activity after cancer: Does it increase length and quality of survival? 3. Research on muscular fatigue and loss of strength in patients undergoing treatment for cancer 4. Psychosocial and behavioral consequences of long-term physiological sequelae for survivors’ health and well-being 5. Meaning-making coping processes of patients with cancer 6. Long-term impact of cancer on the functioning and wellbeing of the caregivers Research will help improve quality of care and possibly identify newer strategies for the treatment of patients undergoing cancer rehabilitation.

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Conclusion Advances in screening, better healthcare and treatments have led to improved survival rates in patients with cancer. Consequently, patients are expected to live longer with the physical and psychosocial impairments that result from their disease and/or its treatment. Cancer rehabilitation empowers individuals to regain strength, preserve function, and improve quality of life. Rehabilitation improves patient’s perceptions of themselves and equips them with the tools necessary for successful social reintegration. To effectively improve the care and management of the patients, it is crucial to educate and create more awareness among healthcare professionals and rehabilitation specialists. The importance of the multimodal approach by a multidisciplinary team must be emphasized and implemented early in the course of the disease. A well-functioning interdisciplinary team is vital to achieve these objectives. Acknowledgment  The authors wish to thank Dr. Ravi Bhargava for his impeccable research and assistance in preparing this manuscript.

References 1. Cromes GF Jr. Implementation of interdisciplinary cancer rehabilitation. Rehabil Counseling Bull 1978;21:230–237. 2. Dietz JH. Rehabilitation of the cancer patient. Med Clin North Am 1969;53:607–624. 3. Bilimoria KY, Winchester DP. The importance of worldwide Cancer Registration. Journal of Surgical Oncology 2008;97:481–482;DOI 10.1002/jso.20886 4. Wolff SN. The Burden of Cancer Survivorship: a pandemic of treatment success. In: Feuerstein M (ed). Handbook of Cancer Survivorship. New York: Springer (2007). 5. Horner MJ, Ries LAG, Krapcho M, Neyman N, Aminou R, Howlader N, Altekruse SF, Feuer EJ, Huang L, Mariotto A, Miller BA, Lewis DR, Eisner MP, Stinchcomb DG, Edwards BK (eds). SEER Cancer Statistics Review, 1975–2006, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2006/, based on November 2008 SEER data submission, posted to the SEER web site, 2009. 6. Ries LAG, Melbert D, Krapcho M, Stinchcomb DG, Howlader N, Horner MJ, Mariotto A, Miller BA, Feuer EJ, Altekruse SF, Lewis DR, Clegg L, Eisner MP, Reichman M, Edwards BK (eds). SEER Cancer Statistics Review, 1975–2005, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2005/, based on November 2007 SEER data submission, posted to the SEER web site, 2008. 7. Kim Y, Baker F, Spillers RL, Wellisch DK. Psychological adjustment of cancer caregivers with multiple roles. Psychooncology 2006;15:795–804. 8. Nicolas R, Teresa JM, Roy M, Gregory EM. Biologic Cost of Caring for a Cancer Patient: Dysregulation of Pro- and AntiInflammatory Signaling Pathways. Journal of Clinical Oncology June 20, 2009;27(18):2909–2915.

M.R. Chasen and P.B. Jacobsen 9. Institute of Medicine. Cancer care for the whole patient: Meeting psychosocial health needs. Washington, DC: The National Academies Press, 2007. 10. Anonymous. NCCN practice guidelines for the management of psychosocial distress. Oncology (Huntington) 1999;13:113–147. 11. Strong V, Waters R, Hibberd C, et al. Management of depression in people with cancer (SMaRT oncology 1): A randomised trial. Lancet 2008;372:40–48. 12. Carpenter JS, Johnson D, Wagner L, Andrykowski M. Hot flashes and related outcomes in breast cancer survivors and matched comparison women. Oncol Nurs Forum 2002;29:E16–E25. 13. Londono-Schimmer EE, Leong AP, Phillips RK. Life table analysis of stomal complications following colostomy. Dis Colon Rectum 1994;37:916–920. 14. Nugent KP, Daniels P, Stewart B, Patankar R, Johnson CD. Quality of life in stoma patients. Dis Colon Rectum 1999;42: 1569–1574. 15. Havenga K, Enker WE, McDermott K, Cohen AM, Minsky BD, Guillem J. Male and female sexual and urinary function after total mesorectal excision with autonomic nerve preservation for carcinoma of the rectum. J Am Coll Surg 1996;182:495–502. 16. Rothenberger DA, Wong WD. Abdominoperineal resection for adenocarcinoma of the low rectum. World J Surg 1992;16: 478–485. 17. Lari B, Donnelly P, Fowler M, et  al. Resilience, reflection, and residual stress in ovarian cancer survivorship: A gynecologic oncology group study. Psycho-Oncology 2002;11–12:142–153; DOI: 10.1002/pon.567 18. Stewart DE, Wong F, Duff S, Melancon CH, Cheung AM. “What doesn’t kill you makes you stronger”: an ovarian cancer survivor survey. Gynecol Oncol 2001;83:537–542. 19. Sarna L, Evangelista L, Tashkin D, et  al. Impact of respiratory symptoms and pulmonary function on quality of life of long-term survivors of non-small cell lung cancer. Chest 2004;125: 439–445. 20. Schag CAC, Ganz PA, Wing DS, et al. Quality of life in adult survivors of lung, colon and prostate cancer. Qual Life Res 1994;3:127–141. 21. Li WW, Lee TW, Lam SS, et al. Quality of life following lung cancer resection: video-assisted thoracic surgery versus thoracotomy. Chest 2002;122:584–589. 22. Zabora J, Brintzenhofeszoc K, Curbow B, et al. The prevalence of psychological distress by cancer site. Psycho-Oncology 2001;10: 19–28. 23. Maliski SL, Sarna L, Evangelista L, et  al. The aftermath of lung cancer: balancing the good and bad. Cancer Nurs 2003;26: 237–244. 24. Chasen MR, Dippenaar AP. Cancer nutrition and rehabilitation–its time has come! Curr Oncol 2008;15(3):117–122. 25. Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care 1991; 7: 6–9. 26. Ottery FD. Patient-generated subjective global assessment of nutritional status. Nutritional Oncol 1996;2:8–9. 27. Mendoza TR, Wang XS, Cleeland CS, et al. The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer 1999;85:1186–1196. 28. National Comprehensive Cancer Network. Distress management clinical practice guidelines. J Natl Compr Canc Netw 2003;1: 344–374. 29. Simmonds MJ. Physical function in patients with cancer: psychometric characteristics and clinical usefulness of a physical performance test battery. J Pain Symptom Manage 2002;24: 404–414.

Part XIV

Survivorship

Chapter 38

Oral Health and Survivorship: Late Effects of Cancer and Cancer Therapy Joel B. Epstein and Barbara E. Murphy

Incidence of Oral-Health-Related Issues The frequency of acute oral complications in patients receiving chemotherapy depends upon the disease under treatment, the medication(s) used, dose and schedule of therapy, and patient comorbidities including individual genetic susceptibility. Chemotherapy may affect a wide array of oral tissues inclu­ ding the oral mucosa, salivary gland, neurosensory function, the dentition, and periodontium. The estimated incidence of oral complications due to chemotherapy is 10% in adjunctive chemotherapy, 40% with primary standard dose chemother­ apy, and up to 80% with myeloablative chemotherapy. It must be noted that oncologic therapies are constantly evolving. This results in concurrent shifts in the manifesta­ tions of acute and late effects of therapy. The changing nature of treatment-related toxicities challenges both the patient and health-care providers. For example, chemotherapeutic management of malignant disease directed at molecular tar­ gets expressed by tumor cells is generally associated with decreased toxicities [1]. Nonetheless, normal tissues includ­ ing skin, bone marrow, gastrointestinal mucosa, and salivary gland continue to be at risk even with the use of targeted agents. Conversely, in many tumor types, accelerated or intensi­fied therapy may result in increased frequency, sever­ ity, and duration of acute oral complications. Induction and concurrent chemotherapy is increasingly incorporated in the management of head and neck cancer (HNC) and acute and late local effects of combined modality therapy for head and neck cancer are dramatically increased. In addition to the increase in the frequency of direct tissue toxicity, indirect non-oral toxicities including myelosuppression increase significantly as well. Patients experiencing myelosuppres­ sion secondary to the malignant disease and/or high-dose J.B. Epstein (*) Department of Oral Medicine and Diagnostic Sciences, College of Dentistry and Head and Neck Surgery/Otolaryngology, 801 S. Paulina St, Chicago, 60612, IL, USA e-mail: [email protected]

chemotherapy are at risk of clinically significant oral mucositis, salivary gland toxicity, taste change, and increased risk for oral/regional infection and systemic infection of oral origin. Oral health complications are most commonly noted in patients with HNC. Issues may be due to underlying poor dental health, tumor-related complications, and sequelae secondary to disease treatment. The type and severity of oral health issues change across the trajectory of the disease. Oral symptoms at the time of cancer diagnosis may be absent or minimal; most commonly they include oral discomfort and minor bleeding. When more advanced, HNC patients may experience dysarthria, dysphagia, dysphonia, oral bleeding, malodor from necrotic cancer, and weight loss. HNC treatment results in unique symptom and func­ tional deficits which depend largely on the tumor site and the treatment modalities used. Surgical morbidity is related to the amount of tissue removed, the site of tissue removed, and the use of reconstructive techniques. Radiation therapy, which may be used either as primary treatment or as adju­ vant therapy postoperatively, results in a distinctive pattern of acute and late effects. Concurrent chemotherapy may be added to enhance the efficacy of radiation therapy; however, it results in dramatic increases in oral complications. Most cases of HNC are diagnosed when they are locally advanced and locally advanced tumors are increasingly being treated with multimodality therapy. Thus, a marked increase in both acute and late effects from HNC treatment is recognized. The most common acute toxicities due to radiation ther­ apy include mucositis, hyposalivation, mucous production, altered taste, pain, and dysphagia. Oral complications may result in a number of sequelae including increased oral, pul­ monary and systemic infection, dehydration, and nutritional compromise. While patients recover from many of the acute effects of therapy, most patients are left with persisting oral complications including hyposalivation, oral infection, taste change, mucosal sensitivity, trismus, dysphagia, and dental decay. Both acute and late effects of therapy may adversely impact on oral health, general health, and QOL.

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Oral Quality of Life and Symptom Burden Quality of life (QOL) is a global construct that reflects a patient’s general sense of well-being. A number of tools have been developed to measure QOL in the oncologic popula­ tion. Commonly used QOL tools in the oncology population are the Functional Assessment of Cancer Therapies (FACT) and the European Organization for Research into the Treatment of Cancer (EORTC QLQ-C30). Both of these tools assess physical well-being, functional well-being, social well-being, and emotional well-being. Subscales have been developed to assess tumor and treatment-specific symp­ tom and functional issues. QOL must be distinguished from assessment of specific symptoms or functional loss. Symptoms may be defined as the patient’s perception of alteration in sensation and functional loss related to organ system abnormalities. While patients may perceive alterations in function, it should be noted that func­ tion loss may not be reported, and may be subclinical. Thus, objective measures of functionality may be needed to assess function adequately. Although QOL questionnaires contain items that query symptoms and functional outcomes, assess­ ment of symptom burden is not the primary intent of QOL tools. Tools have been developed to assess specific symptom and functional outcomes and they should be used when the description of symptom burden is the desired study outcome. A number of investigators have reported the results of oral health outcomes in the context of QOL assessments in the head and neck cancer population. QOL was assessed in HNC patients who had completed radiotherapy more than 6 months earlier [2]. Persisting symptoms reported included dry mouth (92%), change in taste (75%), and difficulty eating (40%). The majority of patients experienced pain (58%), and 17% reported moderate or severe pain and 31% stated that pain interfered with daily activities. Oral health outcomes were assessed in HNC patients followed up to 5 years following treatment with 87% of survivors participating at 5-year fol­ low-up [3]. Dental problems, trismus, xerostomia, and sticky saliva increased over time after 1  year and persisted at 5 years. Oral complaints were related to gender, age, stage, and site of disease. Similarly, the late effects of oral cancer and its treatment were assessed in a prospective, multicenter study of QOL using patient reported outcomes (PRO) pretreatment and 1 and 5  years following treatment [4]. Dry mouth, sticky saliva, speech changes, dental problems, and sleep disturbance were all associated with a decrease in QOL (p < 0.01). In another study, patients completed QOL surveys up to 36 months after HNC treatment [5]. Most short-term morbidity resolved in 1 year of cancer treatment; however, at last follow-up physical function, taste/smell, dry mouth, and sticky saliva were ­significantly worse than at baseline. Females, higher stage of

J.B. Epstein and B.E. Murphy

disease at entry, and combined treatment were associated with increased symptoms and worse function. A gradual improve­ ment in depression and global QOL were seen in survivors. A prospective study of nasopharyngeal cancer patients assessed before treatment and up to 24  months following treatment found poorer global health, fatigue, loss of appetite and dysphagia (all P < 0.01), xerostomia and sticky saliva (P < 0.001), taste change, dental problems (both P < 0.05), pain and emotional function (P < 0.005) [6]. In a study of naso­ pharyngeal cancer survivors (median follow-up: 3.6 years), xerostomia, hearing loss, dysphagia, and trismus were fre­ quently reported [7].

Late Oral Effects of Cancer Therapy Hyposalivation and Xerostomia Hyposalivation may be defined as a decrement in stimulated or unstimulated salivary flow. Saliva assessment is incorpo­ rated into the Common Toxicity and Adverse Event (CTCAE) criteria for xerostomia. Patients with hyposalivation may complain of the sensation of oral dryness which is commonly referred to as xerostomia. It should be noted that patient perception and objective measurement of salivary flow may not correlate. Thus, when reviewing literature it is important to consider the measurement techniques employed. Saliva has numerous critical functions. It provides oral and pharyngeal wetting and lubrication in order to maximize swal­ lowing and speech, moistens food, allows preparation of a food bolus for deglutition, and initiates digestion. Saliva allows food molecules to be dispersed and presented to taste recep­ tors. Importantly, saliva helps to preserve dental integrity by maintaining normal oral flora, oral pH, and providing calcium and phosphate to reduce demineralization and to promote remineralization of enamel. Furthermore, it aids in the control of oral infections and maintains mucosal integrity. Hyposalivation and xerostomia are commonly noted in patients treated with chemotherapy and radiation therapy. Furthermore, medications commonly used in the supportive care of chemotherapy patients (e.g., antiemetics, analgesics, antianxiety/antidepressants) may affect salivary gland func­ tion. Xerostomia associated with standard dose chemother­ apy is usually mild and transient. Studies evaluating the frequency and severity of chronic xerostomia in this setting are limited. In one study of breast cancer patients undergoing chemotherapy, both resting and stimulated flow rates were decreased during chemotherapy, and remained reduced at 6 months, with return to baseline at 1 year [8]. Changes in the composition of saliva including decreased phosphate and secretory IgA were also noted.

38  Oral Health and Survivorship: Late Effects of Cancer and Cancer Therapy

Hyposalivation and xerostomia are more common and protracted in patients undergoing high-dose chemotherapy with stem-cell rescue. In one study, 16% of patients had per­ sisting xerostomia, up to 3 years post-transplantation [9]. In the setting of stem-cell transplant, chronic hyposalivation may be secondary to progressive salivary gland damage resulting from chronic graft-versus-host disease (GVHD)[10, 11]. GVHD is characterized by acute or chronic donor T-cell reactivity against the host tissues. The damage may be due to direct target tissue damage or may be secondary to inflam­ matory mediators. The gastrointestinal tract, including the oral mucosa, is one of the primary target organs. In one report of patients with chronic GVHD, the oral cavity was involved in almost 80% of patients who underwent a bone marrow transplant and almost 90% of patients who underwent periph­ eral blood stem-cell transplantation [12]. Similar results have been reported by others [13, 14]. Symptoms are more severe in myeloablative transplantation as compared to reduced intensity conditioning. Patients receiving radiation therapy for treatment of locally advanced HNC experience severe hyposalivation and xerostomia. The salivary glands are highly sensitive to the radiation. Dramatic decrements in salivary flow are noted within 1–2  weeks of initiating standard dose radia­ tion therapy. Hyposalivation may be permanent if the sali­ vary gland receives doses of greater than 3,500  cGy. The sequelae of hyposalivation in the HNC population are pro­ found. Hyposalivation results in potential devastating radi­ ation caries (see dental health section below). In addition, patients with severe xerostomia may experience dietary adaptations such as the need to intake moist or pureed con­ sistency foods. Patients frequently drink large amounts of fluid in order to moisten and swallow solid foods. Although it is clear that hyposalivation results in dietary changes, the long-term effect on nutrient intake and diet quality is unknown. It may be hypothesized that patients with signifi­ cant dietary adaptations may experience long-term macroand micronutrient deficiencies that are associated with adverse health effects. Several approaches have been examined to prevent xeros­ tomia and hyposalivation in HNC patients receiving radia­ tion therapy. The first approach is the use of pharmacologic agents to prevent tissue damage. Amifostine (WR-2721) is a free radical scavenger that was FDA approved to prevent hyposalivation in patients undergoing radiation therapy to the salivary glands [15, 16]. A recent meta-analysis demon­ strated that amifostine resulted in a decrease in acute (OR, 0.24; CI 0.15–0.36; p < 0.00001) and late hyposalivation (OR 0.33; CI, 0.21–0.51; p < 0.00001) [17], and there is lim­ ited evidence of clinically significant improvement in dental outcomes in patients receiving amifostine [17]. A more recent study has focused on intramuscular delivery of ami­ fostine, which is associated with fewer and less severe side

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effects and lower cost, than intravenous delivery [18]. Pharmacologic agents have also been used to maximize residual function of salivary glands. Saliva stimulation with secretogogues, such as pilocarpine [19, 20], cevimeline [21, 22], and bethanechol may impact symptoms of xerostomia and has been shown to increase stimulated and unstimulated salivary flow, however, the effect on important sequelae such as dental caries or dietary adaptations has not been documented. Salivary gland transfer is a surgical technique where transplant of the salivary gland outside of the radiation port is conducted, thus sparing it from radiation induced damage. Currently available data demonstrates that this is a highly effective method for preventing the development of xerosto­ mia and hyposalivation [23]. However, the use of this tech­ nique is limited due to the increased use of intensity modulated radiation therapy (IMRT). IMRT is a radiation technique that allows the radiation beam to be targeted specifically at the tumor volume while sparing adjacent normal tissues. One of the primary benefits for the use of IMRT in the HNC population has been the abil­ ity to limit radiation to the salivary glands. Measurements of salivary flow after IMRT where the major glands are spared high-dose exposure, show decrease in hyposalivation and improved QOL compared to patients treated with standard irradiation techniques [24–26]. Regardless of the cause of hyposalivation and/or xerosto­ mia, supportive measures are indicated to maximize comfort and to minimize the adverse effects on dental health, dietary intake, and quality of life. As noted above, sialogogues may increase salivary flow and diminish xerostomia; however, this can be accomplished only in patients with residual sali­ vary gland function. Frequent oral rinsing with water, sodium bicarbonate solution, or products for mouth-wetting (“salivary substitutes”) may provide symptomatic palliation when saliva production cannot be stimulated. There has been no assessment of saliva viscosity and related function, and while mucolytics such as guafenasin and acetyl cysteine can be considered for patients with thickened secretions, their effectiveness is not well-documented.

