Management of Prostate Cancer

Management of Prostate Cancer SECOND EDITION Edited by Eric A. Klein, MD Humana Press MANAGEMENT OF PROSTATE CANCE...

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Management of

Prostate Cancer SECOND EDITION

Edited by

Eric A. Klein, MD

Humana Press

MANAGEMENT OF PROSTATE CANCER

CURRENT CLINICAL UROLOGY Eric A. Klein, MD, SERIES EDITOR Management of Prostate Cancer, Second Edition, edited by Eric A. Klein, 2004 Essential Urology: A Guide to Clinical Practice, edited by Jeannette M. Potts, 2004 Management of Benign Prostatic Hypertrophy, edited by Kevin T. McVary, 2004 Laparoscopic Urologic Oncology, edited by Jeffrey A. Cadeddu, 2004 Essential Urologic Laparoscopy: The Complete Clinical Guide, edited by Stephen Y. Nakada, 2003 Urologic Prostheses: The Complete Guide to Devices, Their Implantation, and Patient Followup, edited by Culley C. Carson, III, 2002 Male Sexual Function: A Guide to Clinical Management, edited by John J. Mulcahy, 2001 Prostate Cancer Screening, edited by Ian M. Thompson, Martin I. Resnick, and Eric A. Klein, 2001 Bladder Cancer: Current Diagnosis and Treatment, edited by Michael J. Droller, 2001 Office Urology: The Clinician’s Guide, edited by Elroy D. Kursh and James C. Ulchaker, 2001 Voiding Dysfunction: Diagnosis and Treatment, edited by Rodney A. Appell, 2000 Management of Prostate Cancer, edited by Eric A. Klein, 2000

MANAGEMENT OF PROSTATE CANCER SECOND EDITION

Edited by

ERIC A. KLEIN, MD Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH

HUMANA PRESS TOTOWA, NEW JERSEY

© 2004 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 www.humanapress.com For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel.: 973-256-1699; Fax: 973-256-8341, E-mail: [email protected]; or visit our website: http://humanapress.com All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. All articles, comments, opinions, conclusions, or recommendations are those of the author(s), and do not necessarily reflect the views of the publisher. Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy of the information published and to describe generally accepted practices. The contributors herein have carefully checked to ensure that the drug selections and dosages set forth in this text are accurate and in accord with the standards accepted at the time of publication. Notwithstanding, as new research, changes in government regulations, and knowledge from clinical experience relating to drug therapy and drug reactions constantly occurs, the reader is advised to check the product information provided by the manufacturer of each drug for any change in dosages or for additional warnings and contraindications. This is of utmost importance when the recommended drug herein is a new or infrequently used drug. It is the responsibility of the treating physician to determine dosages and treatment strategies for individual patients. Further it is the responsibility of the health care provider to ascertain the Food and Drug Administration status of each drug or device used in their clinical practice. The publisher, editors, and authors are not responsible for errors or omissions or for any consequences from the application of the information presented in this book and make no warranty, express or implied, with respect to the contents in this publication. Production Editor: Tracy Catanese Cover Illustration: Figure 7B from Chapter 11, “Contemporary Technique of Radical Prostatectomy: Laparoscopic Approach,” by Eric A. Klein. Cover design by Patricia F. Cleary. This publication is printed on acid-free paper. ' ANSI Z39.48-1984 (American National Standards Institute) Permanence of Paper for Printed Library Materials. Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Humana Press Inc., provided that the base fee of US $25.00 per copy is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to Humana Press Inc. The fee code for users of the Transactional Reporting Service is: [1-58829-304-1/04 $25.00]. Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1 1-59259-776-9 (e-book)

Library of Congress Cataloging-in-Publication Data Management of prostate cancer / edited by Eric A. Klein.-- 2nd ed. p. ; cm. -- (Current clinical urology) Includes bibliographical references and index. ISBN 1-58829-304-1 (alk. paper) 1. Prostate--Cancer. [DNLM: 1. Prostatic Neoplasms--therapy. 2. Gene Therapy. 3. Prostatectomy. 4. Radiotherapy. WJ 752 M2675 2004] I. Klein, Eric A., 1955- II. Series. RC280.P7M315 2004 616.99'463--dc22 2004002702

Dedication This book is dedicated to three individuals who shaped my early academic career, helped me become who I am, and for whom I have a great deal of gratitude, respect, and affection: Carl Grecco, my high school debate team coach, who taught me how to read literature with a critical eye, how to think on my feet, and how to speak and write lucidly, with whom I had the distinct pleasure of reacquainting some 30 years later (during his whirlwind Midwest Roller Coaster Tour in the summer of 2002) to find that his late-1960sderived free spirit remains intact even in retirement; Milton Strauss, Professor of Psychology first at Johns Hopkins and now at Case Western Reserve University, who during my undergraduate years taught me the joy and value of scientific investigation and tolerance for the full spectrum of human behavior, and who alone among all understands my appearance in “that picture”; and Robert Glew, Professor of Biochemistry at the University of Pittsburgh and currently at the University of New Mexico School of Medicine, who challenged me and my medical school classmates to understand biochemistry at the same level he did (no mean feat!), infused all of us with his enthusiasm for scientific inquiry, and who somehow knew my wife and I were right for each other long before either of us did.