Dental Health Dental enamel is composed largely of hydroxyapetite crys­ tals containing calcium and phosphate. Although commonly thought of as static structures, dental enamel is in constant flux. Depending on the oral environment and availability of enamel substrates, demineralization or remineralization will predominate. Demineralization predominates in an acid environment. The oral pH commonly reaches an acidic range when eating. Bicarbonate, which is present in saliva, helps

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buffer the change in pH accompanying a normal meal. Hyposalivation leads to a diminished buffering capacity that may lead to an acidic pH and favors demineralization. Furthermore, calcium and phosphate, which are critical in maintaining mineralization of enamel, are largely supplied by submandibular saliva and lack of dental substrates may inhibit remineralization. Hyposalivation may also lead to a shift in the oral flora with high levels of colonization by car­ iogenic and acidogenic bacteria such as streptococcus and lactobacillus species. Cancer therapies, particularly radiation therapy to the head and neck region, that are associated with hyposaliva­ tion, may lead to demineralization and dental decay. Of note, radiation-associated dental demineralization and car­ ies are particularly problematic. They may develop within months after completing treatment, and commonly progress rapidly. Due to the underlying pathology, reversal of the process once initiated may be difficult, thus, prevention is critical. Prevention requires recognition of the risk to sali­ vary gland function during treatment planning, and attention to preventive measures such as excellent oral hygiene and maintenance of a non-cariogenic diet. The bacterial compo­ nent can be managed with the use of chlorhexidine rinse, which has an effect upon cariogenic flora. Fluoride shifts the equilibrium toward deposition of calcium in enamel and has antibacterial effects that may be important in protecting against dental damage. Remineralization is favored in the presence of calcium, phosphate, and fluoride. Furthermore, fluoride present in the enamel matrix (flourapetite) is more resistant to acid dissolution. Thus, the structural integrity and mineralization of teeth should be optimized with use of fluoride and when dry mouth is present include provision of calcium and phosphate in the oral environment (remineral­ izing products).

Oral Pain Acutely, oral pain may be secondary to cancer, cancer ther­ apy, or complications of cancer therapy. Cancer-related oral pain is most commonly seen in patients with HNC in which the tumors ulcerate or infiltrate into soft tissue or bone. Less commonly, oral pain may be due to bone metastases from other sites or infiltration of oral tissues by hematologic can­ cers. The most common cause of treatment-related oral pain is mucositis secondary to chemotherapy and/or radiation therapy. However, oral infections such as candidiasis or ulcerations secondary to herpes viruses may also cause con­ siderable discomfort in the acute setting. Less commonly recognized, but clinically important is chronic oral discom­ fort after completion of therapy. Chronic oral discomfort after completion of therapy may be problematic in HNC

J.B. Epstein and B.E. Murphy

patients treated with radiation, stem-cell transplant patients with GVHD, and patients treated with standard-dose chemo­ therapy and targeted therapy. Post-radiation mucosal sensitivity is a commonly reported syndrome in patients who have received radiation therapy to the oral cavity. Although data regarding this phenomenon are limited, it appears to be more common and severe in patients with high-grade, diffuse, or protracted mucositis. It is hypoth­ esized to be a neuropathic pain syndrome resulting from peripheral nerve sensitization secondary to release of inflam­ matory mediators. Clinically, patients describe the discom­ fort as a “burning” pain which is worsened by acid or spiced foods and dry air. Characteristically, post-radiation mucosal sensitivity responds poorly to opioid analgesics. Agents used for neuropathic pain, such as clonazapam and gabapentin may be more effective. Patients who undergo hematopoietic stem-cell transplanta­ tion are also at risk for chronic oral pain. In this cohort of patients, pain is most commonly secondary to GVHD. In the oral cavity, this may present as mucosal “autoimmune” dis­ ease (lichenoid, lupus-like or systemic sclerosis, Sjogrenslike) which may cause considerable symptomatic difficulties [27]. The clinical manifestations of chronic GVHD in the oral cavity include mucosal inflammation, atrophy, hyperkeratosis, ulcerations, and perioral fibrosis. Patients complain of oral pain, mucosal sensitivity, xerosotmia, and taste alterations. A number of less common oral pain syndromes warrant dis­ cussion. Some chemotherapeutic agents are neurotoxic (e.g., vinca alkaloids, platinum agents, taxanes) and may lead to peripheral neuropathy, orofacial dysesthesia, and pain that can be confused with pulpal disease, which must be recognized by dental providers [28]. Some patients may develop dental hyper­ sensitivity following cancer therapy that may be due to dental demineralization and possibly neuropathy. Patients may expe­ rience symptomatic relief with topical application of fluorides and/or a desensitizing agents including toothpaste. Pain may be impacted by anxiety, depression, and sleep disturbances that a cancer diagnosis and cancer therapy can create. Clenching and bruxism may be increased and result in orofacial pain including temporomandibular disorders. These patients may benefit from physical therapy including massage, physiotherapy, and/or muscle relaxants, depression or anxiolytic management, sleep hygiene, and sleep medications. Custom-made occlusal bite guards for use during sleep may be beneficial.

Taste Alterations Taste is related to a combination of sensory mecha­nisms including taste, texture, temperature, and smell that is ­perceived when placing food or other agents in the mouth. Taste com­ prises five basic qualities: sweet, bitter, salty, sour, and umami.

38  Oral Health and Survivorship: Late Effects of Cancer and Cancer Therapy

Umami is a taste sensation more recently described that is associated with pleasure or desirable flavor [29, 30] which may have the strongest correlation with impact upon quality of life. Taste is mediated by epithelial receptors distributed throughout the oropharynx, larynx, and upper esophagus. Taste is impacted by hyposalivation, as saliva allows food par­ ticles to reach the receptor sites. Oral factors impacting taste include oral hygiene, dental and periodontal disease, mucosal infection, diet, and oral products used. Both standard-dose and high-dose chemotherapy with stem-cell rescue have been reported to cause reduced or alterations in taste. Chemotherapy has been shown to be secreted in saliva, thus resulting in taste change until the drug is cleared. In addition, chemotherapy may cause direct dam­ age to taste receptors. Similar to xerostomia, taste alterations are more severe in myeloablative transplantation as com­ pared to reduced intensity conditioning. Hyposalivation and reduced sweet/salt taste up to 3  years post-transplant [27]. Interestingly, no correlation was seen between GVHD and taste change, suggesting an independent relationship. Taste changes associated with standard-dose chemotherapy may be less severe and more transient [31]. Radiation therapy causes direct damage to receptors and results in synaptic uncoupling. Taste is affected in up to 100% of HNC patients during and following radiation therapy with or without chemotherapy. Taste change typically begins in the second week of RT [32, 33]. Recovery of taste is variable, in some studies improving in 2–6 months following cancer therapy; however, taste alteration may continue indefinitely. IMRT may spare salivary glands and thus reduce the impact of RT upon taste. However, low-dose irradiation of wider areas of the oral cavity may impact taste. Radioprotectors, such as amifostine may have utility in affecting taste by direct cellular protection or indirectly by maintenance of saliva. In addition, taste disorders may follow oncologic surgery. Surgical trauma to the lingual branch of the glossopharyn­ geal nerve may result in ipsilateral alterations in taste. The true incidence of postsurgical taste changes is unknown because it is may be underreported due to the fact that ­damage is unilateral and may resolve over time without treatment. A number of nontreatment-related factors may impact on taste abnormalities. Taste is impacted by the altered quality or reduced volume of saliva by altered delivery of tastants to recep­ tors. In addition, hyposalivation may lead to increased second­ ary infection, alterations in taste, and lead to compromised oral hygiene. Tissue necrosis, oral bleeding, and postsurgical wounds may lead to taste change, halitosis, and altered smell. The sequelae of altered taste are significant. Patients with altered taste no longer enjoy food. This has a dramatic impact on social interactions and quality of life. When severe, taste alterations may result in nausea and gagging with oral intake. Oral intake may be diminished, resulting in weight loss, and nutritional compromise. To date, there are

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no treatments which have demonstrated efficacy in ­improving taste. Although preliminary data supported the use of zinc supplements to treat and prevent taste changes, a large ran­ domized phase III trial failed to confirm any benefit at the doses studied [34]. Dietary counseling/modification, adding seasoning to food, avoiding unpleasant foods, and food rota­ tion are recommended. Local infection and hyposalivation should be managed if possible.

Trismus Radiation therapy and surgery may lead to fibrosis and scar tissue formation in the orofacial region, neck and shoulders. Fibrosis leads to decreased tissue compliance and contrac­ ture. In the oral cavity, this may involve the oral aperture, tongue mobility, and the masticatory musculature and the surrounding temporomandibular joint. The incidence of tris­ mus is as high as 45% in patients who undergo surgery or radiation therapy which involves the tissues surrounding the TMJ [35, 36]. Trismus is defined as decrease in oral opening due to any cause, with most studies reporting the inter-incisal distance (normal >40  mm in adults). Although there is no consensus on how to define mild, moderate, and severe tris­ mus, in general an inter-incisal distance of between 25 and 35 mm reflects mild-to-moderate trismus, while severe tris­ mus is present in patients with an inter-incisal distance of less than 25  mm. When trismus is severe, patients may be restricted to a liquid or puree diet. Severe trismus also limits the mobility of the tongue impacting speech, mastication, and deglutition. Finally, trismus impacts on oral access for dental care (hygiene, dental treatment, and dental prostheses fit and function) and intubation if needed. It has been hypothesized that prevention of radiation expo­ sure to the tissues of the TMJ may decrease the development of trismus. However, IMRT may not reduce the incidence or severity of trismus [37, 38]. To date, there are no rigorously tested treatments with established efficacy for patients with moderate-to-severe trim­ sus. Early identification of trismus with active physical therapy intervention is the most appropriate course of action. Although studies demonstrate that physical therapy produces only a modest improvement in established trismus, it may prevent progression of disease [39]. In patients with trismus who failed to improve with physical therapy, coronoidectomy may lead to increased jaw opening [40]; however, surgical intervention in fields of RT requires extreme caution. Early studies with pen­ toxyfilline, which affects fibrogenic cytokine production, indi­ cate the potential for improving established trismus; however, the studies are small and require confirmation [41]. Botulinum toxin has been assessed for management of trismus, although benefits are not clearly documented [42].

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Infection Acute and chronic oral infections are associated with sys­ temic chemotherapy and local radiation therapy to the head and neck. Several factors predispose to the development of clinical important infections including (a) mucosal barrier injury, (b) alterations in oral flora, (c) decreased saliva, (d)  preexisting chronic dental and periodontal infection, and (e)  poor dentition. Chemotherapy can be associated with myelosuppression which compromises immune defense mechanisms leading to local and systemic infec­ tions. Common microbial organisms associated with oral infections include anaerobic bacteria, fungal infections such as candidiasis, and activation of latent herpes viruses. Salivary gland hypofunction with resultant reduction in the antimicrobial functions of saliva, and myelosuppression may lead to exacerbation of preexisting sites of chronic infections. The manifestation of oral infections varies from superficial candidal infections that result in mild discomfort to dental abscesses requiring extraction and protracted anti­ biotic therapy. Pretreatment dental assessment, appropriate dental hygiene, and routine oral examination are mandatory to prevent, diagnose, and treat oral infectious complications of therapy.

Growth and Development of Children High-dose chemotherapy can impact orofacial and dental development in children. Radiation therapy in the head and neck in children may impact growth and facial and dental development. The possible effects upon the dentition of cancer therapy include agenesis and alterations in tooth formation and tooth eruption, morphologic changes in enamel, altered crowns of teeth, and shortened and/or con­ ical shape root structures. Dental malformations may result in reduced occlusal vertical dimension and mobility of teeth with agenesis of roots. These changes may not be readily clinically apparent. Diagnostic imaging including cephalometric study is important for documenting the extent of skeletal changes. Individuals in whom the hypo­ thalamus is affected may have delayed or altered matura­ tion and sexual development.

Compromised Wound Healing High-dose chemotherapy, selected targeted agents, radiation therapy, myelosuppression, and poor nutritional status may compromise tissue healing. In addition to cancer therapy, comorbid conditions may affect wound healing (e.g., diabetes

J.B. Epstein and B.E. Murphy

mellitus, myelosuppression, anemia, nutritional compromise). In patients who are at risk for poor wound healing, dental pro­ cedures including extractions must be done with due consider­ ation. Guidelines have been developed for dental extractions in oncology patients; however, they are primarily based upon expert opinion. The evidence base for clinical practice is limited; current recommendations include the following: • Expert and minimally traumatic extractions, at least 10 days prior to radiation therapy, or anticipated absolute neutrophil count becoming <500  mm−3; antibiotic pro­ phylaxis if neutrophil count is <1,000  mm−3 is often recommended • Minimizing tissue trauma and primary closure of surgical site, if possible • Platelet support if baseline platelet levels are <40,000 mm−3

Halitosis Halitosis is a poorly studied but a not uncommon complaint in the cancer population. In the general population, halitosis is postulated to be secondary to the production of volatile sulfa compounds by oral bacteria. Well-conducted descrip­ tive studies are not available to provide data on the inci­ dence, etiology, and clinical course of halitosis; however, clinical experience suggests that halitosis may be associated with tissue necrosis, hyposalivation, mouth breathing, poor oral hygiene, altered diet, infection, and oral bleeding. Treatment is directed at the cause when possible [43]. Of particular importance is the identification and treatment of oral infections and persistent or recurrent cancer and tissue necrosis. Increased intensity of oral hygiene including tongue brushing/scraping and frequent use of oral rinses may improve symptoms. The use of agents such as chlorine dioxide, chlorophyll, green tea, or peppermint oil may mask the odor. Severe halitosis may cause significant emotional burden for patients and families, and may result in social isolation and thus, it should be treated aggressively.

Osteonecrosis The risk for osteonecrosis of the jaws are seen in patients fol­ lowing head and neck radiation therapy (osteoradionecrosis – ORN), and in patients treated with bisphosphonates (bisphosphonate associated osteonecrosis – BON). Although much has been written about the potential mechanisms of BON, the etiology remains to be clearly defined. Mucosal necrosis and bone exposure can be asymptomatic or mini­ mally symptomatic and therefore not recognized until late-stage disease is present. Comorbid risk factors include

38  Oral Health and Survivorship: Late Effects of Cancer and Cancer Therapy

diabetes, use of immunosuppressive therapy, and immmuno­ suppression, local trauma, and tobacco use. Prevention is the primary goal, and pretreatment dental management and pre­ ventive dental care to reduce local tissue irritation and dental disease following treatment is critical for both patients under­ going radiation therapy and those for whom bisphosphonate therapy is being initiated [44–47]. In ORN management may include antimicrobials, hyperbaric oxygen, sequestrectomy, and surgery with vascularized free flaps in advanced cases [46, 47]. Other adjunctive approaches are in study [47]. In BON, management includes antimicrobials, gentle sequest­ rectomy, and avoidance of surgery if possible with a number of approaches under investigation [44, 45].

Second Cancers Patients with prior cancers are at increased risk for cancer recurrence and new secondary malignancies. In patients fol­ lowing SCT, increased risk of oral cancers is seen 5–9 years after treatment; three-quarters of these patients have GVHD before oral malignancy and these cancers are associated with past mucositis, xerostomia, and erosive lichenoid changes [27]. The majority of oral cancers are SCC of the tongue, fol­ lowed by salivary gland [27]. The increased risk is related to prior exposure to carcinogens (e.g., tobacco, alcohol) and viral cofactors, and possibly related to prior cancer therapy. Survivors of transplant may are at risk of developing recur­ rence of the primary cancer and post-transplant lymphoprolif­ erative disorders (PTLD), which can manifest in the head and neck and oral cavity as gingival enlargement and masses requiring early detection and diagnosis [48].

Conclusion Acute complications are universal in HNC patients, stemcell transplant patients, and are more common than in cycled chemotherapy. Most acute toxicities resolve over time. However, with increasing numbers of cancer survivors it is important to identify and understand the late oral effects of treatment. Unfortunately, our knowledge of the risk factors, manifestations, sequelae, and treatment of late oral effects is limited. Further research in this arena will enhance our understanding of oral late effects of therapy, thus enabling us to identify preventive strategies and interventions with the potential to ameliorate the symptom burden and improve functional outcomes and quality of life. Although there are many oral late effect issues that require additional research, several recommendations can be made to clinicians based on our current knowledge. First

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and foremost, prevention and management of oral health is best achieved by integrating oral and medical care of cancer survivors. Close communication between the oral health providers and the medical staff is critical. Hyposalivation and xerostomia is the most common and severe late effect of cancer therapy. Aggressive oral hygiene with regular dental follow-up can impact dramatically on dental outcomes. Dietary and nutrition consults can be used to help assess the adequacy of diet, to identify dietary deficiencies, and to develop strategies for dealing with barriers to adequate nutrient intake. Appropriate referral to Speech and Language Pathologists, Lymphedema Therapists, and Physical Thera­ pists can impact physical functioning and minimize symp­ tom burden. Cancer survivors require access to a comprehensive and integrated multidisciplinary cancer care team. By attending to preventive protocols and treatment of late oral effects in a timely and aggressive manner, we can optimize long-term quality of life and limit the impact of treatment sequelae.

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406 12. Flowers MED, Parker PM, Johnston LJ, et  al. Comparison of chronic graft-versus-host disease after transplantation of periph­ eral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial. Blood 2002;100: 415–419. 13. Kruse AL, Gratz KW. Oral carcinoma after hematopoietic stem cell transplantation-a new classification based on a literature review over 30 years. Head Neck Oncol 22 July 2009;1:29. 14. Imanguli MM, Alevizos I, Brown R, Pavletic SZ, Atkinson JC. Oral graft versus host disease. Oral Dis 2008;14:396–412. 15. Wasserman TH, Brizel DM, Henke M, Monnier A, et al. Influence of intravenous amifostine on xerostomia, tumore control and survival after radiotherapy for head and neck cancer: a two year follow-up. Int J Radiat Oncol Biol Phys 2005;63:985–990. 16. Buentzel J, Glatzel M, Mucke R, Micke O, Bruns F. Influence of amifostine on late radiation-toxicity in head and neck cancer: A follow-up study. Anticancer Res 2007;27:1953–1956. 17. Worthington HV, Clarkson JE, Eden OB. Interventions for prevent­ ing oral mucositis for patients receiving cancer treatment. Cochrane Data Base Systematic Rev Oct 17, 2007;4:CD000978. 18. Law A, Kennedy T, Pellitteri P, Wood C, Christie D, Yumen O. Efficacy and safety of subcutaneous amifostine in minimizing radi­ ation-induced toxicities in patients receiving combined-modality treatment for squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. Dec 1 2007;69(5):1361–1368. 19. Scarantino C, LeVeque F, Swann RS, White R, Schulsinger A et al. Effect of pilocarpine during radiation therapy: results of RTOG 97-09a phase III randomized study in head and neck cancer patients. J Support Oncol 2006;4:252–258. 20. Burlage FR, Roesink JM, Kampinga HH, Coppes RP, Terhaard C, Langendijk JA, van Luijk P, Stokman MA, Vissink A. Protection of salivary function by concomitant pilocarpine during radiotherapy: a double-blind, randomized, placebo-controlled study. Int J Radiat Oncol Biol Phys Jan 1 2008;70(1):14–22. 21. Chambers MS, Jones CU, Biel MA, et  al. Open-label, long-term safety study of cevimeline in the treatment of post-irradiation xeros­ tomia. Int J Radiat Oncol Biol Phys 2007;69(5):1369–1376. 22. Chambers MS, Posner M, Jones CU, et  al. Cevimeline for the treatment of post-irradiation xerostomia in patients with head and neck cancer. Int J Radiat Oncol Biol Phys. Jul 15 2007;68(4): 1102–1109. 23. Seikaly H, Jha N, Harris JR, Barnaby P, Liu R, Williams D, McGaw T, Reiger J, Wolfaardt J, Hanson J. Long-term outcomes of subman­ dibular gland transfer for prevention of postradiation xerostomia. Arch Otolaryngol 2004;130(8):956–961. 24. Henson BS, Inglehart MR, Eisbruch A, Ship JA. Preserved salivary output and xerostomia related quality-of-life in head and neck can­ cer patients receiving parotid-sparing radiotherapy. Oral Oncol 2001;1:84–93. 25. Lin A, Kim HM, Terrell JE, Dawson LA, Ship JA, Eisbruch A. Quality of life after parotid sparing IMRT for head and neck cancer: A prospective longitudinal study. Int J Radiat Oncol Biol Phys 2003;57(12):61–70. 26. Pacholke HD, Amdur RJ, Morris CG, et al. Late xerostomia after intensity-modulated radiation therapy versus conventional radio­ therapy. Am J Clin Oncol 2005;28(4):351–358. 27. Schubert MM, Correa ME. Oral graft versus host disease. Dent Clin North Am 2008;52:79–109. 28. Epstein JB, Elad S, Eliav E, Jurevic R, Benoliel R, Orofacial pain in cancer Part II: clinical perspectives and management. J Dent Res 2007;86:506–18.

J.B. Epstein and B.E. Murphy 29. Yamashita H, Nakagawa K, Hosoi Y, Kurokawa A, Fukuda Y, Matsumoto I, Misaka T, Abe K. Umami taste dysfunction in patients receiving radiotherapy for head and neck cancer. Oral Oncol 2009;45:e19–e23. 30. Shi HB, Masuda M, Umezaki T, Kuratomi Y, Yamamoto T, Komiyama S. Irradiation impairment of umami taste in patients with head and neck cancer. Auris Nasus Larynx 2004;31:401–406. 31. Peregrin T. Improving taste sensation in patients who have under­ gone chemotherapy or radiation therapy. J Am Diet Assoc 2006;106:15–40. 32. Yamahita H, Nakagawa K, Nakamura N, Abe K, Asakage T, et al. Relation between acute and late irradiation impairment of four basic tastes and irradiated tongue volume in patients with head and neck cancer. Int J Radiat Oncol Biol Phys 2006;66:1422–1429. 33. Sandow PL, Hejrat-Yazdi M, Heft MW. Taste loss and recovery following radiation therapy. J Dent Res 2006;85:608–611. 34. Halyard MY, Jatoi A, Sloan JA, Bearden JD 3rd, Vora SA, et al. Does zinc sulfate prevent therapy-induced taste alterations in head and neck cancer patients? Results of phase III double-blind, placebocontrolled trial from the North Central Cancer Treatment Group (N01C4). Int J Radiat Oncol Biol Phys 2007;67:1318–1322. 35. Dijkstra DU, Kalk WW, Roodenberg JL. Trismus in head and neck oncology: a systematic review. Oral Oncol 2004;40:879–889. 36. Louse Kent M, Brennan MT, Noll JL, Fox PC, Burri SH, et  al. Radiation-induced trismus in head and neck cancer patients. Support Care Cancer 2008;16:305–309. 37. Gomez DR, Zhung JE, Bomez J, Chan K, Wu AJ, et al. Intensitymodulated radiotherapy in postoperative treatment of oral cavity cancers. Int J Radiat Oncol Biol Phys 2009;73:1096–1103. 38. Hsiung CY, Huang EY, Ting HM, Huang HY. Intensity-modulated radiotherapy for nasopharyngeal carcinoma: the reduction of radia­ tion-induced trismus. Br J Radiol 2008;81:809–814. 39. Shulmann DH, Shipman B, Willis FB. Treating trismus with dynamic splinting: a cohort case series. Adv Ther 2008;25:9–16. 40. Bhrany AD, Izzard M, Wood AJ, Futran ND. Coroniodectomy for the treatment of trismus in head and neck cancer patients. Laryngoscope 2007;117:1052–1056. 41. Nieder C, Zimmermann FB, Adam M, Mools M. The role of pen­ toxyfilline as a modifier of radiation therapy. Cancer Treat Rev 2005;44:8–55. 42. Hartl DM, Cohen M, Julieron M, Marandas P, Janot F, Bourhis J. Botulinum toxin for radiation-induced facial pain and trismus. Otolaryngol Head Neck Surg 2008;138:459–463. 43. Loesche WJ. Microbiology and treatment of halitosis. Curr Infect Dis Rep 2003;5:220–226. 44. Migliorati CA, Siegel MA, Elting LS. Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treat­ ment. Lancet Oncology 2006;7:508–514. 45. Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007;65:369–376. 46. Teng MS, Futran ND. Osteoradionecrosis of the mandible. Curr Opin Otolaryngol Head Neck Surg 2005;13:217–221. 47. Pitak-Arnnop P, Sader R, et al. Management of osteoradionecrosis of the jaws: an analysis of evidence. Eur J Surg Oncol 2008 Oct;34(10):1123–1134. 48. Landgren O, Gilbert ES, Rizzo JD, Socie G, Banks PM et al. Risk factors for lymphoproliferative disorders after allogeneic hematopoi­ etic cell transplantation. Blood 2009;113:6263–6264.

Chapter 39

Survivorship: Psychosocial, Physical Issues, and Insomnia Melissa Y. Carpentier, Tammy Weitzmann, Ziv Amir, Grace E. Dean, and Ian N. Olver

Those who survive cancer may have to adapt to residual physical affects from the cancer, late and persisting side effects from the therapy, and co-morbid illnesses, which increase with age. The psychosocial impact of surviving cancer and the adjustment to returning to everyday life events can be a great challenge. First we will consider the psychological impact and the symptoms which may require treatment.

Depression As increasing numbers of cancer patients are entering survivorship, greater research attention has been directed to a number of psychosocial issues that can often accompany a history of cancer diagnosis and treatment. Depression, in particular, has received considerable attention. Prevalence rates of depression among individuals recently diagnosed with or currently being treated for cancer range from 10 to 25%, as compared to 6.6% in the general population [1, 2]. Less researched, however, is the extent of depressive symptoms among longer-term cancer survivors, with findings in this area largely equivocal in nature [3]. Some population-based studies have found higher levels of depressive symptoms among colorectal cancer survivors as compared to matched or normative populations, yet other studies with breast and testicular cancer survivors have not demonstrated such differences [4–7]. These latter results have recently been confirmed by Pirl et al. and Keating et al., who found that longer-term cancer survivors are not at increased odds of major depressive disorder (MDD), although they may experience greater impairment from MDD in their home, social, and work life as compared to the general population [3, 8]. In light of the inconsistency of findings across studies, it is evident that

M.Y. Carpentier () Department of Oral Medicine Pediatrics, Indiana University School of Medicine, 401 West 10th St., Suite 1001, Indianapolis, IN 46202, USA e-mail: [email protected]

longitudinal research is necessary to confirm previous findings and inform future efforts at intervention throughout critical points in treatment and/or survivorship.

Anxiety Another psychosocial issue that has been examined in cancer populations is anxiety, although it is important to note that our understanding of anxiety in cancer is still fairly limited. The reason for this stems from the fact that anxiety following a cancer diagnosis and treatment is not necessarily abnormal or problematic and, rather, may represent a constructive part of one’s coping with a very real threat, such as cancer recurrence [9]. Our limited understanding of the nature of anxiety in cancer survivors is illustrated by the wide range of prevalence estimates of abnormal anxiety documented in cancer populations [10]. For instance, one review of the literature has found anxiety prevalence rates ranging from 0.9 to 49%, while other individual studies using standardized interview and diagnostic criteria have found a more narrow prevalence range, from 1.3 to 23% [11, 12]. These results stand in contrast to yet another investigation which has documented that 77% of its sample of 913 cancer survivors reported experiencing anxiety within 2 years of treatment [13]. Potential explanations for such variable ranges of anxiety symptoms include (1) varying definitions of what constitutes morbid anxiety, (2) social and/or demographic factors, and (3) cancer diagnosis and/or treatment factors that may impact anxiety [10]. For those with a single type of anxiety, phobic anxiety appears to be the most prevalent, although the largest group of cancer patients appears to consist of those with several co-existing forms of anxiety [10]. Moreover, anxiety appears to increase as illness progresses, such that more extensive disease is associated with a greater prevalence of anxiety [14]. Collectively, this line of research suggests that anxiety represents a significant problem for many cancer survivors and requires a continued research focus on careful delineation of an appropriate taxonomy for what constitutes morbid anxiety [15].

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_39, © Multinational Association for Supportive Care in Cancer Society 2011

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Posttraumatic Stress Given the threat to life and profound sense of fear, devastation, and/or lack of control inherent in a cancer diagnosis and treatment, research over the past two decades has increasingly focused on assessment of posttraumatic stress disorder (PTSD) symptoms among cancer survivors. Cancer-related PTSD prevalence rates vary markedly based on many factors, including the time since diagnosis and variability in assessment methods and instruments. With the use of diagnostic clinical interviews (e.g., Structured Clinical Interview for DSM-IV, Clinician Administered PTSD Scale – Structured Interview), PTSD rates range from 0 to 32%, whereas PTSD rates based on self-report instruments (e.g., PTSD Checklist – Civilian Version) range from 5 to 19% [16–22]. PTSD symptoms decline considerably within 3 months post-diagnosis or following treatment completion [23]. Nevertheless, investigations assessing lifetime rates of cancer-related PTSD (i.e., retrospective report of PTSD symptoms at any point since cancer diagnosis) suggest rates ranging from 3 to 35% [23, 24]. Taken together, research on cancer survivors generally indicates that the majority do not meet the full criteria for a PTSD diagnosis. Nevertheless, other investigations have found that many survivors report at least one or more symptoms of PTSD and would clearly benefit from targeted intervention based on their particular cluster of symptoms [18, 19, 21, 25].

Psychosocial Sequelae in Pediatric Cancer Survivors Much of what we know regarding the psychosocial sequelae of pediatric cancer survivors stems from the Childhood Cancer Survivor Study (CCSS), a national cohort study of psychological and health-related quality of life in adult survivors of pediatric cancer as compared to a matched cohort of siblings and population norms. Results from the CCSS suggest that most survivors are psychologically healthy and report good life satisfaction; however, a significant proportion report more symptoms of global distress and poorer physical, although not emotional, health-related quality of life [26]. Risk factors for distress and lowered quality of life include female gender, lower educational attainment, unmarried status, annual household income less than $20,000, unemployment, lack of health insurance, and presence of a major medical condition. Pediatric brain tumor survivors are a particularly vulnerable group, demonstrating lower rates of future life satisfaction, as well as higher rates of psychological distress, including depression and somatization, and more symptoms of fatigue and daytime sleepiness [27–29].

M.Y. Carpentier et al.

Taken together, it is evident that a majority of adult cancer survivors do not have evidence of significant symptoms of depression, anxiety, and/or posttraumatic stress, although some level of symptomatology does exist for many survivors. Although such findings are promising, it must be emphasized that a wide variability exists across multiple study findings, likely due to the many methodological limitations present in this type of research (e.g., small sample sizes, varying assessment instruments). In contrast, research with pediatric cancer survivors has seen a much more standardized approach toward assessment of psychosocial sequelae of cancer survivors. Research with pediatric cancer survivors has found that a significant proportion experiences difficulty with psychological distress and physical health-related quality of life. Significant risk factors for psychosocial distress and specific subgroups at-risk for distress have also been identified. Across both pediatric and adult cancer survivorship research, though, it is evident that prospective, longitudinal research with attention to standardized assessment instruments is necessary to confirm previous findings and inform future efforts at intervention throughout critical points in survivorship.

Adjustment Disorders and Cancer Survivorship Adjustment disorder is a stress-related, short-term, nonpsychotic condition. Patients are seen as overwhelmed or intense in their reactions/responses to situations or events happening to them. Behavioral and emotional responses/reactions are experienced as a direct manifestation to an identifiable stressful event or change in an individual’s life routine [30]. The Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association defines adjustment disorder as a “maladaptive reaction to an identifiable psychosocial stressor, or stressors that occurs within 3 months after onset of that stressor” [31]. Adjustment disorder is noted to be a common condition in the medically ill as well as the cancer survivorship population. Snyder and colleagues showed that as much as 22.6% in clinical populations are affected [32]. Depressed mood was cited as one of the most common subtypes of adjustment disorder with 11.6% affected, followed by adjustment disorder with anxious mood, where anxiety is the prominent clinical feature. In their study of long-term Hodgkin lymphoma survivors, Fobair and colleagues identified an 18% occurrence of depression, and Weddington and colleagues noted that 0% of the 35 extremity sarcoma survivors followed long-term met the diagnostic criteria for a psychiatric disorder [33, 34]. Grassi and Rosti’s study evaluated the prevalence of psychiatric disorders and psychosocial adjustment in long-term cancer survivors and found that over

39  Survivorship: Psychosocial, Physical Issues, and Insomnia

a third of the long-term survivors’ studied were found to have a psychiatric diagnosis compared to almost half at their baseline assessment [35]. Furthermore, this study by Grassi and Rosti also revealed that those patients in their study who did present with adjustment disorders at their time of initial diagnosis, tended to do worse over time as they entered the survivorship phase of their care (chronic disturbances, generalized anxiety, and dysthymia).