v

Preface Although much progress has been made in the four years since the first edition of Management of Prostate Cancer, prostate cancer remains a significant biological, medical, and personal challenge for millions of men. In this interval, some important trends and observations have emerged that represent real progress in the field and which will shape the direction of clinical practice and research in the next 5–10 years. These observations include: (1) a decline in prostate-related cancer mortality in the United States, likely owing to a combination of factors including screening, more aggressive and earlier therapy, and improvements in specific therapies; (2) a significant downward pathological stage migration, so that an individual’s chance of cure for a given stage, grade, and PSA is better now than it was early in the PSA era, even without associated improvements in individual therapies; (3) the recognition of new PSA isoforms that may refine screening strategies; (4) several randomized, phase III clinical trials demonstrating survival advantages of one form of therapy over another in selected populations (external beam radiotherapy with adjuvant hormones vs radiotherapy alone, radical prostatectomy vs observation); (5) a focus on the biology of bone and bone metastasis, and new agents that reduce skeletal-related events and which may inhibit the growth of new metastases; (6) second-generation anti-PSMA antibodies with improved potential for imaging and therapy; (7) the development and widespread adoption of nomograms that assist in clinical decision-making for individual patients; (8) the identification of new genes that predispose some individuals to hereditary and sporadic forms of prostate cancer, and which will be targets for new therapies and prevention strategies; and (9) the demonstration in a large population-based phase III clinical trial (the Prostate Cancer Prevention Trial) that prostate cancer can be prevented (albeit perhaps at the cost of a slightly increased risk of high-grade cancer in some men) by inhibiting the conversion of testosterone to DHT. Together these findings are cause for optimism in the battle to prevent and cure this disease. Needless to say, despite this progress, many challenges remain. Perhaps the most important is to develop biologic and clinical tools that can accurately identify who needs treatment and who does not, taking into account both the biological features of the tumor and the potential time-related competing causes of death for an individual patient. The development of such tools will be useful not only in newly diagnosed men, but also in those who fail initial definitive therapy. A second biologic challenge will be to identify specific molecular pathways operative in individuals to allow for individually tailored therapy. A further challenge is to convince the nonurologic world that screening works to reduce mortality at an acceptable cost (both in terms of treatment-related morbidity and dollars). It is not possible to summarize in one volume all that has been accomplished since the first edition—a PubMed search in August 2003 revealed 11,399 scientific articles under the heading “prostate cancer” since 2000 alone—but my hope is that the collected wisdom of the contributors will fairly reflect our current state of knowledge and highlight vii

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Preface

what still needs to be done in their respective fields. As always, I am deeply appreciative to all who contributed to this second edition, to my clinical and scientific colleagues at the Cleveland Clinic who keep my professional life interesting and engaging, and the editorial staff at Humana Press for their guidance. Eric A. Klein, MD

Contents Preface ........................................................................................................................ vii List of Contributors ................................................................................................... xiii Value-Added EBook/PDA ....................................................................................... xvii

Part I. Screening, Risk Factors, Diagnosis, and Prevention 1 Prostate Cancer Overdiagnosis and Overtreatment: Analysis of US Mortality and SEER Incidence Trends in the PSA and Pre-PSA Eras ....................................... 3 Robert A. Stephenson 2 Total, Complexed, and Free PSA Forms and Human Glandular Kallikrein 2: Clinical Application for Early Detection and Staging of Prostate Cancer ............. 15 Alexander Haese and Alan W. Partin 3 Defining an Optimum PSA-Based Screening Strategy for Young Men ....................... 37 Judd W. Moul 4 Hereditary Prostate Cancer and Genetic Risk ................................................................ 57 Phillippa J. Neville, Graham Casey, and John S. Witte 5 Strategies for the Chemoprevention of Prostate Cancer ................................................ 71 Ronald Lieberman, Jacob Kagan, Margaret G. House, Joseph Kelaghan, David J. Kausal, and Howard L. Parnes 6 The Special Problems of Prostate Cancer Among African Americans: Clinical and Molecular Factors .............................................................................. 107 Isaac J. Powell 7 Current Issues in Pathologic Evaluation ...................................................................... 121 Howard S. Levin 8 Current Trends in Biopsy Techniques .......................................................................... 143 Joseph C. Presti, Jr.