Treatment Survivors can have both short- and long-term psychological effects from their cancer experience. Furthermore, attempting to regain control, self efficacy as well as a new sense of identity, often will take time, effort, and a great deal of precious energy on the Survivor’s behalf. As clinicians, it is important to be able to tease out what may be most helpful to survivors as we meet them at this juncture of their care. Expressive supportive therapy, and/or cognitive behavioral therapy alone or in conjunction with pharmacological treatment (when indicated) are proving to be common forms of treatment for cancer survivors. All forms of therapy and treatment must be tailored to the survivor’s needs. Expressive supportive therapy encourages the open expression of emotions and feelings while attempting to reduce symptoms of anxiety and strengthening survivors coping strategies. This form of therapy can be held individually or in group settings [36]. Cognitive Behavioral interventions work by identifying and changing thoughts and feelings which contribute to maladaptive coping strategies. Often they are used in conjunction with relaxation and stress management techniques to enhance survivors coping strategies and reduce symptoms. The overall goal of all of these interventions is to facilitate the expression of feelings, build a secure and supportive therapeutic relationship and safe environment which will lead to strengthening the survivor’s sense of self and enhancement of coping strategies. Our efforts as oncology clinicians should be focused on improving our knowledge base about the various emotional, psychological, and social consequences of cancer care and its treatments. The importance of early identification of emotional/psychological issues in patients receiving cancer care becomes important, if we consider that emotional/ psychological complications can negatively impact on the patient’s conditions over time and impair their quality of life. We must stay attuned to those patients who do not have access to local and community-based resources or few social supports to aid them throughout their cancer experience. Our goal is always to enhance our patients coping, reduce symptoms of anxiety or depression, and strengthen their sense of efficacy. Finally, it is by maintaining a model of continuity of

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psychosocial care for long-term cancer survivors that we may be able to better recognize and treat the emotional and psychological disorders that might arise.

Social Difficulties in Cancer For an increasing proportion of the cancer patient population, survival becomes a way of life. Advances in cancer care are responsible for the increased survival rate but have not prevented social problems from developing. The detection and characterization of social problems may lead to an improvement in the care of cancer patients and result in enhanced patient well-being. Nevertheless, addressing social problems has a relatively low priority in oncology. Defining social problems is difficult, the range of potential problems is enormous and there may be complex interactions between social problems which are a direct result of cancer and its treatment and those problems which are an underlying reflection of the life, social, or economic status of the individual patient. Cancer patients belong to diverse backgrounds with differing social histories. They belong to families, local communities, and the wider world. Furthermore, patients have responsibilities in the home, the workplace, and recreationally. A cancer diagnosis may affect any of these duties and might result in a range of potential social problems. However, there is fairly little knowledge about the range and effects of social problems.

Family and Other Support Networks Cancer affects not just those who have the disease but also their caregivers and families. Most of the research on the impact of cancer on the family has related more to care giving than to the family as a unit. There is evidence on emotional distress and behavioral disruption in family members; however, the sources of these changes remained unclear [37]. Furthermore, a systematic review of the literature regarding the quality of life (QoL) of family of caregivers of patients with cancer indicates that none of the tools, used in the reviewed literature to evaluate the QoL, addressed every domain of QoL identified as important for caregivers; in particular, economic and spiritual well-being were often neglected [38]. Several studies have suggested that levels of social functioning are similar in survivors and control groups [39, 40]. In contrast, a survey of ovarian cancer survivors revealed that 23% of the women reported poor social functioning scores, which may be related to distress [41]. Survivors have

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expressed satisfaction with both their marital status and social contact [42]. However, other survivors have cited their diagnosis as the reason for their divorce [43]. Differences in interaction with family and friends were reported. Joly et al. reported friendships were more likely to remain intact for survivors (testicular cancer) than the health comparison group [44]. Conversely, younger women diagnosed with breast cancer reported a decrease in size and amount of their support network due to their diagnosis [45]. Other breast cancer survivors reported that relatives were closer but friends often avoided them [46].

Sexuality and Body Image Sexual problems are relatively common in the general population, and new problems may result from cancer and its treatment. Sexual problems were reported by survivors of breast, gynecological, testicular cancers, leukemia, and lymphoma [41, 44, 45, 47–49]. Survivors of Hodgkin ­disease reported significantly less satisfaction with their sex lives compared with matched controls [39]. Changes in body image since diagnosis had an impact on reported problems [49]. Significantly more survivors of breast cancer have reported lack of sexual interest, lack of enjoyment, and lack of arousal in contrast to their healthy friends [50]. Many survivors of various cancer sites reported significant concerns about body image. Nearly a third of Bone Marrow Transplant survivors were dissatisfied with their appearance, which had an impact on their sexual functioning, sexual appeal, the ability to share warmth and intimacy or interest in sexual thoughts or feelings [49].

The Economic Impact of Cancer Many people with cancer diagnoses want to regain routines of family and work life; however, one difficult issue for many of them is maintaining financial stability during and after cancer treatment. The impact of cancer on people’s working lives is an increasingly important concern. Returning to paid work after a cancer diagnosis is an important milestone in the transition from patient to survivor for many people of working age [51]. However, cancer survivors experience numerous dimensions of disadvantage in the labor market compared to the general population. These include lower employment rates and higher rates of disability and work limitation [52]. One barrier to returning to work is the lack of worthwhile advice regarding the appropriate time to get back to work [53].

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Even though the risk of unemployment is higher in cancer survivors, the unemployment rate amongst survivors across all studies was 34%, thus many survivors do return to work. There is evidence showing that most cancer survivors, who were in paid employment prior to diagnosis, return to work, or maintain their employment during the 18 months following completion of their primary treatment [54, 55]. A UK study reported that approximately 83% of cancer survivors returned to work, but over half of those returning were off work for 6 months or more, a scenario that may have caused a degree of income loss [56]. Furthermore, the vast majority of people affected by cancer report some degree of economic hardship resulting from extra costs due to cancer. For example, in studies conducted to assess cancer costs, costs pertaining to transport have been cited along with costs involved in eating away, “health food,” special diets and supplements, special clothing, telephone calls, etc. [57]. Out-of-pocket expenses as a percentage of total income are highest amongst those patients on a low income, younger age, single parents, and those living rurally [between 15 and 27% of annual income spent on health-care-related expenses] [58, 59]. A number of studies report that patients had to cut back and/or adjust other outgoings to meet additional costs due to cancer. A way of meeting additional costs was borrowing and the use of credit [60, 61]. Finally, a diagnosis and treatment for cancer impacts on everyday lives of patients: at home, work and leisure. Social difficulties may be resolved by patients with no reference to anyone outside their circle of family and friends [62]. However, others might benefit from information or assistance from health- and social-care professionals. Evidence shows that most patients and their family members are not receiving these services [63]. Introducing routine assessment of social difficulties may provide a better way of identifying patients with problems who might benefit from discussion and possible referral to expert service and contribute to patients’ well-being.

Physical Symptoms Having survived cancer and its treatment the physical sequelae are often the result of the interaction of the late side effects of treatment, the effects of the tumor and co-morbid conditions impacting on organ systems. It has been estimated that at 30 years almost 75% survivors have a chronic health condition [64]. Given that the death rate from non-cancer causes is higher in people who have had cancer than in the general population, education about lifestyle modification early on in the course of cancer and its treatment may be important, particularly in those with childhood cancer who

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are at increased risk of conditions such as obesity and heart disease [64, 65]. Of the late side effects of treatment, the most confronting is the development of a second malignancy. Much of the data of the risk of radiation comes from diseases treated with curative intent, like Hodgkin disease, or the treatment of childhood cancers. There is a long latency between exposure and the development of the cancer (median 7 years) in tissues in the radiation field. The risk increases with radiation dose and is greater in younger patients and when concomitant chemotherapy is given. Overall the risk of a radiationinduced cancer is 1–2% at 10 years [66]. The major secondary malignancy induced by chemotherapy is acute myeloid leukemia. There are different types, one being induced by alkylating agents (peaking after 5 years) and often involving changes on chromosomes 5 and 7, including the platinums and topoisomerase inhibitors. The epipodophyllotoxins and the intercalating anthracyclines have a shorter induction period (2–3 years) and are associated with translocations such as those involving chromosome bands 11q23, 21q22, or 3q2 [67, 68]. Other second cancers include non-Hodgkin lymphomas after treatment of Hodgkin lymphoma, bladder cancer after cyclophosphamide, lung cancers after treating non-Hodgkin lymphoma, leukemia and solid tumors after treating testicular cancer, leukemias, gastrointestinal, and urogenital cancers after treating ovarian cancer and indeed second primary breast cancer, ovarian cancer or leukemia after treating breast cancer, and specifically endometrial cancer after the treatment of breast cancer with tamoxifen. The risk of second cancers after the treatment of children is 6.2fold compared to the general population [68]. Late effects can be generalized, such as fatigue, or organ specific. They can be specific to particular treatments, like specific drugs, or part of more generalized late effects such as the radiation fibrosis syndrome [69]. The late effect of treatment on the heart is the development of cardiomyopathy, measured as a drop in the ejection fraction preceding the symptoms of cardiac failure. Commonly this is a cumulative toxicity of anthracyclines (at doses exceeding 450  mg/m2). Trastuzumab has also been associated with cardiomyopathy, but with some recovery seen over several months. Radiotherapy, particularly to the left breast, has resulted in an excess of late cardiac mortality associated with a higher than expected incidence of atherosclerosis of the coronary arteries [70, 71]. The late consequence of pulmonary toxicity is fibrosis. Preceded by the measurement of reduced diffusing capacity due to the restrictive defect, the clinical manifestations are breathlessness and a dry cough which can be accompanied by fevers and malaise. Pulmonary toxicity may be caused by the cumulative toxicity of drugs such as bleomycin at cumulative doses over 360 mg or other drugs including the

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alkylating agents, cyclophosphamide, busulphan, carmustine, antimetabolites methotrexate, and cytosine arabinoside and procarbazine [72]. Fibrosis also occurs as a late effect of radiotherapy and is determined by the dose and fractionation, concomitant use of chemotherapy, and co-morbid conditions. Peripheral neuropathy is a common chronic late effect of a many chemotherapy agents including the platinums (cisplatin, carboplatin, and oxaliplatin) the taxanes (paclitaxel and docetaxel) the vinca alkaloids (vincristine vinblastine, vinorelbine), and the newer targeted therapies (such as bortezomib and thalidomide). Platinum analogues damage the neuron cells causing severe sensory deficits, sensory ataxia, and pain whereas the other agents cause a motor and sensory length-dependent axonal neuropathy, resulting in paresthesias and weakness in a distal glove and stocking pattern. Radiation fibrosis can damage the nervous system in the periphery, particularly in areas such as the brachial plexus, and the patient may complain of muscle cramps, pain, and weakness [73, 74]. Encephalopathy can be a late effect of chemotherapy [75]. Methotrexate can cause motor symptoms and cranial nerve palsies, particularly when given intrathecally or with radiation. Cytosine arabinoside is associated with ataxia and disorientation, while 5 fluorouracil is associated with cerebellar ataxia as well as upper motor neuron symptoms and somnolence. Late cognitive dysfunction can be a problem with cranial irradiation in the aged. Radiation necrosis in the central nervous system can manifest with symptoms ranging from headaches to seizures, paralysis, and coma. Other organs in the field can include the pituitary gland causing multiple endocrine and biochemical abnormalities, the optic chiasm, which when irradiated with too high a dose can result in blindness, and the lens of the eye, which can develop cataracts. The most common cytotoxic to cause renal toxicity is cis­ platin which causes proximal tubular damage. Methotrexate can damage kidneys by precipitating in the tubules in an acidic environment while supportive care drugs such as the bisphosphonates used to treat hypercalcemia and reduce bone symptoms can also result in decreased renal function [76, 77]. The liver can also be damaged by cytotoxics such as methotrexate or cytosine arabinoside. Bleomycin is associated with elevations in bilirubin while dacarbazine can cause hepatic necrosis. Irinotecan is associated with steatohepatitis and oxaliplatin with sinusoidal dilatation. There is concern about bevacizumab and cetuximab and liver regeneration post hepatectomy [78]. Drugs which are metabolized by the liver must be given in reduced doses with liver dysfunction.

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Many other organ systems such as the genitourinary system or the lymphatic system can be impaired in the long term by treatment and are discussed elsewhere in this book. With respect to the more general symptoms, there is a separate chapter on fatigue. Other symptoms such as insomnia can occur at all stages of treatment but will be discussed here because it can be an important issue for survivors.

Insomnia Insomnia is the most common sleep disturbance reported by healthy adults and patients with cancer [79]. While insomnia is common, few researchers have examined insomnia in patients with cancer as a primary variable. In fact, much of the evidence for insomnia in patients with cancer has emerged from research focusing on symptoms and quality of life. In the clinical setting, insomnia is under recognized and undermanaged among patients with cancer, particularly among those receiving chemotherapy [80]. Sleep is a fundamental biological process that is as essential to physical health as breathing or eating [81]. Although sleep is often thought of as a time of rest and recovery from the stresses of everyday life, research is revealing that sleep is a dynamic activity. Sleep plays an important role in many aspects of health and disease, including metabolism [82], cardiovascular disease [83], quality of life [84], and even caregiver burden [85]. The consequences of insufficient sleep on neurobehavioral and cognitive functioning, such as deficits in sustained attention, working memory, memory retention, decision making and hand–eye coordination is well documented [86–88].

Definition Insomnia is divided into primary and secondary insomnia. Primary insomnia includes sleep-disordered breathing (SDB)/sleep apnea, restless leg syndrome (RLS)/periodic limb movement disorder, and circadian dysfunction. Secondary insomnia arises out of underlying medical or psychiatric disorders or medication effects. The majority of patients with cancer suffer from secondary insomnia [89]. Insomnia symptoms include difficulty falling asleep, difficulty staying asleep, early morning awakening, and daytime sleepiness that negatively impacts functioning (Table 39.1). A key component in this definition is the difficulty initiating or returning to sleep. Short sleepers must be distinguished from those with true insomnia by the complaint of daytime dysfunction.

M.Y. Carpentier et al. Table 39.1  General criteria for insomnia in adults • Complaint of difficulty initiating sleep, difficulty maintaining sleep, or waking up too early or sleep that is chronically nonrestorative or poor in quality • Sleep difficulty occurring despite adequate opportunities and circumstances for sleep • At least one of the following forms of daytime impairment related to the nighttime sleep difficulty as reported by the patient: – Fatigue or malaise – Attention, concentration, or memory impairment – Social or vocational dysfunction – Mood disturbance or irritability – Daytime sleepiness – Motivation, energy, or initiative reduction – Proneness for errors or accidents at work or while driving – Tension, headache, or gastrointestinal symptoms in response to sleep loss – Concerns or worries about sleep From the American Academy of Sleep Medicine [118]

Consequences Insomnia is not only of major importance because it is underreported, but because insomnia results in significant sequelae. In patients with cancer, insomnia is associated with fatigue and pain [90, 91], psychological distress, [92] contributes to immunosuppression [93], impaired daytime functioning and poorer quality of life both before [94] and after treatment [95]. An early study using polysomnography (i.e., sleep recordings) compared patients with lung cancer, breast cancer, chronic insomnia, and matched controls and found that patients with lung cancer slept as poorly as insomniacs but were genuinely unaware of how poorly they slept [96]. Indeed, current findings from sleep deprivation studies involving healthy controls revealed that sleep-deprived individuals are inadequate judges of their sleepiness and their ability to function [97]. A Canadian study involving 434 newly diagnosed cancer patients reported that symptom distress was a predictor of survival in a subset of 82 lung cancer patients who reported high levels of fatigue (39%) and insomnia (31%) [98]. In addition, there is a growing body of evidence that implies sleep deprivation may impact mortality [81, 99–103].

Prevalence The prevalence data has been challenging to evaluate as a result of the wide estimates ranging from 24 to 95%. Most studies report that approximately half of patients with cancer suffer from insomnia, with 23–44% reporting insomnia complaints up to several years following diagnosis and treatment. A recent study involving 991 cancer patients who completed various self-report scales and an insomnia

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39  Survivorship: Psychosocial, Physical Issues, and Insomnia

diagnostic interview at the perioperative phase (T1) and 2 months later (T2), reported that 28.5% of the patients met the diagnostic criteria for an insomnia syndrome (T1), and 31.0% had insomnia symptoms; these rates decreased to 26.2 and 22.2%, respectively, at T2 [104]. The extent of sleep problems seems to vary with different types of cancer. The highest rates of insomnia were found in breast cancer patients, whereas the lowest rates were obtained in prostate cancer patients. Several characteristics were associated with an increased risk for insomnia: female sex, the presence of an arousability trait, a diagnosis of head and neck cancer, the administration of surgery, an increase in anxiety symptoms between T1 and T2, and higher baseline levels and increases between T1 and T2 in dysfunctional beliefs about sleep, sleep monitoring, and maladaptive sleep behaviors. A population-based survey of 1,372 women who completed primary treatment for early-stage breast cancer in the USA reported “disturbed” sleep in 57% of respondents using a single item from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [105]. Parker and colleagues collected 42 h of continuous in-home ambulatory polysomnography recordings on 114 participants with advanced cancer (solid tumors) and reported reduced quality and quantity of nocturnal sleep and episodes of sleep scattered throughout the day [106]. Participants experienced severe difficulty to maintain both the sleep and waking states, being awake approximately 25% of the time during sleep. In addition, lung cancer patients had more nocturnal stage 1 sleep and a higher index of awakenings than other cancer participants. These three recent studies are indicative of the methodologies that vary widely in how insomnia is diagnosed. Unfortunately, there are no standard quantitative criteria to diagnose insomnia, and standardized and operationally defined criteria are lacking, which contributes to the variability in prevalence rates.

Causes of Insomnia A variety of theories and models have been proposed to explain the causes for insomnia [107]. The classic model of insomnia by Spielman identifies three factors that are applicable for studying sleep in patients with cancer (Table 39.2) [108]. The first, predisposing factors are those psychological or biological characteristics that increase vulnerability, or predisposition, to sleep disturbances. In accord with the model, predisposing factors are not a direct cause of sleep disturbances, but they increase the risk that an individual will develop sleep disturbances. Secondly, precipitating factors are the life events and the medical, environmental, or psychological factors that trigger sleep disturbances. Finally,

Table 39.2  Three-factor model of insomnia in cancer 1.  Predisposing factors (increased risk for sleep disturbances) (a) Older age – increased age is associated with poorer sleep quality (b) Female – women typically report poorer sleep quality than men (c) Hyperarousability trait – tendency to be easily aroused (d) Personal or family history of sleep disorder (e) Personal or family history of a mood disorder (anxiety-heightened cortical and peripheral arousal) 2.  Precipitating factors (triggers for disturbed sleep) (a) Acute distress related to cancer diagnosis and rigorous therapeutic schedules (b) Cancer disease and treatment side effects (c) Medications for treatment side effects 3.  Perpetuating factors (maintain sleep disturbances) (a) Poor sleep hygiene – irregular sleep schedules and daytime napping (b) Poor sleeping environment – light, noise, temperature Adapted from [89] with permission

perpetuating factors are those elements that maintain or exacerbate sleep disturbances.

Assessment Because of the complex nature of insomnia, no single parameter is recommended to screen for insomnia in the general population or in patients with cancer [109]. At the minimum, a sleep history should be conducted when a patient is identified with a sleep complaint (Table  39.3). Using a structure interview guide to obtain the nature, history and severity of insomnia reduces subject burden and improves clinical efficiency. Special attention is required to determine whether medication-induced insomnia is a probability (i.e., bronchodilators, central nervous system depressants, chemotherapeutics, steroids, etc.). The Epworth Sleepiness Scale, an eight-item self-report survey (scores range from 0 to 24, normal <10) is routinely used in sleep clinics to identify sleepy patients. This survey can be found a http://www.sleepmed.com/new_patient/i7.pdf. Additionally, a 2-week sleep diary should be obtained to identify sleep– wake patterns from day-to-day and week-to-week variability (Table  39.4). The sleep diary yields a variety of sleep parameters including sleep onset latency (i.e., minutes to fall asleep), total sleep time (TST), wake after sleep onset (WASO), time in bed (TIB), and sleep efficiency (SE), which is a percentage calculated by dividing TST by TIB and multiplying by 100. Although no specific quantitative sleep parameters define insomnia disorder, common complaints for insomnia patients are an average sleep onset latency >30  min, WASO >30  min, SE <85%, and/or TST <6.5 h [110]. Because sleep diaries are subjective estimates, obtaining corroboration from a bed partner would be beneficial.

414 Table 39.3  Sleep history Describe history of sleep complaint Onset, precipitants, course, frequency Daytime consequences Ameliorating and exacerbating factors Behaviors (e.g. pre-bedtime activities) Emotions (e.g. frustration) Cognitions (“worrying about lack of sleep”) Substance use (alcohol, caffeine, nicotine) Review comorbidities (e.g. heart disease, diabetes, arthritis, mood disorders, etc.) Medication use, both prescribed and OTC History about patient’s sleep from bed partner, where possible

Table 39.4  US FDA-approved pharmacological agents for the treatment of insomnia Drug name Type Action Dose (mg) Half-life (h) Estazolam 1 BzRA 1–2 10–24 Flurazepam 1 BzRA 15–30 48–120 Temazepam 1 BzRA 15–30 8–20 Triazolam 1 BzRA 0.125–0.25 2.4 Quazepam 1 BzRA 7.5–15 48–120 Zolpidem 2 BzRA 5–10 1.4–3.8 Zolpidem ER 2 BzRA 6.25–12.5 2.8 Zaleplon 2 BzRA 5–20 1 Eszopiclone 2 BzRA 1–3 6 Ramelteon 3 MtRa 8 1–2.6 Type 1 indicates benzodiazepines, type 2 indicates non-benzodiazepines, and type 3 indicates melatonin From [120], used with permission

M.Y. Carpentier et al.

sleep, falls, and memory and performance impairment. Nonbenzodiazepine pharmaceuticals have shorter active metabolic half-lives and, as a result are less associated with daytime impairments. Ninety-six percent of prescriptions for insomnia in the USA involved zolpidem, temazepam, and trazodone [114]. These prescribed medications provide short-term relief, but their efficacy has not been demonstrated beyond 12 weeks [115]. Sleep clinicians often recommend a 1 month trial due to the lack of long-term efficacy data and the potential issues with rebound insomnia and withdrawal. No intervention studies have tested the effects of sedative/ hypnotic pharmacologicals in patients with cancer [109]. Regardless, short-term hypnotic treatment should be supplemented with behavioral and cognitive therapies whenever possible.

Nonpharmacologic Treatments Cognitive behavior therapy involves a variety of treatment strategies to treat insomnia. Behavioral therapies appear to be as effective as pharmacological treatments [116]. Cognitive behavioral therapy is likely to be effective in cancer patients with insomnia according to a recent review [109]. Table 39.5 presents primary components, goals, and interventions that can be delivered by health-care providers working with cancer patients who are positively screened for insomnia. The table includes primary components of cognitive behavioral treatment for insomnia

Treatment Pharmacologic Treatments In 2005, the National Institutes of Health State of the Science Conference focused on chronic insomnia in adults and reported that the only support for pharmacological treatment of insomnia was with the use of benzodiazepine receptor agonists [111]. Table  39.4 describes the Food and Drug Administration-approved benzodiazepine receptor agonists for insomnia management, which include benzodiazepines, non-benzodiazepines, and ramelteon, a melatonin receptor agonist. Hypnotics are the class of pharmaceuticals most often prescribed for insomnia. Short or intermediate acting benzodiazepines have been shown to have positive effects on sleep latency, TST, and/or WASO in placebo-controlled clinical trials involving noncancer insomniacs [112, 113]. Long-acting benzodiazepines may result in adverse effects such as residual sedation, undesired behaviors during

Table  39.5  Cognitive–behavioral interventions for individuals with sleep problems Focus: Sleep Hygiene Goal: To increase awareness, and encourage changes in daily activities and environmental factors that may be contributing to the sleep problem Intervention • Refute the myth that alcohol promotes sleep • Educate on the importance of avoiding stimulants such as caffeine (e.g., coffee, tea, chocolate, soda) and nicotine in the hours before sleep • Encourage “wind down time” for the last hour before bed • Endorse regular exercise, but not within 3 h of bedtime • Promote a sleep environment with a comfortable bed in a dark and quiet bedroom that is about 65°F • Recommend limiting liquid intake in the hours before bedtime • Address the importance of keeping a regular schedule for bedtime and wake time for each day of the week. Weekends should not be an exception to the schedule • Support spending time outside each day since bright light exposure sets and strengthens the biological clock and helps maintain a healthy sleep–wake cycle (continued)

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39  Survivorship: Psychosocial, Physical Issues, and Insomnia Table 39.5  (continued) Focus: Control Goal: To re-establish the properties of sleep and sleep compatible stimuli with the act of sleeping and to stabilize the sleep/wake timing system Intervention • Discourage the use of the bed for activities other than sleep and sexual activity (e.g., reading, watching television, eating) • Instruct to set alarm for the same time every morning and get up regardless of how much sleep was received the night before. This will strengthen the circadian sleep–wake cycles and lead to regular sleep onset • Educate on the importance of getting into bed only when sleepy • Recommend getting out of bed and go into another room if unable to fall asleep within 15–20 min of going to bed • Direct engagement of quiet activities that are of interest, if unable to sleep, avoiding stimulating activities, foods, nicotine, and beverages • Discourage daytime napping Focus: Relaxation Therapy Goal: To reduce physiological and cognitive arousal Intervention • Demonstrate the process of progressive muscle relaxation • Provide instruction in use of guided imagery • Practice thought stopping techniques: (1) concentrating on unwanted recurring thoughts, and once clearly established (2) saying aloud, “Stop” to interrupt the thought and removing it from the awareness, and (3) then immediately shifting to thoughts that are pleasant and desirable Focus: Cognitive Therapy Goal: To alter beliefs, attitudes, and expectations related to preoccupation with sleep Intervention • Promote cognitive restructuring. (i.e., appraisal of a given situation [sleeplessness] can trigger negative emotions [fear, anxiety] that are incompatible with sleep.) • Refute unrealistic expectations. (i.e., “I must get 8 h of sleep every night.”) • Discourage belief and attitudes that insomnia causes all daytime impairments • Advise sleep only when sleepy vs. trying to sleep • Reframe that a poor night’s sleep is not a catastrophe • Brainstorm how the effects of insomnia can be tolerated until sleep/ wake cycle is restored Focus: Sleep Restriction Goal: To curtail time in bed to actual sleep time, creating a mild sleep deprivation Intervention • Determine sleep efficiency (SE). SE = time asleep/time in bed. (Example: 7 h asleep/9 h in bed = SE of 78%) Establish goal of ³85% SE • To increase SE, recommend that time in bed (TIB) be reduced by 15 min on the previous week’s SE value without reducing TIB to less than 5 h. (Based on above example, reduce TIB to 8 h, 45 min.) • Establish schedule for bedtime. Determine time for wakening, and working backward, determine bedtime. (For example, if normal waking time is 6:00 am and the average hours spent sleeping is 7.5 h each night, the bedtime should be 10:30 PM.). Advise to maintain strict bedtime for 1 week. • Educate that spending extra time in bed to “catch up” on lost sleep is not effective in restoring natural sleep routine • Discourage sleep at times outside of sleep schedule Adapted from [117] with permission

adapted from Arnedt et al. [117] for patients with cancer. Armed with these resources, health-care providers across all settings from the community to acute care, from primary care to comprehensive cancer treatment settings will be better equipped to promote sleep quality, improve quality of life, and potentially to help improve the course of the disease.

Conclusions Surviving cancer can be accompanied by a range of symptoms. The physical symptoms can be residual effects of the cancer or late effects of the therapy. If anticipated some of these can be treated early. Symptoms like fatigue and insomnia may be managed by lifestyle changes such as exercise or alterations in the diet. Anxiety and depression should be identified early and treated. Adjustment disorders can be short term but highlight the need for continued monitoring after cancer treatment. A range of social and economic supports may be required. All aim to maximize a patient’s quality of life after treatment, beyond the assumption that just the absence of cancer will suffice.

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Chapter 40

Spiritual Issues in Supportive Cancer Care Antonella Surbone, Tatsuya Konishi, and Lea Baider

Introduction The field of spiritual and religious support in relation to medicine is growing, as both patients and physicians try to recuperate the humanistic essence of the therapeutic relationship among patients, families, and health professionals. Despite a wealth of scholarly publications and the beginning of empirical research, however, this area remains ambiguous [1]. Different spirituality assessment tools have been proposed, yet their validation and application across different patients and different cultures is difficult. Evidence-based intervention on spirituality is missing, in part because we lack a universally accepted definition of spirituality. The concept of based on Viktor Frankl’s theories of logotherapy, has been adopted in meaning therapy for palliative care on terminal patients [2], along with the concept of “dignity” for terminal patients as a metaphor for spirituality [3]. Outcome evaluation of these or less structured forms of intervention-related to the function of religiosity in cancer patients or the use of “prayer” in oncology settingsposes methodological problems, as spirituality is ineffable and subjective by definition [2, 3]. While the limitations in this chapter are many, we try to delineate the sphere of influence of spirituality and provide clinical guidelines on how to integrate the spiritual dimension in cancer care in different cultural contexts. We address the issue of whether the spiritual dimension of cancer care should be the responsibility of oncology professionals or of dedicated spiritual teams. Finally, we discuss the increasingly important role of chaplaincy in providing ecumenical cross-cultural spiritual support to those cancer patients who request it.

A. Surbone (*) Department of Medicine, Division of Medical Oncology, New York University Medical School, 550 First Ave BCD 556 New York, NY 10016 USA e-mail: [email protected]; [email protected]

Cancer: Responding to Life-Threatening Events In the lifetime of every person, high-stress situations and periods of intense and unanticipated crises occur. Of these life events, those which make the greatest demands on a person’s coping ability are the unexpected ones that are beyond the person’s direct responsibility – such as life-threatening diseases which intrude into and engulf every dimension of the patient’s life. Cancer is one such event. Its unexpectedness and unpredictability, coupled with frequent metaphoric symbolic implication of death and with the emotional response of intense fear, anger, and depression that cancer evokes, has become a frequent paradigm of lack of control, dependency, and arbitrariness in this century. Despite greatly improved odds of cure, long periods of remission and long-term survival with an acceptable quality of life, cancer patients today still experience an internal perception of constant fear, disruption, and ongoing stress. Cancer-related stress may be more extreme and more prolonged than ever before, as cancer patients are now increasingly informed about the nature and prognosis of their illness and of the potential short- and longterm side effects of standard and experimental therapies. On the other hand, they are expected by society to return to their “normal life” once treatments are over, resuming their jobs or regular activities as if being a survivor were not a unique physical, psychological, and spiritual condition [4]. Paradoxically, today’s medical environment contributes toward this increased stress. Patients and families are sometimes overwhelmed with survival statistics, which are as difficult to interpret as they are inapplicable to the individual patient. Patients are often encouraged to seek other opinions, and they face an array of highly sophisticated personal medical decisions. The current emphasis on cancer patients’ rights to know and to choose often translates into a sort of private decision making that creates new and additional stressors, responsibilities, uncertainties, and ambiguities [5]. People respond to cancer’s enormous and multifaceted challenges either rationally and objectively or more subjectively,

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1_40, © Multinational Association for Supportive Care in Cancer Society 2011

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with an uncontrollable flow of emotions, or in both ways at once. The instinctual and rational responses that the individual utilizes to cope with the crisis cannot be neatly separated but rather flow into an indistinguishable confluence of thoughts, feelings, and behaviors. Included in this amalgam is an internal system of beliefs, which is brought to bear at the “zero hours” in one’s life, and which is at the foundation of what we call “spirituality.” [6] For centuries, most individual systems of belief inevitably were derived from formal institutionalized religions. Religious beliefs and language were a part of one’s identity; personal systems of belief were generally shared, regardless of the social, economic, or demographic sphere. In modern Western society, where organized religion has ceded its central position, particular systems of belief, nonetheless, persist at different levels among formalized groups and individual persons. Whether in religious or secular terms, in fact, each person who confronts a life-threatening event instinctively and urgently searches for meaning and for powerful sources of support.

Spirituality: Meaning and Definitions Spirituality has been studied with regard to its contribution to coping with chronic and terminal illness. Spirituality is a broader concept than religiosity and might include aspects of religious faith, in addition to meaning and inner peace [7]. Spirituality is difficult to define. The word “spirit” derives from the Latin “spiritus,” meaning breath. Human minds can be seen as unified by their conscious perception of existence and might hold an innate ability to develop a spiritual propensity and language, which serve the purpose to provide a response to universal existential questions such as where we come from, why we suffer, and why we die. “Spirit” is a life force that vitalizes human life. Yet, as a psychic phenomenon, it is intangible [8]. Through this life force, human beings are motivated to search for the meaning of existence in a “transpersonal” way, which goes beyond the purely individual sphere of one’s perceptions to reach other sources of life and energy that cannot be described or quantified in strictly empirical terms (Fig. 40.1). Spirituality is thus a broad and ill-defined term, encompassing different dimensions and levels of expression, from the generic notion of a “soul” to its anthropological and cultural developments to the many dimensions of faith, including customs and rituals. While a connection with transcendent aspects of human life is at the core of spirituality, this may be manifested in different forms according to the culture and faith of groups or individuals [1]. The personal experience of the transcendent is innate and universal, and in turn, acts as a

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Fig.  40.1  Spirituality as bridging. Quartz crystal marks the passage between two valleys at 3,000 m altitude in the Alps

Table 40.1  Central features of spirituality • Meaning: the ontological significance of life, making sense of life situations, deriving purpose in existence • Value: beliefs and standards that are cherished; having to do with the truth, beauty, and worth of a thought, object, or behavior; often discussed as “ultimate values” • Transcendence: experience and appreciation of a dimension beyond the self; expanding self-boundaries • Connecting: relationship with self, others, God/higher power, and the environment • Becoming: an unfolding of life that demands reflection and experience; includes a sense of who one is and how one knows

foundation of the unique identity of individuals. For some people, transcendence beyond self is represented by a relationship with a single supreme being, such as God or another spiritual entity. For others, transcendence is evident in nature and the cycle of the seasons. For others, the human community and the power of relationships with people represent both transcendence and connectedness as the force of spirituality. Regardless of its specific expression and interpretation, through spirituality people derive meaning and purpose in their lives [9]. The central features of spirituality are listed in Table 40.1 [8]. Spiritual development has been described as a continuum, ranging from a complete disregard for issues in spirituality and faith to what Koenig described as “mature faith,” in which one’s spiritual beliefs are a major organizing principle in one’s life [10]. Mature faith occurs more frequently in elders who have a lifetime of spiritual experience and are intimately involved in answering the spiritual questions raised in the final developmental stage of life in preparation for dying and death. Development of spirituality is a lifetime question that is heightened by the challenges and immediacies of maturation.