Part II. Localized Disease: Treatment and Outcomes 9 Predicting Outcomes: Artificial Neural Networks and Nomograms ........................... 159 Audrey C. Rhee, Christopher J. Di Blasio, Daniel Cho, and Michael W. Kattan 10 When Is Observation Appropriate? .............................................................................. 195 Kisseng Hsieh and Peter C. Albertsen 11 Contemporary Technique of Radical Prostatectomy: Open Approach ....................... 217 Eric A. Klein 12 Contemporary Technique of Radical Prostatectomy: Laparoscopic Approach ......... 243 Sidney C. Abreu, Andrew P. Steinberg, and Inderbir S. Gill 13 Contemporary Technique of Radical Prostatectomy: Perineal Approach .................. 263 Vernon E. Weldon 14 Anesthetic Considerations for Contemporary Radical Prostatectomy ........................ 297 Jerome F. O’Hara, Jr. and David Whalley ix

x

Contents 15 Conformal External Beam Radiotherapy ..................................................................... 309 Arul Mahadevan and Patrick A. Kupelian 16 Brachytherapy ............................................................................................................... 329 Kenneth W. Angermeier and Jay P. Ciezki 17 Androgen Deprivation and Radiation Therapy for Localized Prostate Cancer .......... 341 Patrick A. Kupelian and Tom Carlson 18 Prostate Brachytherapy: The Role of Supplemental External Beam Radiotherapy .................................................................................................. 357 Gregory S. Merrick and Wayne M. Butler 19 Health-Related Quality of Life Issues .......................................................................... 373 John T. Wei and David Miller 20 The Evaluation and Management of Postprostatectomy Urinary Incontinence ................................................................................................ 393 Adonis Hijaz, M. Louis Moy, Sandip P. Vasavada, and Raymond R. Rackley 21 Sural Nerve Grafting During Radical Prostatectomy: Techniques and Results ......... 411 Edward D. Kim 22 Management of Erectile Dysfunction Following Radical Prostatectomy ................... 431 Craig D. Zippe and Rupesh Raina 23 Counseling Patients With Localized Prostate Cancer: Radiation or Surgery? .......... 459 Eric A. Klein and Patrick A. Kupelian 24 Counseling the Patient With Prostate Cancer: The Radiation Oncologist’s Perspective ................................................................. 481 Anthony Zietman 25 Counseling Patients on Choice of Therapy: The Medical Oncologist’s Perspective .................................................................... 491 Celestia S. Higano 26 Emotional and Informational Support for the Patient Undergoing Radical Prostatectomy .............................................................................................. 501 Dorothy A. Calabrese 27 Prostate Cancer: A Survivor’s View .............................................................................. 513 Nathaniel K. Cooke 28 Prostate Cancer: A Spouse’s View ................................................................................ 519 Nancy L. Cooke

Part III. Advanced Disease 29 Management of PSA Recurrence After Definitive Therapy for Prostate Cancer ....... 525 Ilia S. Zeltser, Richard K. Valicenti, and Leonard G. Gomella 30 When to Refer a Patient With Prostate Cancer to a Medical Oncologist: The Earlier the Better .............................................................................................. 553 Jeanne Smoot and Nancy A. Dawson 31 Management of Newly Diagnosed Metastatic Disease ............................................... 561 Thomas E. Hutson 32 Management of the Patient With Androgen-Independent Metastatic Prostate Cancer ......................................................................................................... 579 Robert Dreicer

Contents

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33 Bone-Targeted Therapy for Prostate Cancer................................................................ 589 Navjeet Gandhok and Oliver Sartor

Part IV. Applied Molecular Biology 34 Biology of PSMA As a Diagnostic and Therapeutic Target ....................................... 609 Sam S. Chang, Neil H. Bander, and Warren D. W. Heston 35 Opportunities for Targeted Molecular Therapy for Prostate Cancer .......................... 631 Evan Y. Yu, William C. Hahn, Daniel J. George, and Philip W. Kantoff Index .......................................................................................................................... 653

Contributors SIDNEY C. ABREU, MD • Section of Laparoscopic and Minimally Invasive Surgery, Cleveland Clinic Foundation, Cleveland, OH PETER C. ALBERTSEN, MD • Division of Urology, University of Connecticut Health Center, Farmington, CT KENNETH W. ANGERMEIER, MD • Section of Prosthetic Surgery and Genitourethral Reconstruction, Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH NEIL H. BANDER, MD • Department of Urology, Weill College of Medicine of Cornell University, and The New York Hospital, New York, NY WAYNE M. BUTLER, PhD • Schiffler Cancer Center, Wheeling Hospital, and Wheeling Jesuit University, Wheeling, WV DOROTHY A. CALABRESE, MSN, RN, CNP • Taussig Cancer Center and Glickman Urologic Institute, Cleveland Clinic Foundation, Cleveland, OH TOM CARLSON, MD • Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH GRAHAM CASEY, PhD • Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, OH SAM S. CHANG, MD • Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN DANIEL CHO, MD • Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY JAY P. CIEZKI, MD • Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH NANCY L. COOKE • Spouse of Prostate Cancer Survivor, Cleveland Heights, OH NATHANIEL K. COOKE • Prostate Cancer Survivor, Cleveland Heights, OH NANCY A. DAWSON, MD • Professor of Medicine, Greenebaum Cancer Center, University of Maryland, Baltimore, MD CHRISTOPHER J. DI BLASIO, MD • Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY ROBERT DREICER, MD, FACP • Director, Genitourinary Medical Oncology, Associate Director, Experimental Therapeutics, Department of Hematology/Oncology and The Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH NAVJEET GANDHOK, MD • Stanley S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, LA DANIEL J. GEORGE, MD • Associate Professor of Medicine and Surgery, Division of Urology, Section of Genitourinary Medical Oncology, Duke University Medical Center, Durham, NC INDERBIR S. GILL, MD • Head, Section of Laparoscopic and Minimally Invasive Surgery, Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH LEONARD G. GOMELLA, MD • The Bernard W. Godwin Professor of Prostate Cancer, Chairman, Department of Urology, and Director of Urologic Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA xiii

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Contributors

ALEXANDER HAESE, MD • Department of Urology, University Clinic Hamburg-Eppendorf, Hamburg, Germany WILLIAM C. HAHN, MD, PhD • Assistant Professor of Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA WARREN D. W. HESTON, PhD • Department of Cancer Biology, Lerner Research Institute, and Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH CELESTIA S. HIGANO, MD • Associate Professor, Departments of Medicine and Urology, University of Washington, Seattle, WA ADONIS HIJAZ, MD • Section of Female Urology and Voiding Dysfunction, Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH MARGARET G. HOUSE, RN, BSN • Nurse Specialist, Prostate and Urologic Cancer Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD KISSENG HSIEH, MD • Division of Urology, University of Connecticut Health Center, Farmington, CT THOMAS E. HUTSON, DO, PharmD • GU Oncology Program, Texas Oncology, PA Sammons Cancer Center, Baylor University Medical Center, Dallas, TX JACOB KAGAN, MSc, PhD • Program Director, Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD PHILIP W. KANTOFF, MD • Director, Lank Center for Genitourinary Oncology, Chief, Division of Solid Tumor Oncology, Associate Professor of Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA MICHAEL W. KATTAN, PhD • Departments of Urology and Biostatistics and Epidemiology, Memorial Sloan-Kettering Cancer Center, New York, NY DAVID J. KAUSAL, MA • Program Specialist, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD JOSEPH KELAGHAN, MD, MPH • Program Director, Community Oncology and Prevention Trials Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD EDWARD D. KIM, MD • Associate Professor of Surgery/Urology, Department of Surgery, Division of Urology, University of Tennessee Medical Center at Knoxville, Knoxville, TN ERIC A. KLEIN, MD • Head, Section of Urology Oncology, Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH PATRICK A. KUPELIAN, MD • Department of Radiation Oncology, M. D. Anderson Cancer Center Orlando, Orlando, FL HOWARD S. LEVIN, MD • Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH RONALD LIEBERMAN, MD • Program Director, Medical Project Officer, Prostate and Urologic Cancer Research Group, Division of Cancer Prevention, Bethesda, MD ARUL MAHADEVAN, MD • Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH GREGORY S. MERRICK, MD • Schiffler Cancer Center, Wheeling Hospital, and Wheeling Jesuit University, Wheeling, WV

Contributors

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DAVID MILLER, MD • NIH Clinical Research Fellow, Department of Urology, The University of Michigan, Ann Arbor, MI JUDD W. MOUL, MD, FACS, COL, MC, US ARMY • Urology Service, Department of Surgery, Walter Reed Army Medical Center, Washington DC; Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD M. LOUIS MOY, MD • Section of Female Urology and Voiding Dysfunction, Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH PHILLIPPA J. NEVILLE, PhD • Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, OH JEROME F. O’HARA, JR., MD • Head of Anesthesia, Glickman Urological Institute, Vice Chairman, Department of General Anesthesiology, The Cleveland Clinic Foundation, Cleveland, OH HOWARD L. PARNES, MD • Chief, Prostate and Urologic Cancer Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD ALAN W. PARTIN, MD • Professor, The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, MD ISAAC J. POWELL, MD • Professor, Department of Urology, Karmanos Cancer Institute, Wayne State University, Detroit, MI JOSEPH C. PRESTI, JR., MD • Associate Professor of Urology, Department of Urology, Stanford University School of Medicine, Stanford, CA RAYMOND R. RACKLEY, MD, • Co-head, Section of Female Urology and Voiding Dysfunction, Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH RUPESH RAINA, MD • Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH AUDREY C. RHEE • Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY OLIVER SARTOR, MD • Patricia Powers Strong Professor of Oncology, Director, Stanley Scott Cancer Center, Chief, Hematology/Oncology, LSU School of Medicine, New Orleans, LA JEANNE SMOOT, CRNP • Greenebaum Cancer Center, University of Maryland, Baltimore, MD ANDREW P. STEINBERG, MD • Fellow, Section of Laparoscopic and Minimally Invasive Surgery, Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH ROBERT A. STEPHENSON, MD • Professor of Surgery, Jon M. Huntsman Chair of Urological Oncology, Division of Urology, University of Utah Health Sciences Center, Salt Lake City, Utah RICHARD K. VALICENTI • Associate Professor, Department of Radiation Oncology and Co-Director GU Multidisciplinary Clinic, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA SANDIP P. VASAVADA, MD • Co-head, Section of Female Urology and Voiding Dysfunction, Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH JOHN T. WEI, MD, MS • Assistant Professor, Director, Division of Clinical Research and Quality Assurance, Department of Urology, The University of Michigan, Ann Arbor, MI