40  Spiritual Issues in Supportive Cancer Care

Religion and Spirituality: Differences and Interrelations Expressions of spirituality, including religiousness, are first acquired through families and social networks, verbal and written traditions, and rituals. The meaning of innate spirituality may, therefore, be said to assume a global relevance, while religions are witness to diversities between ethnic and cultural groups and the right of each group and individual to be respected in their beliefs and ways of life. Diverse communities will, therefore, interpret and explain life, illness, and death in their own language [11]. The word “religion” derives from the Latin “relegare”, which means to bind together. Religiosity is a complex phenomenon, which can have a profound impact on the daily lives of human beings and is related to many aspects of the individual subjective experience such as meaning, personal happiness, and the effects of traumatic life events [12]. Various theoretical attempts have been made to describe and define religiosity. Most of the definitions are multidimensional and address different aspects of human experience, systems of belief, religious attitudes and practices and/or behaviors, religious identification, and affiliation [13, 14]. Several authors have investigated religious approaches that may help patients gain more control on their lives with cancer and have studied the associated psychosocial outcomes. Through qualitative studies and reviews of the literature,

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five ways were identified through which religion helps people seek more control over their lives (Table 40.2) [13]. In this multidimensional model, the five coping methods differ as a function of control – primary (personal) versus secondary (divine). Collaborative religious coping reflects both primary and secondary control processes in a balanced and coordinated effort. Pleading for direct intercession also has both active and passive elements. Although ultimate control and responsibility are viewed as belonging to God, what appears to be fatalism may represent a proactive attempt to maintain a sense of control. Religious identification/affiliation is an additional measure of religiosity, whose potential effects on health are highly controversial. While religious identity seems to relate to a social process, the system of belief seems to be a more private aspect of religiosity (Fig. 40.2). Table 40.2  Religion’s way to increase one’s feeling of being in control Collaborative Seeking control in solving problems religious coping through a partnership with God Active religious Turning control over to God after all else surrender has failed Pleading for direct Seeking control indirectly by praying for a intercession miracle or divine intercession Passive religious Waiting for God to control the situation deferral Self-directing Believing that God gives individuals the religious coping tools and resources to solve problems

Fig. 40.2  Spirituality as faith. Views from Jerusalem (courtesy of Prof. Baider)

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Spiritual Counseling in the Clinical Setting: Role of Chaplains Ministers are most commonly regarded as the professional spiritual caregivers, as they have traditionally provided care for the religious and spiritual dimension of the people. Although the care offered by ministers was originally called pastoral care particularly in the Protestant traditions, it is also called spiritual care when it is provided to people from various religious backgrounds [15]. Ministers offering pastoral/spiritual care in settings such as hospitals are generally known as chaplains, and their role is increasingly recognized worldwide (Fig. 40.3). The education and training for hospital chaplains involves specific initial requirements, as well as continuous updating through local, national, and international organization meetings and conferences. The ICPCC (International Committee on Pastoral Care and Counseling) organizes a worldwide congress every four years and regional congress regularly. It includes members from Africa (Nigeria and South Africa), America (Brazil, Canada, and USA), Asia Pacific (Australia, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Philippines, and Thailand), and Europe (Austria, Belgium, Denmark, Finland, France, Germany, Hungary, Ireland, Italy, Norway, Poland, Sweden, and UK) [16]. The ENHCC (European Network of HealthCare Chaplaincy) also schedules a conference every two years. Despite the attempt for unity and uniformity, chaplaincy activities in many countries

Fig. 40.3  Spirituality: connecting with inner self (original: calligraphy entitled “The Awakened (True Self or Spirit)” by Shin’ichi Hisamatsu from Japanese Zen Buddhist Tradition. Reprinted with permission)

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are based on national organizations mainly due to uniqueness of their cultural and historical backgrounds [17]. One of the most essential differences between pastoral/ spiritual care in the church and in the hospital is that the latter is offered to people from various religious backgrounds, which are often different from those of the caregivers. In these cases, care should be provided based on the beliefs and values of the care seeker, without the caregiver imposing his or her own beliefs and values [18]. Special professional training is needed for such situations. The USA boasts well-developed professional chaplaincy and educational organizations (the Association for Clinical Pastoral Education [ACPE] and the Association of Professio­ nal Chaplains [APC]). The APC recommends that there be one chaplain for every 50 in-patients [19]. According to a 1998 US national survey, however, the average number of chaplains per 100 patients was 1.33 [20]. The ACPE provides an educational training program (Clinical Pastoral Education [CPE]), which was established in 1925 and is recognized by the US Department of Education. The program is available at approximately 350 accredited centers in hospitals and has attracted students from various religious backgrounds from all over the world. There are more than 650,000 ACPE graduates since its inception. One of the significant characteristics of the CPE program is that students go through a very intensive process in which they become aware of the different levels and aspects of their own values and beliefs. Students partake in verbatim (a record and analysis of conversations with a care seeker), engage in a spiritual autobiography (an in-depth history of one’s inner and spiritual life), and participate in an interpersonal relationship seminar (a confidential group seminar during which the participants inquire into their own clinical experiences and spiritual dimensions and that of other group members) [18]. To become an APC-certified chaplain in the USA, a candidate must complete the 1-year CPE program and an equivalent of 3 years of graduate-level theological studies, where basic philosophical and theological questions are thoroughly explored and form the foundation for providing professional pastoral care to patients. In many countries, however, the concept of hospital chaplain is relatively new. For example, its earliest introduction in Japan occurred when some Christian hospitals were established in the 1950s. A Buddhist chaplain called vihara priest was first introduced in 1993. One of the training programs for spiritual caregivers, in Japan is provided by the Professional Association for Spiritual Care and Health (PASCH), which was established in 1995 by Japanese professors in Christianity who had experienced CPE and its supervision in the USA and a professor in Buddhism. They started a training program in 1996. The Clinical Pastoral Care Education and Research Center was initiated by a German catholic priest in 1998 [21]. In 2007, a well-known Japanese Christian physician and a catholic priest initiated the Japan Society of

40  Spiritual Issues in Supportive Cancer Care

Spiritual Care (JSSC) together with health professionals, including physicians, nurses, clinical psychologists, and music therapists, religious professionals such as ministers and chaplains from various religious backgrounds, and professors of religion and medicine. Now the JSSC is developing a nationwide training and certification system in Japan together with existing training institutions to provide quality professional spiritual caregivers and supervisors, along with a basic training for other healthcare professionals who wish to offer better spiritual care in hospital settings.

Providing Spiritual Care in Cancer Clinical Settings: Spiritual Assessment Tools and Role of the Oncology Team How does the oncology team provide spiritual care? Are dedicated spiritual teams necessary and to what extent are they now available? Would they be feasible in all local realities, including low resource ones? The answers to these key questions require the input of oncology professionals, chaplains, and other potential members of spiritual teams, as well as the commitment of institutions and policy makers, based on different local resources and cultures [4]. The following considerations, however, may be of help to all of us working in the field of supportive cancer care. In addition to being a professional in a particular field, every team member is a human being with a spiritual dimension, and thus is also capable of connecting with patients at spiritual levels. Yet oncology professionals should not be expected to act as spiritual advisors, for this role requires specific education and training, in order to avoid any potential risk of expanding the role of health professionals beyond due limits [1]. As caring for cancer patients includes a spiritual dimension, oncology professionals should be familiar with common methodologies of spiritual assessment, which have been developed in recent years and validated in western settings to assist health professionals in gathering a “spiritual history” of cancer patients [10]. These instruments measure multidimensional indicators of religion and spirituality and have demonstrated good psychometric properties, including selfratings used to predict a range of social attitudes and health behaviors [22]. The SPIRIT scale, developed by Maugans, is based on an assessment of spiritual beliefs, personal spirituality, integration with a spiritual community, and ritualized practices and restrictions, with implications for use in medical care and terminal events planning. The Systems of Belief Inventory (SBI-15R) is a brief self-report inventory designed and validated by Holland and Baider and their colleagues for use in quality of life and psychosocial adjustment to cancer illness, measures of religious and spiritual beliefs, and the social support derived from a community sharing those

423

beliefs. The Spiritual Involvement and Belief Scale and the HOPE questions were developed by Hatch and Anandarajah for family physicians. The FICA scale, designed by Puchalski et al., is based on the ­assessment of faith and beliefs, importance of spirituality, spiritual community support, and how patients address immediate spiritual needs. A measure of spiritual wellbeing developed by Peterman distinguishes spiritually-related elements among both religiously diverse populations and persons who consider themselves spiritual but not religious. In Table  40.3, we summarize the references to the most widely used spiritual assessment tools. Table 40.3  Most widely used spiritual assessment tools Maugans TA The SPIRITual Arch Fam Med 1996; history 5:11–16 Psychooncology 1998; A brief spiritual Holland JC, 7:460–469 beliefs Kash KM, inventory for Passik KS, use in quality Sison A, of life research Lederberg M, in life-threatenet al. ing illness (SBI) Psychooncology 2001; Baider L, Holland The System of 10:534–541 J, De-Nour A Belief Inventory (SBI-15R): a validation of study in Israel J Fam Pract 1998; The Spiritual Hatch RL, 46:476–486 Involvement Burg MA, and Beliefs Baberhaus DS, Scale. Hellmich LK Development and testing of a new instrument Am Fam Physician 2001; Anandarajah G, Spirituality and 63:81–89 Hight E medical practice: using the HOPE questions as a practical tool for spiritual assessment J Pall Med 2002; Puchalski CM Spirituality and 5:289–294 end-of-life care: a time for listening and caring Measuring spiritual Ann Behav Med 2002; Peterman AH, 24:49–58 well-being in Fitchett G, people with Brady MJ, cancer: The Hernandez L, Functional Cella D Assessment of Chronic Illness TherapySpiritual Well-Being Scale (FACIT-Sp)

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Basic spiritual assessment, as recommended in the United States by the Joint Commission, is necessarily limited and yet may open the doors for patients to feel at ease to raise spiritual concerns, takes only a few minutes [23]. Clearly, ­different forms of spirituality throughout the world may require different approaches, and western assessment tools or interventional models may not always be adaptable to other cultures. Rather than exporting such western tools and models, supportive care professionals should consider the needs and expressions of their local communities and involve community members in approaching the spiritual dimension of cancer care in their specific sociocultural context. Although it is natural to expect chaplains to assume the primary role of spiritual caregiver, every team member should acquire the basic skills of spiritual assessment and care to be able to listen to those patients who wish to talk about their spiritual concerns and to refer them to spiritual advisors, whether hospital chaplains or community members [24, 25]. The creation of “dedicated spaces” within cancer facilities, where patients and spiritual advisors may discuss spiritual issues as separate from more clinical discussions, has been proposed as a way to facilitate open communication among different interlocutors [26]. In Tables 40.3–40.5, we list simple principles that can be easily applied in every context to approach the spiritual concerns and needs of our cancer patients (Tables 40.4–40.6). Integrative spiritual care requires a team effort to discuss and implement spiritual, as well as physical and psychosocial, care plans. Chaplains can support the team in the planning process by giving their assessment and advice, and in the implementation phase by serving as a consultant to each team member [18]. Finally, chaplains can offer spiritual care not only to patients and their families but also to members of the oncology team, who are exposed to a stressful environment where they often encounter their patients’ intense suffering and dying and may benefit from sharing their own spiritual concerns [24]. Along with psychologists and psychiatrists, chaplains can provide counseling to the oncology team, or to individual members of it, and ease some of the distress that often leads to various degrees of burn-out affecting the performance of oncology professionals. Thus, they may also indirectly contribute to improving the quality of life of cancer patients and their families.

Table 40.4  Patient’s search for spirituality: common questions Who am I? Who is the I? How do I show my need for compassion? How do I share uncertainties and hopes? What are my thoughts about searching for spirituality? How do I find the right prayers for myself?

Table 40.5  Patients’ inner journey: what helps? Finding sources of strength and support Accessing their own spiritual dimension Thinking of God or praying Sharing thoughts with oncology professionals or others Sharing their silence

Table 40.6  Professional caregivers: how can they assist their patients? Do not avoid patient’s feelings (covert and overt) Do not use metaphoric language Do not give “verbal” prescriptions Do not be afraid of patients’ spiritual questions Always be honest in answering , admitting uncertainty or discomfort Use answers that reflect a spirit of open search, such as: “I have not thought about this…” “Let’s think about it together…” “Let’s find the answers together…”

Conclusion Spirituality refers to the subjective experiences that relate to an individual’s sense of connection with something transcendent – deity, truth, family, beauty – and that are manifested by the complexity of emotions of awe, gratitude, love, compassion, and forgiveness. The human capacity for positive emotions is what makes us spiritual. Focusing on these positive emotions is the best and safest route to spirituality found within ourselves and our patients [27]. Common themes have been identified in observing and describing the significance of spirituality in chronically ill patients [28]. First is the importance of embracing the present moment. This includes appreciating the preciousness of time and the importance of being truly present in the moment, no matter how painful this can be or how short a time can be left. A second theme is finding meaning in past memories as part of constructing meaning in life, an important function of the life review process. A third theme is the recognition of spirituality in their patients’ lives. After confronting one’s limitations and accepting both the positive and negative aspects of one’s life, a person has the opportunity to seek reconciliation and forgiveness. Spiritual issues, unlike some psychosocial problems, cannot be reduced to the result of faulty thinking patterns or unresolved conflicts from earlier in life but are rather an expression of the basic need for people to connect with others or to find meaning in their lives. Change happens for some people not when their personal crisis is corrected but when their spiritual needs are met by sharing their spiritual search with others, praying, meditating, or joining a faith community. Recent consensus has been reached that reframing psychosocial concerns and needs as spiritual issues may foster a global healing process for the patient, and stimulate oncology professionals

40  Spiritual Issues in Supportive Cancer Care

to consider and deliver a new and broader range of integrated psychosocial and spiritual interventions [29, 30].

References 1. Surbone A, Baider L. The spiritual dimension of cancer care. Crit Rev Oncol Hematol 2010; 73(3):228–235. 2. Breitbart W. Spirituality and meaning in supportive care: group psychotherapy interventions in advanced cancer care. Support Care Cancer 2001; 10:272–280. 3. Chochinov H. Dignity as the essence of medicine: the A, B, C and D of dignity care. Br Med J 2007; 335:184–187. 4. Surbone A, Baider L, Weitzman TS, Brames MJ, Rittenberg CN, Johnson J. Psychosocial care for patients and their families is integral to supportive care in cancer: MASCC position statement. Support Care Cancer 2010; 18(2):255–263. 5. Holland JC (ed), Psycho-Oncology. New York and London: Oxford University Press, 1998. 6. Levin JS, Larson DN, Pulchaski CM. Religion and spirituality in medicine: research and education. JAMA 1997; 278:792–793. 7. Salander P. Who needs the concept of spirituality? Psychooncology 2006; 15:647–649. 8. Swinton J. Spirituality and mental health care: rediscovering a forgotten dimension. London and Philadelphia: Jessica Kingsley Publishers, 2001. 9. Miller WR, Thoresen CE. Spirituality, religion and health. Am Psychol 2003; 58:24–35. 10. Koenig HG. Taking a spiritual history. JAMA 2004; 291: 2881–2882. 11. Daaleman TP, Usher BM, Williams SW, Rawlings J, Hanson LC. An exploratory study of spiritual care at the end of life. Ann Fam Med 2008; 6:406–411. 12. James A, Wells A. Religion and mental health: towards a cognitive behavioral framework. Br J Health Psychol 2003; 8:359–376. 13. Pargament K, Koenig H, Perez L. The many methods of religious coping. J Clin Psychol 2000; 56:519–543. 14. Phelps AC, Maciejewski PK, Nilsson M, Balbone TA, Wright AA, et al. Religious coping and use of intensive life prolonging. JAMA 2009; 301:1140–1147.