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Contributors

VERNON E. WELDON, MD • Chief, Division of Urology, Marin General Hospital, San Rafael, CA DAVID WHALLEY, MB, ChB • Chairman, Department of Anesthesiology, Cleveland Clinic Naples, Naples, FL JOHN S. WITTE, PhD • Departments of Epidemiology and Biostatistics, and Urology, University of California, San Francisco, CA EVAN Y. YU, MD • Clinical Fellow in Hematology/Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA ILIA S. ZELTSER, MD • Senior Resident, Department of Urology, Thomas Jefferson University, Philadelphia, PA ANTHONY ZIETMAN, MD • Professor of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA CRAIG D. ZIPPE, MD • Co-Director, Prostate Center, Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH

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I

SCREENING, RISK FACTORS, DIAGNOSIS, AND PREVENTION

1

Prostate Cancer Overdiagnosis and Overtreatment Analysis of US Mortality and SEER Incidence Trends in the PSA and Pre-PSA Eras

Robert A. Stephenson

INTRODUCTION The widespread use of serum prostate-speciﬁc antigen (PSA) testing has had profound effects on the diagnosis and treatment of prostate cancers since its introduction in the 1980s (1). As a result of PSA-based improvements in diagnosis and increased levels of diagnostic activity, prostate cancer incidence rates rose abruptly at a rate unprecedented in the history of oncology in the United States. The magnitude of change seen in prostate cancer incidence during the 1990s has not previously been observed in any other cancer (2). Factors that contributed to the unprecedented increase in prostate cancer incidence include the high preclinical prevalence of prostate cancer and the increased detection of prostate cancer using PSA testing resulting from widespread acceptance and use of the PSA test. It appears unlikely that changes in incidence of this magnitude will be seen again for prostate cancer or any other malignancy. Subsequent to the introduction of PSA testing, substantial declines in the age at diagnosis, marked shifts toward earlier clinical stage, declines in prostate cancer volume, changes in grade, and increased rates of cancer treatment have been observed; these factors raise the possibility that improved prostate cancer control rates are being achieved as a result of prostate cancer detection and earlier treatment (1). At present, more information is needed to elucidate the survival beneﬁt, treatment burden, and cost related to earlier diagnosis and increased levels of treatment for prostate cancer. More work is also needed to understand the positive and negative outcomes of both watchful waiting and early diagnosis and treatment of prostate cancer. Particular attributes of prostate cancer and of PSA detection methods suggest the high likelihood that we have experienced increases in overdiagnosis and overtreatment of prostate cancer during the PSA era. It is also probable that substantial declines in

From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

3

4

Stephenson

underdiagnosis and undertreatment have taken place. Increases in overdiagnosis and overtreatment are related to several factors: (1) the prolonged natural history of prostate cancer, with death of the host from prostate cancer possibly occurring decades from the time of diagnosis whether or not treatment is undertaken; (2) the generally older age of men when diagnosed with prostate cancer, with the effect of competing causes of death possibly leading to death of the host prior to the time when death or morbidity from prostate cancer would have occurred; and (3) the lack of speciﬁcity of PSA for prostate cancer vs other prostate disease states, together with the high prevalence of clinically unimportant cancer in the general population, possibly resulting in detection of increased numbers of unimportant cancers (those not destined to result in difﬁculty during an individual’s lifetime). Overdiagnosis and overtreatment of prostate cancer cannot be easily or directly measured, but inferences or estimates can be made by examination of population-based datasets. Trends in incidence and mortality in the pre-PSA and PSA eras are reviewed ﬁrst, then incidence and mortality data with overdiagnosis and overtreatment in mind, and ﬁnally a published estimate of overdiagnosis.

INCIDENCE Figure 1 shows SEER incidence data for the years 1973–1999. These data can be divided into the pre-PSA and PSA eras roughly as drawn, with the PSA era beginning in the late 1980s. The pre-PSA era is characterized by a gradual increase in prostate cancer incidence over time. The observed rise in incidence in the pre-PSA era can be attributed to one or both of two possible effects. One possible effect is increasing incidence owing to gradually increasing environmental risk for prostate cancer in the population caused by changing exposures to unknown dietary or environmental factors. The other effect causes gradual increases in incidence owing either to increased diagnostic activity or to gradual improvement in the effectiveness of diagnostic methods. Merrill et al. (3) demonstrate clearly that virtually all the increase in prostate cancer incidence in the prePSA era can be explained by rising rates of transurethral resection of the prostate (TURP)-diagnosed prostate cancer. Once rates are controlled for the increases in diagnosis derived from increasing rates of TURP-diagnosed prostate cancer, there is little evidence for an effect on incidence owing to changes in dietary or environmental exposure. As the PSA era began, an abrupt rise in prostate cancer incidence was observed through 1992, the peak year (Fig. 1). This abrupt rise appears to be a result of enhanced prostate cancer detection caused by increased use of PSA, thereby making possible the diagnosis of large numbers of previously preclinical prostate cancers. The equally rapid decline in prostate cancer incidence through about 1995 was probably owing to a cull effect whereby fewer cases of prostate cancer were detected in previously screened individuals (4). Subsequent to the peak incidence years, a new, relatively stable incidence rate is observed in 1995–1999 (Fig. 1). This incidence rate is higher than incidence rates seen prior to the PSA era, suggesting that PSA-based methods continue to diagnose prostate cancer at higher rates despite the earlier cull effect.

MORTALITY Figure 2 shows US mortality rates from 1973 to 2000. Prostate cancer mortality rates rose slowly from 1973 through the late 1980s. The observed increase in mortality

Chapter 1 / Overdiagnosis and Overtreatment of Prostate Cancer

5

Fig. 1. SEER prostate cancer incidence (age-adjusted/100,000). A vertical line is drawn roughly separating the pre-PSA and PSA eras.

Fig. 2. US prostate cancer mortality (age-adjusted/100,000). Two vertical lines are drawn to denote a region of suspected increased attribution bias.

could possibly result from a gradual increase in the number of biologically lethal cancers secondary to changing environmental risk factors, a decreasing use or effectiveness of therapy over time, or very gradual attribution bias effects. The magnitude of the increase in mortality during these years is quite small. Since prostate cancer treatment rates increased from 1973 to the late 1980s, it is unlikely that changes in therapy explain the observed increase in prostate cancer mortality. In the early 1990s an abrupt rise in mortality was observed. This abrupt, yet relatively

6

Stephenson Table 1 Percent US Mortality Declines by Year Percent decline from Year

Previous year

Peak year (1991)

1992 1993 1994 1995 1996 1997 1998 1999

0.3 0.0 2.3 3.4 3.5 5.3 4.4 3.7

0.3 0.0 2.3 5.6 8.9 13.8 17.6 20.7

small-magnitude, increase in mortality may have been caused by an increase in attribution bias, which may have occurred when the National Center for Health Statistics made a change from manual to automated methods for assignment of cause of death. This change in death attribution methods may have introduced a small increase into US prostate cancer mortality data. This observed change in prostate cancer mortality seen in the early 1990s makes interpretation of more recent mortality trends somewhat problematic. Subsequent to 1991, the peak mortality year, steady declines in prostate cancer mortality have been reported through 1999 (Table 1, Fig. 2). If methods of death attribution have been readjusted to correct for the increase in attribution bias presumably seen in the early 1990s, then part or perhaps all of the decline in prostate cancer mortality seen subsequently is owing to this correction. However, the magnitude of subsequent mortality declines is nearly 2.5 times larger than the increase in mortality seen as a result of possible increases in attribution bias. (Possible attribution-bias increase from 1988 to 1991 was from 35.9 to 39.2 deaths/100,000, for an increase of 3.3; the subsequent mortality decline from 1991 to 1999 was from 39.2 to 31.1 deaths/100,000, for a decline of 8.1.) This suggests that correction of attribution bias is, at most, only a partial explanation for subsequent declines in mortality rates. Alternatively, if death attribution methods have remained stable subsequent to the introduction of automated methods, then it is possible that the “real” mortality rate has declined somewhat more than is represented in currently reported mortality data. This effect is represented graphically in Fig. 3. Because increases in mortality rates that may have been caused by increased attribution bias in the early 1990s are small in magnitude compared with mortality declines subsequent to 1991, it appears likely that we are experiencing signiﬁcant declines in prostate cancer mortality in the United States. These mortality declines are related temporally to increased diagnostic and treatment activity in both the pre-PSA and PSA eras. Rates of both radical prostatectomy and radiation therapy rose steadily through the 1980s (pre-PSA era) whereas hormone therapy and no-treatment rates remained stable (Fig. 4). Patients treated in the 1980s with these modalities should be reﬂected in the mortality data of the 1990s. For patients who received treatment in the PSA era (the 1990s), much less time has passed to have an impact on mortality data. Early-stage cancers from the PSA era would not be expected to have a substantial effect on currently available mortality data, but for some aggressive/more advanced

Chapter 1 / Overdiagnosis and Overtreatment of Prostate Cancer

7

Fig. 3. US prostate cancer mortality (age-adjusted/100,000). Two vertical lines are again drawn to denote a region of suspected increased attribution bias. The dashed curve represents a hypothetical mortality curve if the effects of attribution bias could be removed from mortality data.