425 15. Lee SJ. In a secular spirit: strategies of Clinical Pastoral Education. Health Care Anal 2002; 10:339–356. 16. International Committee on Pastoral Care and Counseling Page. http://www.icpcc.net/. Accessed September 10, 2009. 17. Fitchett G, King SDW, Vandenheck A. Education of chaplains in psycho-oncology. Chapter 88 in JC Holland (ed.) Psycho-oncology, 2nd edition. New York: Oxford University Press 2010. 18. Puchalski CM et al. Interdisciplinary Spiritual care for seriously ill and dying patients: a collaborative model. Cancer J 2006; 12:398–416. 19. Wintz SK, Handzo GF. Pastoral care staffing and productivity: more than ratios. Chaplain Today 2005; 21:3–10. 20. VandeCreek L, et  al. How Many chaplains per 100 inpatients? Benchmarks of health care chaplaincy departments. J Pastoral Care 2001; 55:289–301. 21. Kubotera T. An Outline of the Spiritual Care Studies (in Japanese). Tokyo: Miwa Shoten Publishing, 2005. 22. Lo B, Quill T, Tulsky J. Discussing palliative care with patients. ACP-ASIM End-of-Life Care Consensus Panel. American College of Physicians. American Society of Internal Medicine. Ann Intern Med 1999; 130:744–749. 23. Kristeller JL, Zumbrun CS, Schilling RF. “I would if I could”: how oncologists and oncology nurses address spiritual distress in cancer patients. Psychooncology 1999; 8:451–458. 24. McClung E, et  al. Collaborating with chaplains to meet spiritual needs. Medsurg Nurs 2006; 15:147–156. 25. Sulmasy DP. Spiritual issues in the care of dying patients. “…It’s okay between me and God.” JAMA 2006; 296:1385–1392. 26. Milstein JM. Introducing spirituality in medical care. Transition from hopelessness to wholeness. JAMA 2008; 299: 2440–2441. 27. Villant GE. Spiritual Evolution. New York : Broadway Books, 2008. 28. Stefanek M, McDonald PG, Hess SA. Religion, spirituality and cancer: methodological challenges. Psychooncology 2005; 14:450–463. 29. Graham MA, Kaiser T, Garrett KJ. Naming the spiritual: the hidden dimension of helping. Soc Thought 1998; 18:49–61. 30. Puchalski C, Ferrel B,Virani R, Otis-Green S, Handzo G, Becker NH, Prince-Paul M, Pugliese K, Sulmasy D. Improving the quality of spiritual care as a dimension of palliative care: the report of the consensus conference. J Palliat Med 2009; 12:885–903.

Index

A Alopecia. See Chemotherapy-induced alopecia Anthracyclines. See also Cardiac health, breast cancer patient cardiac monitoring, 75–76, 78 clinical manifestations, 74–75 mechanisms, 74 patient-related, 164 prognosis and management, 76–77 risk factors, 74, 75 treatment-related, 163–164 Anti-cancer agents, 73 Appetite stimulation cannabinoids, 209–210 corticosteroids, 209 megestrol acetate, 209 Ascites anatomy, 261 clinical manifestations, 261–262 diagnosis ascitic fluid and malignancy, 262 flank dullness, 262 magnetic resonance imaging (MRI), 262 puddle sign, 262 serum-to-ascites albumin gradient (SAAG), 263 shifting dullness, 262 ultrasonography, 262 etiology and pathogenesis, 261 treatment drainage catheters, 263 intraperitoneal therapy, 264 paracentesis, 263 peritoneovenous shunting, 263 surgery, 263–264 tumour-targeted, 264 B Bleeding pathogenesis drugs effect, 175 fibrinolysis, 175 paraproteins, 175 platelet dysfunction, 174 thrombocytopenia, 174 tumor infiltration, 174–175 Bone marrow transplantation, 197–198 Bone metastases, 47 Brachytherapy, 225

C Cancer cachexia and anorexia anabolic steroids, 210 anti-inflammatory agents, 210 appetite stimulation cannabinoids, 209–210 corticosteroids, 209 megestrol acetate, 209 autonomic nerve modulators, 211 biological criteria, 207–208 clinical work-up, 205–206 definition, 205 dietary intake assessment, 207 enteral and parenteral feeding, 210 gastric stimulants and laxatives, 210 general therapeutic platform, 208 hypothalamic neurotransmitters, 211 muscle mass evaluation, 207 muscle synthesis, 211 nutritional risk factors assessment, 208 pharmaceutical therapy, 209 nutrient supplement therapy, 208–209 weight loss assessment, 206–207 Cancer pain acute pain, 19 adjuvant analgesics, 20–21 anatomy allergic medications, 12–13 bone pain, 12 calcium channels, NMDA receptors, 13 central excitatory mechanism, 13 cerebral pain matrix, 13–14 opioid receptors and tolerance, 14 vanilloid, sodium channels, 12 visceral pain, 14 assessment, 15 breakthrough pain, 17–18 control, opioid side effects, 18 equianalgesia and opioid rotation, 19 imaging liver and abdominal imaging, 16 lung imaging, 16–17 skeletal metastases, 15–16 management, 17 and nociception, 11 nondrug treatment for, 21 opioid overdose, 20 pain management, actively dying, 20

I.N. Olver (ed.), The MASCC Textbook of Cancer Supportive Care and Survivorship, DOI 10.1007/978-1-4419-1225-1, © Multinational Association for Supportive Care in Cancer Society 2011

427

428 Cancer pain (cont.) patient-controlled analgesia, 19 spinal analgesia, 19–20 uncontrolled pain, 18 Cancer-related fatigue (CRF). See Fatigue Cancer therapy, oral effects children growth and development, 404 dental health, 401–402 halitosis, 404 hyposalivation and xerostomia, 400–401 infection, 404 oral pain, 402 osteonecrosis, 404–405 second cancers, 405 taste alterations, 402–403 trismus, 403 wound healing, 404 Cardiac health, breast cancer patient adaptation pathway components, 162 anthracycline and cardiotoxicity doxorubicin, 162–163 methods of monitoring, 165 patient-related, 164 risk factors, 163 treatment-related, 163–164 cardiac function preservation, 164–165 cardiotoxicity, 161–162 lifestyle modifications management, 165 monitoring, 165–166 multiple-hit hypothesis, 162 therapeutic modifications and interventions ACE inhibitors and beta-blockers, 166 dose limitation and schedule modification, 166 iron-chelating agents, 166 liposomal anthracyclines, 166–168 treatment, 161–162 Cardiac tamponade, 85 Cardiac toxicities acute, 73 anthracyclines cardiac monitoring, 75–76, 78 clinical manifestations, 74–75 risk lowering, 75 mechanisms, 74 prognosis and management, 76–77 risk factors, 74 anti-cancer agents, 73 cardioprotective agents, 73 chemotherapy, 73 early, 73 late, 73 non-anthracycline agents capecitabine, 80–81 5-fluorouracil, 80 taxanes, 81 radiation therapy clinical manifestations, 79–80 disadvantage, 79 modification, 80 risk factors, 79 trastuzumab cardiac monitoring, 78 clinical manifestations, 78 lowering the risk, 78 mechanisms, 77 prognosis and management, 79 risk factors, 77

Index Cardioprotective agents, 73 Cellulitis, 189 Central nervous system symptoms chronic encephalopathy, 317–318 encephalopathy acute, 315–316 posterior reversible syndrome, 316–317 headache acute radiation toxicity, 314 brain tumors, 313 intrathecal administration, chemotherapeutic agents, 314 isolated headache, 313 nocturnal headache, 313 primary and metastatic tumors, 313 seizures antiepileptic drug prophylaxis, 315 drug withdrawal states, 314 metabolic evaluation, 314 metastatic disease, 314 Chemotherapy-induced alopecia adverse effect, 381 grading, 383 hair loss assessment, 383 MASCC grading hair growth, 385 scalp hair loss grading, 384 telogen hair, 381 terminal hair, 381 treatment, 383, 386 types anagen effluvium, 382 hair growth, disruption, 382–383 telogen effluvium, 381–382 Chemotherapy-induced nausea and vomiting (CINV), 304 Chemotherapy-induced peripheral neuropathy (CIPN) paclitaxel acute pain syndrome, 324 prevention acetyl-L-carnitine, 322 alpha-lipoic acid/thiotic acid, 323 calcium/magnesium infusions, 322 drugs, 323 glutamine, 323 glutathione, 322 vitamin E, 323 symptoms, 322 treatment gabapentin, 323 lamotrigine, 323–324 serotonin and norepinephrine reuptake inhibitors (SNRIs), 324 topical baclofen, 324 tricyclic antidepressant agents, 323 Chemotherapy-related cardiac dysfunction (CRCD), 163 Colony-stimulating growth factor (G-CSF), 104 Comprehensive geriatric assessment (CGA), 45, 46 Congestive heart failure (CHF), 161 Constipation constipation management algorithm, 256 thalidomide therapy, 254 therapy, 255 vinca alkaloids, 254 Cryopreservation human embryo fertility, 137 in vitro fertilization, 136 radical trachelectomy, 136–137 oocytes, 135 ovarian tissue, 136

Index Cushing's syndrome corticotrophin-releasing hormone (CRH) testing, 122 symptoms, 122 treatment, 122–123 Cytotoxic agents alkylating agents, 269 antimetabolites, 271 antitumor antibiotics, 273 azathioprine, 272 bleomycin, 273 busulfan, 270 chlorambucil, 270 cyclophosphamide, 269–270 cytosine arabinoside, 271 dacarbazine, 270, 274 dactinomycin, 274 doxorubicin, 273 etoposide, 274 floxuridine, 272 fluorouracil and capecitabine, 271 gemcitabine, 272 ifosfamide, 270 irinotecan and topotecan, 275 ixabepilone, 275 melphalan, 270 mercaptopurine, 272 methotrexate, 272–273 mitomycin, 273–274 mitoxantrone, 273 platinum derivatives, 275 plicamycin, 274 taxanes, 274–275 temozolomide, 271 6 thioguanine, 272 vinca alkaloids, 274 D Delirium, palliative care, 36 Dentist/hygienist role dental visits, 218 diet modifications, 219 oral candida therapy, 219 oral hygiene, 218 topical fluorides and remineralizing solutions, 218–219 Dermatologic toxicity dermatomyositis-like rash, 372 eccrine squamous syringometaplasia, 370 epidermal growth factor receptors (EGFR), 361 eruption of lymphocyte recovery (ELR), 371 grading, 361–363 graft versus host disease, 371 hand foot skin reaction (HFSR), 364 hand-foot syndrome (HFS) 5-flourouracil (5-FU), 367 management, 367 pegylated liposomal doxorubicin (PLD), 367 symptoms, 367 intertrigo-like rash, 369–370 morbilliform eruption/maculopapular rash, 368 neutrophilic eccrine hydradenitis, 370 papulopustular rash/acneiform characterization, 361, 363 lapatinib, 361 treatment, 364 photosensitivity, 372–374 pigmentary changes, 378

429 radiation dermatitis and enhancement, 372 sclerodermiform dermatitis, 371–372 seborrheic dermatitis-like rash, 369 skin changes actinic keratoses (AK), 375–376 beau's lines, 378 leukonychia, 378 nail toxicity, 376 onycholysis, 377–378 paronychia, 376–377 pigment, 374–375 squamous cell carcinomas (SCCs), 376 subungual hemorrhage, 377 xerosis, 374 Stevens Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), 369 Diarrhea clinical assessment, 251–253 etiology and specific agents epidermal growth factor receptor (EGFR), 251 5-fluorouracil, 249–250 irinotecan (CPT-11), 250 multikinase inhibitors, 251 targeted inhibitors, 251 treatment, 253–254 Diffuse alveolar damage (DAD), 99 Drug-drug interactions, 46 Dry mouth management. See also Xerostomia acupuncture and electrostimulation, 217 artificial salivas, 217 hyposalivation, 217 masticatory, gustatory and mild acid stimulation, 216 nonstimulatory techniques, 218 pharmacologic aids, 216–217 water intake, 217 Dysphagia clinical assessment/investigation, 224 esophageal stent, 225 prevalence, 223 swallowing mechanism, 223–224 treatment behavioral interventions, 225 incurable esophageal cancer, 225–226 mechanical interventions, 225 supportive interventions, 224 types, 224 Dyspnea definition, 107 factors, 108 incidence, 107 non-pharmacological management, 111 palliative care, 36–37 prevalence, 107 symptomatic treatment cough suppressants, 111 heliox28, 110–111 non-opioid medications, 110 oxygen, 110 systemic opioids, 109–110 E Edmonton system assessment (ESAS), 206 Elderly cancer patients bisphosphonates, 47 bone metastases, 47 comprehensive geriatric assessment (CGA), 45, 46

430 Elderly cancer patients (cont.) denosumab, 47 depressive disorders, 45 evaluation, 45 nausea and vomiting, 46 neutropenia, 46 organ function, 45 osteopenia, 47 osteoporosis, 47 pain control, 45–46 polypharmacy, 46 undernutrition, unexpected toxicities, 46 Encephalopathy acute autologous lymphokine-activated, 316 5-FU and levamisole, 315 ifosfamide-induced, 315 leptomeningeal carcinomatosis, 315 toxic-metabolic, 315 radiation induced acute encephalopathy syndrome, 317 radiosurgery and brachytherapy, 317 somnolence syndrome, 317 Endocrine and metabolic symptoms cushing's syndrome, 122–123 electrolyte abnormality, 120 hypercalcemia, 119–120 hypernatremia, 120 hypoglycemia, 123 hypomagnesemia, 121–122 hyponatremia, 120 SIADH secretion, 120–121 sweats and hot flashes, 118–119 syndrome of inappropriate antidiuretic hormone (SIADH), 120–121 tumor fever, 117–118 tumor lysis syndrome (TLS), 117 End of life symptoms. See Palliative care Epidural spinal cord compression (ESCC), 326–327 Extravasation chemotherapy drugs, 352 etiology, 354 incidence, 352 irritant, 351 management conservative, 356 healthcare, 355 medical record, 355 pharmacologic, 356–357 surgical, 356 temperature monitoring, 355 non-vesicant, 351 oxaliplatin, 351 prevention, 353 risk factors, 353–354 signs and symptoms, 354 treatment antidote, 357 hyaluronidase, 357 sodium thiosulfate, 357 totect and savene, 358 vesicant chemotherapy drugs, 351–352 Eye symptoms and toxicities alkylating agents nitrosoureas, 334 non-platinum agents, 333–334

Index platinum agents, 334–335 antibiotics, 337 antimetabolites folic acid analogs, 336 purine analogs, 336–337 pyrimidine analogs, 335–336 biological response modifiers denileukin diftitox, 342 interferons, 341 interleukins, 341 ocular effects, chemotherapy agents, 343–344 hormonal agents anastrazole, 339 leuprolide, 339 nilutamide, 339 raloxifene, 339 steroids, 339 tamoxifen, 338–339 mitotic inhibitors docetaxel, 337–338 taxanes, 337 vinca alkaloids, 338 molecular targets, 340 targeted monocloncal antibodies, 341 F Fatigue assessment, 24–25 barriers, 24 comorbidities, 24, 26 definition, 23–24 differential diagnosis, 25 energy conservation and distraction, 25 mechanisms, 24 NCCN evidence-based guidelines, 24 patient and family education, 25 prevalence rates, 23 principles activity and deconditioning, 26–27 anemia, 26 cognitive impairment, 29 comorbidity, 26 emotional distress, 27 nutrition, 27–28 pain, 28 sleep-wake disturbances, 29–30 symptom clusters, 28–29 provider education, 25 radiation therapy (RT), 23 screening, 24 treatment, 25 G Gastrointestinal mucositis. See Mucositis Gonadal dysfunction, 140 Granulocyte colony-stimulating factors (G-CSF), 46 Gynecological symptoms cervical cancer, 301 chemotherapy anthracyclines, 305 cytotoxics, 305 platinum compounds, 303–305 targeted therapy, 305 taxanes, 305

431

Index Gynecological symptoms (cont.) ovarian cancer radiotherapy acute radiotherapy-induced, 306–307 chronic radiotherapy-induced toxicity, 306 survivorship problems gynecologic cancer, 307–308 months after completion of treatment, 307 years after completion of treatment, 307 symptoms and complications bleeding complications, 302 lymphedema, 301 lymph node dissection, 301 malignant intestinal obstruction, 302 postoperative radiotherapy, 301 self-expanding metallic stents (SEMS), 302 vaginal bleeding, 302 H Haemoptysis, 112–113 Hand-foot syndrome (HFS) 5-flourouracil (5-FU), 367 management, 367 pegylated liposomal doxorubicin (PLD), 367 symptoms, 367 Health-related quality of life (HRQL) barriers, 68 cancers and treatments, 64 examples, 67 frequency of, assessments, 67–68 in oncology, 63–64 and patient reported outcomes (PROS), 64 patient-reported outcomes measurement information system (PROMIS), 67 selection, for measurement, 64–67 steps for improvement, missing data, 68 Hemorrhage, 38 Hepatotoxicity and hepatic dysfunction biologic response modifiers combination chemotherapy regimens, 276 hepatic veno occlusive disease, 276 interferon, 276 interleukin 2, 276 radiotherapy and hepatotoxicity, 277 tamoxifen and hormones, 276 chemotherapy and the liver cytotoxic agents alkylating agents, 269 antimetabolites, 271 antitumor antibiotics, 273 azathioprine, 272 bleomycin, 273 busulfan, 270 chlorambucil, 270 cyclophosphamide, 269–270 cytosine arabinoside, 271 dacarbazine, 270, 274 dactinomycin, 274 doxorubicin, 273 etoposide, 274 floxuridine, 272 fluorouracil and capecitabine, 271 gemcitabine, 272 ifosfamide, 270 irinotecan and topotecan, 275 ixabepilone, 275

melphalan, 270 mercaptopurine, 272 methotrexate, 272–273 mitomycin, 273–274 mitoxantrone, 273 platinum derivatives, 275 plicamycin, 274 taxanes, 274–275 temozolomide, 271 6 thioguanine, 272 vinca alkaloids, 274 liver disease chemotherapy induced hepatotoxicity, 269 hepatitis B infection, 268 hepatitis C infection, 268–269 non alcoholic steatohepatitis, 269 radiologic imaging tyrosine kinase inhibitors erlotinib, 276 imatinib, 275 lapatinib, 275 sorafenib, 275 Hiccups acupuncture and cupping, 228 breathing pace makers, 228 clinical assessment/investigation, 227 mechanism, 227 pharmacology, 228 phrenic nerve blockade, 228 prevalences, 223 treatments, 227–228 Hodgkin disease cancer infections, 195 fertility treatment effect, male, 139 Hypercalcemia bisphosphonate, 120 classification, 120 management, 120 severity, 120 symptoms, 119 Hypercoagulability. See also Thromboembolism management, 173–174 markers, 171 venous thromboembolism (VTE), 171–172 Hypernatremia, 120 Hypoglycemia, 123 Hypomagnesemia, 121–122 Hyponatremia clinical manifestions, 121 osmotic demyelination syndrome (ODS), 121 I Infections, cancer abdominal tumors, 196 antibiotic regimes aminoglycoside antibiotics, 198–199 blurred vision, 199 computerized tomography (CT), 199 erythematous papular lesion, 199 historical perspective, 198–199 neutropenic fever, 199 vancomycin, 199 antifungal therapy, 200 ecthyma gangrenosum, patients, 198 granulocyte-colony stimulating factors (G-CSFs), 201