Fig. 4. SEER prostate cancer incidence (age-adjusted/100,000) by type of treatment for men with local and regional stage. Note substantial increases in rates of radical prostatectomy and radiation.

cancers that were treated with surgery, radiation, and/or hormone therapy and in which progression was delayed, more prolonged survival or perhaps cure in some cases may also have had an impact on currently reported mortality data.

OVERDIAGNOSIS AND OVERTREATMENT There are always some patients, regardless of cancer type, who are overdiagnosed/ treated and some who are underdiagnosed/treated. Conservative strategies result in

8

Stephenson

undertreatment of some patients who will beneﬁt, whereas some will be spared treatment they do not need. Aggressive strategies result in overtreatment of some patients who will not beneﬁt from therapy but reduce cancer-related morbidity in some patients and cure cancer in others. In the case of aggressive strategies, there are two categories of overtreated patients. In one category, patients die of other causes but never would have been troubled by their cancer. In the other category, patients receive cancer treatments that offer no beneﬁt owing to cancer aggressiveness and extent, which are beyond the therapeutic scope of treatment. Both conservative and aggressive treatments are correct cancer management strategies, but only some of the time. Unfortunately, the selection of the right treatment approach for individual patients is an endeavor associated with considerable uncertainty. At the time of patient death, the date of death and interval from diagnosis to death are precisely known. Although not perfectly determined, the cause of death is also very well attributed. However, at the time of cancer diagnosis, when treatment decisions must often be made, the date of death, cause of death, and degree of patient morbidity from cancer and/or treatment are matters of weak statistical speculation for the individual patient. Unfortunately, the key to making a completely correct treatment decision at diagnosis for each individual requires precise knowledge of when death would occur from non-prostate cancer causes and when death or signiﬁcant morbidity would occur from untreated prostate cancer. It is also important to determine what additional beneﬁt is achieved when aggressive therapy is applied. Given the uncertainty of life, better methods for determining time to death from prostate cancer and nonprostate cancer causes are unlikely ever to be sufﬁciently robust to address this important question precisely for individual patients. Therefore, unavoidably, incorrect decisions will be made for many individuals with cancer. The paradox of prostate cancer in the PSA era appears to be that, concurrent with the successful life-saving efforts of diagnosis and treatment we may achieve in some men, we are also treating many men who do not need treatment, men destined to die from other causes of death (or men with incurable cancers in whom treatment offers no beneﬁt). Although we may currently be experiencing substantial declines in prostate cancer mortality, there are several forms of information indicating that we are also overdiagnosing and overtreating prostate cancer at higher rates than we did in previous years. Let us examine some population-based evidence for increasing levels of overdiagnosis and treatment. Using a population-based cohort, Albertsen et al. (5) demonstrate that many pre-PSA era patients, when followed without treatment, were destined to die of non-prostate cancer causes. In Fig. 5 mortality and incidence rates are plotted concurrently. It is striking to note the large differences in magnitude of mortality and incidence rates. Although overdiagnosis and treatment clearly occurred in the pre-PSA era, the rising gap between incidence and mortality rates seen in the PSA era is strongly indicative of increasing rates of overdiagnosis. There are also strong shifts to earlier cancer stages, with the result that many men are diagnosed and treated at points in the course of their disease at which death from prostate cancer is remote and the risk of death subsequent to an unneeded prostate cancer treatment from competing non-prostate causes is therefore increased substantially (6). It is also important to note that, to date, declines in mortality are quite small compared with the large numbers of men diagnosed and treated with prostate cancer. Even if prostate cancer mortality could be completely eradicated, it would be accomplished at the expense of substantial overtreatment.

Chapter 1 / Overdiagnosis and Overtreatment of Prostate Cancer

9

Fig. 5. SEER prostate cancer incidence and US prostate cancer mortality (age-adjusted/100,000) shown concurrently. The ﬁgure denotes the rising gap between incidence and mortality rates, an indirect measure of increasing overdiagnosis.

Table 2 Average Ratio of Mortality to Incidence (×100) for Common Cancers: 1980–1999 Cancer type

Ratio

Pancreatic Lung and bronchus Ovarian Colorectal Breast Prostate

92.5 84.8 54.9 41.1 25.2 24.5

If one examines the average yearly ratio of mortality to incidence for prostate cancer and other common cancers, one gets a general impression of both the relative lethality of particular cancers and the potential for overdiagnosis and treatment (Table 2). For the 20-yr span from 1980 through 1999, the average yearly ratio of mortality to incidence is 0.24 for prostate cancer, whereas the same ratio for pancreatic cancer is 0.93. This ratio disparity illustrates the substantially higher lethality of pancreatic cancer relative to prostate cancer, and it also indicates that many more individuals must be diagnosed and successfully treated to have a measurable impact on mortality in prostate cancer than in pancreatic cancer. This is another way to look at the issue of overdiagnosis and treatment. Simply stated, one must diagnose more individuals with prostate cancer and achieve successful treatment to have a similar impact on mortality rates compared with pancreatic cancer. This is because many more men with prostate cancer receive a treatment they do not need because they are destined to die of non-prostate cancer causes.