432 Infections, cancer (cont.) head and neck tumors, 196 hematological malignancy immunosuppression neutropenic fever mucositis, 198 patients, 198 solid tumors febrile neutropenia, 197–198 immunosuppressive agents bone marrow transplantation, 197 corticosteroids, 196–197 monoclonal antibodies, 197 splenectomy, 197 intravenous devices, 196 mucosal immunity, 196 neutropenia, 196 radiation therapy, 196 superinfection Infertility. See Sterility Insomnia adults, 412 assessment, 413–414 causes, 413 characteristics, 413 definition, 412 factor model, 413 survivorship, 411 Interstitial lung disease (ILD), 99 L Lambert-eaton myasthenic syndrome (LEMS), 325 Liposomal anthracyclines cardiac health, preservation, 166–168 metastatic breast cancer, 167 Liver disease chemotherapy induced hepatotoxicity, 269 hepatitis B infection, 268 hepatitis C infection, 268–269 non alcoholic steatohepatitis, 269 Lymphedema care, 23 cellulitis, 189 diagnostic testing optoelectronic volumetry (OEV), 185 radiology, 185 ultrasonography, 185 water displacement, 185 human anatomy, lymphatic system, 180 lower extremity, 20 lymphatic system, 179 metastasis, 180 molecular biology, 181 pain, 189 psychosocial issues, 189–190 risk factors blood draws, 184 glycemic control, 184 medical interventions, 183–184 radiation therapy, 183 surgical procedures, 182–183 axillary lymph node dissection (ALND), 182 radical mastectomy, 182 SLNB, 182 sentinel lymph node biopsy (SLNB), 182

Index treatment gene therapy, 189 laser therapy, 189 lymph node transplantation, 189 metastatic breast cancer, 186–187 metastatic prostate cancer, 187–189 M Malignant pericardial effusion and cardiac tamponade. See Pericardial effusion Menopause symptoms hot flashes and night sweats assessment, 148–149 definition, 146 herbs and supplements, 147 non-pharmacologic interventions, 147–148 pharmacologic treatment options, 146–147 physiology, 146 osteoporosis assessment, 152 behavior and dietary supplements, 150 bisphosphonates, 150–151 definition, 149–150 novel agents, 151 parathyroid hormone, 152 physiology, 150 selective estrogen receptor modulator (SERMS), 151 vaginal atrophy assessment, 154–155 definition, 152–153 dehydroepiandrosterone (DHEA), 154 estrogen treatment, 154 lubricants and moisturizers, 154 physiology, 153 symptoms, 153 vs. systemic treatment, 153 tamoxifen, 153 Mitochondrial pathway, 100 Mitomycin C, 337 Mouth dryness. See Xerostomia Mucositis, 198 clinical signs and symptoms, 243 diagnosis and complicating factors, 243 management, 243–245 measurement, 243 morbidity and economic impact, 241 nutritional support, 245 pain control, 245 preventive measures, 245 therapeutic interventions for anti-inflammatory agents, 246 antioxidants, 246 GI mucositis, 246–247 growth factors, 245–246 laser therapy, 246 promoters of healing, 246 Myasthenia gravis (MG), 325 N National Osteoporosis Risk Assessment (NORA), 152 Nausea and vomiting antiemetic guidelines high emetic potential chemotherapy, 235

433

Index low and minimal emetic potential chemotherapy, 236 moderate emetic potential chemotherapy, 235 Multinational Society For Supportive Care In Cancer (MASCC), 234 multiple day cisplatin chemotherapy, 235–236 benzodiazepines, 233 chemotherapy, 233 dexamethasone, 233 5 HT3 receptor antagonists, 233 niche areas control anticipatory nausea and vomiting, 236 children receiving chemotherapy, 236 high dose chemotherapy, 236 radiation induced emesis, 236 NK1 receptor antagonists, 234 NCCN fatigue guidelines, 24 Neuromuscular disease muscle disease, 326 paraneoplastic syndromes ANNA-1 and ANNA-2, 325 cancer-related antibodies, 324 compound muscle action potential (CMAP), 325 lambert-eaton myasthenic syndrome (LEMS), 325 myasthenia gravis (MG), 325 treatment, 325–326 peripheral neuropathy, 321–324 spinal cord compression clinical presentation, 327 diagnosis, 327–328 epidural spinal cord compression (ESCC), 326–327 treatment, 328–329 Nonspecific interstitial pneumonitis (NSIP), 99 Nonsteroidal anti-inflammatory drugs (NSAIDs), 118 O Obstruction anticholinergics, 255 corticosteroids, 255 malignant bowel obstruction algorithm, 257 octreotide, 255 Opioids, 109–110 Oral health cancer therapy oral effects children growth and development, 404 dental health, 401–402 halitosis, 404 hyposalivation and xerostomia, 400–401 infection, 404 oral pain, 402 osteonecrosis, 404–405 second cancers, 405 taste alterations, 402–403 trismus, 403 wound healing, 404 incidence, 399 quality of life (QOL), 400 Oral hygiene, 218. See also Xerostomia Oral mucositis. See Mucositis Osmotic demyelination syndrome (ODS), 121 Osteoporosis assessment, 152 behavior and dietary supplements, 150 bisphosphonates, 150–151 definition, 149

elderly cancer patients, 47 novel agents, 151 parathyroid hormone, 152 physiology, 150 selective estrogen receptor modulator (SERMS), 151 P Palliative care contingency planning, 41–42 nursing aspects, 39–40 parenteral administration, drugs, 38–39 patient-controlled analgesia (PCA), 35 patient's comfort improvement, 40–41 prognosis, 33 symptoms management, dying patients close to death, 40 delirium, 36 dyspnea, 36–37 hemorrhage, 38 pain, 34–36 retained respiratory secretions, 37 seizures, 38 symptoms prevalence, 33–34 therapy of dying, 33 Palmoplantar erythrodysesthesia. See Hand-foot syndrome Paracentesis, 263 Patient generated subjective global assessment (PG-SGA), 206 Patient reported outcomes (PROs). See Health-related quality of life (HRQL) Pediatric oncology adverse effects, 60–61 antiemetics, 58–60 anti-viral drugs, 53–54 central venous catheters role, 54 epidemiology and incidence, 49–50 fever of unknown origin (FUO), 49 fever without neutropenia, treatment, 53 immunisation during chemotherapy, 54–55 immunisation post-chemotherapy, 56 infection prevention, 50–52 initial antibiotic therapy, 53 pain-management, 56–57 pain syndromes, 58 therapy related pain/tumor related pain, 57 treatment modification, 52, 53, 58 tumour lysis syndrome (TLS), 56 vaccinations during chemotherapy influenza, 55–56 pneumococcal, 56 varicella zoster, 56 Pericardial effusion (PCE) bleomycin, 88 diagnosis cardiac tamponade, 85 chest imaging, 84 cytology / histology, 85 ECG findings, 85 echocardiography, 84–85 signs and symptoms, 84 etiology and pathogenesis causes, 83 drugs, 84 graft-versus-host disease reaction (GVHD), 84

434 Pericardial effusion (PCE) (cont.) malignancy, 83 radiation therapy, 83–84 management balloon pericardiotomy, 87 indwelling pericardial catheter, 87 local sclerotherapy/chemotherapy, 87–88 pericardiocentesis, 87 videoassisted thoracoscopy (VATS), 87 noninvasive modalities, 90 platinum agents, 88 prognosis, 90 recommended therapy for, 89 surgical treatment anterolateral thoracotomy, 90 subxiphoid pericardiotomy, 89 thoracoscopy, 89–90 tetracyclines, 88 thiotepa, 88–89 Pericardiocentesis, 86, 87 Peripheral neuropathy chemotherapy-induced peripheral neuropathy (CIPN) paclitaxel acute pain syndrome, 324 prevention, 322–323 symptoms, 322 treatment, 323–324 mononeuropathy, 321 plexopathy, 321 polyneuropathy, 321–322 radiculopathies, 321 Pleurodesis, 112 Pneumonitis, 101 Pulmonary toxicity clinical manifestations, 99 diagnosis, 104 pathogenesis angiogenesis, 100–101 apoptotic dysfunction, 100 drug-associated, 99 epidermal growth factor (EGF), 100 impaired repair, 100 radiotherapy induced, 101 systematic drug induced anticancer drugs, 101 novel chemotherapy agents, 102–103 older chemotherapy agents, 101–102 supportive care, 104 targeted therapies, 103 treatment, 104 Q Quality of life assessment. See Health-related quality of life (HRQL) R Reflux gastroesophageal reflux disease (GERD), 226 investigations, 226 pathophysiology, 226 prevalences, 223 treatment general considerations, 226 medical therapy, 226–227 Rehabilitation breast cancer, 392 caregivers, 390–391

Index classification, 391 colorectal cancer, management bowel changes/dysfunction, 392–393 ostomy issues, 393 sexual dysfunction, 393 urologic dysfunction, 393 diagnosis end-of-life phase, 390 posttreatment phase, 390 primary treatment phase, 390 recurrence phase, 390 staging and pretreatment phase, 390 gynaecologic cancer, 393 head and neck cancer, 393–394 history, 389 influencing factor, 390 lung cancer, 394 McGill cancer nutrition, 394–395 palliative treatment, 391 preventive rehabilitation, 391 psychosocial, 391–392 restorative, 391 shoulder dysfunction, 394 supportive, 391 survival rate, 389 voice loss, 394 Renal salt wasting syndrome (RSWS), 121 Respiratory symptoms management assessment breathlessness, 108–109 causes, 108 recurrent laryngeal nerve (RLN), 113 cough, 111 dyspnoea definition, 107 factors, 108 fibrinolytics, 112 incidence, 107 non-pharmacological management, 111 prevalence, 107 symptomatic treatment, 109–111 haemoptysis, 112–113 hoarse voice, 113 pleural effusions nature, 112 pleuroscopy, 112 treatment, 112 S Sarcopenia, 205, 207 Seizures, palliative care, 38 Sentinel lymph node biopsy (SLNB), 182 Sexual problems andrological consultation, 129 females, 131 males, 130–131 mechanisms erectile dysfunction (ED), 128 exenteration, 128 sexual desire, 127–128 somatic, 128 phosphodiesterase type 5 inhibitors (PDE5i), 130 priapism, 130 professional help and treatment, 130 talking about sex, 129

435

Index technical solutions, 130 treatment, limitations, 129–130 Singultis. See Hiccups Spinal cord compression clinical presentation, 327 diagnosis, 327–328 epidural spinal cord compression (ESCC) definition, 326 mechanism, 326 metastasis, common site, 327 treatment bisphosphonates, 329 chemotherapy, 329 corticosteroids, 328 radiation therapy, 329 surgery, 328–329 Spiritual issues counseling, chaplains role, 422–423 differences and interrelations, 421 life-threatening events response, 419–420 meaning and definitions, 420 methodologies and assessment, 423–424 vs. religion, 421 Splenectomy, 197 Sterility female fertility, treatment effect alkylating agents, 134 bone marrow transplantation, 134 chemotherapy, 133–134 premature ovarian failure (POP), 134 radiotherapy, 134–135 male fertility, treatment effect alkylating agents (AA), 138 chemotherapy, 137 in children, 140 gonadal dysfunction, 140 Hodgkin disease, 139 late effects ovary, 140 long-term sterility, 139 oncological surgery, 137–138 platinum compounds, 138 preservation, 139 radiation therapy, 138 sperm cryopreservation, 139–140 testes, 140 testicular cancer, 139 protective measurement embryo cryopreservation, 136–137 gonadotropin-releasing hormone analogue treatment (GnRh-a), 135–136 immature oocytes, 135 mature oocytes, 135 ovarian tissue, 136 sex steroids, 136 radiotherapy, mutagenic effect, 141 teratogenic effects, 140–141 Supportive cancer care. See Spiritual issues Survivorship adjustment disorder, 408–409 anxiety, 407 cognitive-behavioral interventions, 414–415 depression, 407 economic impact, 410 insomnia, 411 maladaptive reaction, 408 pediatric, psychosocial, 408 pharmacologic, 414

physical symptoms, 410–412 posttraumatic stress disorder (PTSD), 408 quality of life (QoL), 409 sexual problems, 410 social difficulties, 409 treatment, 409 Syndrome of inappropriate antidiuretic hormone (SIADH), 120–121 T Teratogenicity. See Sterility Thromboembolism hypercoagulability, epidemiology, 171–172 latrogenic factors, 173 management, 173–174 pathogenesis antiphospholipid syndrome (APS), 173 apoptosis, 173 bleeding, 174–175 hyperviscosity, 172–173 leukostasis, 172 thrombocytosis, 172 Trastuzumab cardiac monitoring, 78 clinical manifestations, 78 lowering the risk, 78 mechanisms, 77 prognosis and management, 79 risk factors, 77 Tumour lysis syndrome (TLS), 56, 117 Tyrosine kinase inhibitors erlotinib, 276 imatinib, 275 lapatinib, 275 pulmonary toxicity, 103 sorafenib, 275 U Urinary incontinence overflow incontinence, 282 stress incontinence, 282 total urethral incontinence, 282 urge incontinence, 282 Urinary outlet obstruction bladder neck and lower androgen suppression therapies, 288 symptomatic treatment, 287–288 long-term intravesical catheters, 288 self-catheterisation, 288 surgery prostate palliative resection, 289 prostate transurethral resection, 289 ureteric and PUJ obstruction internal ureteric stents, 291 self-expanding ureteric stents, 291 unilateral ureteric obstruction, 291 urethral stents, 290 urinary diversion, 291–292 Urological symptoms and side effects haematuria lower renal tract, 283–284 symptomatic lower tract, 284–286 upper renal tract, 283 irritatiative voiding symptoms nonbacterial cystitis, 294–295 post-radiation cystitis, 294

436 Urological symptoms and side effects (cont.) tumour-related irritating symptoms, 293 urethrocutaneous fistulae, 296 urinary fistulae, 295–296 urinary tract infection, 292–293 vesicoenteric fistulae, 296–297 vesicovaginal fistulae, 296 pain obstructive bladder pain, 297 renal colic, 297 physiology voiding bladder wall, 281 parasympathetic system, 281 urinary incontinence overflow incontinence, 282 stress incontinence, 282 total urethral incontinence, 282 urge incontinence, 282 urinary outlet obstruction bladder neck and lower, 287–288 long-term intravesical catheters, 288 self-catheterisation, 288 surgery, 289 ureteric and PUJ obstruction, 290–291 urethral stents, 290 urinary diversion, 291–292 V Vaginal atrophy assessment, 154–155 definition, 152 dehydroepiandrosterone (DHEA), 154 estrogen treatment, 154 lubricants and moisturizers, 154 physiology, 153 symptoms, 153 vs. systemic treatment, 153 tamoxifen, 153 Varicella zoster vaccinations (VZV), 56

Index Vena cava syndrome stenting treatment complications, 95–96 contraindication, 94 indication, 93–94 LMWH therapy, 95 technique, 94–95 symptoms, 93 Voiding symptoms nonbacterial cystitis, 294–295 post-radiation cystitis, 294 tumour-related irritating symptoms, 293 urethrocutaneous fistulae, 296 urinary fistulae, 295–296 urinary tract infection, 292–293 vesicoenteric fistulae, 296–297 vesicovaginal fistulae, 296 X Xerostomia clinical pictures, 213–215 dentist role dental visits, 218 diet modifications, 219 oral candida therapy, 219 oral hygiene, 218 topical fluorides and remineralizing solutions, 218–219 hyposalivation and dental caries, 215–216 management acupuncture and electrostimulation, 217 artificial salivas, 217 hyposalivation, 217 masticatory, gustatory and mild acid stimulation, 216 nonstimulantory techniques, 218 pharmacologic aids, 216–217 water intake, 217 teeth, 215 treatment, 216