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Stephenson

Fig. 6. Ratio of yearly mortality to incidence rates (×100) for prostate and breast cancer. The decline in the ratio is an indirect measure of change in overdiagnosis over time.

Fig. 7. Ratio of yearly mortality to incidence rates (×100) for pancreatic, lung/bronchus, ovary, and colorectal cancers. The mortality-to-incidence ratios are stable in these cancers, suggesting little evidence for increasing overdiagnosis over time.

In Fig. 6 the yearly ratio of mortality to incidence for prostate and breast cancer are plotted for the years 1980–1999. For prostate cancer, the ratio declines from 0.31 in 1980 to 0.17 in 1999. This decline also suggests increasing overdiagnosis over time as our diagnostic ability has increased. Although a similar ratio decline is noted with breast cancer (Fig. 6), another cancer characterized by increasing overdiagnosis, other cancers are associated with more stable ratios over time (Fig. 7).

Chapter 1 / Overdiagnosis and Overtreatment of Prostate Cancer

11

Fig. 8. SEER prostate cancer incidence (age-adjusted/100,000). Line A is a hypothetical line demonstrating “real” incidence of prostate cancer assuming the increasing incidence of the pre-PSA era was owing to increasing environmental risk (probably an erroneous assumption). Line B is a hypothetical line demonstrating the “real” incidence when the artifact of improved diagnosis is removed from both the pre-PSA era (owing largely to TURP-diagnosed cancer) and PSA era (owing largely to PSA-diagnosed cancer). The difference from these hypothetical lines and observed incidence is another indirect measure of increasing overdiagnosis.

Another way of examining the problem of overdiagnosis is shown in Fig. 8. Incidence rates are currently higher than what we would project based on pre-PSA era incidence rates. Incidence rates after the PSA peak in 1992 have reached a relatively steady state. Please note that this “steady state” incidence appears to be higher than incidence rates in the pre-PSA era. There are two ways I would like to consider this new higher steady-state incidence observation. In one scenario we assume that the gradual rise in incidence seen in the pre-PSA era was owing to a gradual increase in the environmental risk of developing prostate cancer. This is demonstrated by line A, which is an extension of the pre-PSA incidence at the same slope through the PSA era and provides an estimate of where PSA incidence might be expected to return if no additional overdiagnosis was occurring once the PSA peak stabilized. Although it is not a direct measure of overdiagnosis (because some individuals who will beneﬁt from diagnosis and treatment are included in those differences as well), the difference in the projected line and the actual incidence is an indicator of increased overdiagnosis. One signiﬁcant problem with this scenario is that the gradual rise in incidence in the pre-PSA era is not caused by rising environmental risk. As shown by Merrill et al. (3), essentially all the increase in incidence of prostate cancer during the pre-PSA era can be accounted for by increases in TURP-based diagnosis of prostate cancer. Since the rise in TURP-diagnosed cancer accounts for nearly all the increase in incidence of the pre-PSA era there is little evidence for changing environmental risk as a cause of rising incidence in the pre-PSA era. Line B in Fig. 8 represents what may be a more realistic projection of incidence with the removal of enhanced diagnosis effects in both the pre-PSA era (from TURP-diagnosed cancers) and the PSA era (from PSA-detected

12

Stephenson

cancers). In the case of line B, the difference between observed incidence and “real” incidence is substantially larger and suggests even larger increases in overdiagnosis and treatment. Again, it is important to point out that among these groups of diagnosed individuals there are also patients who beneﬁt from therapy. However, since declines in mortality are currently small in magnitude (and even if they subsequently fall steeply, or even if prostate cancer death is eliminated!), large numbers must be diagnosed and treated for small gains to be achieved in prostate cancer mortality. Etzioni et al. (7) estimated prostate cancer overdiagnosis for the years 1988–1998 using SEER data and a computer simulation model. The model identiﬁed cases of prostate cancer in which diagnosis was made earlier owing to observed lead time effects associated with the use of PSA testing. It is important to point out that the authors deﬁned overdiagnosis in an unusual way, as the detection of prostate cancer with PSA that otherwise would not have been diagnosed within the patient’s lifetime. The authors did not address the question of whether individuals needed a prostate cancer diagnosis or treatment to alter their life outcome. Using their simulation model, they estimated an overdiagnosis of 29% in White and 44% in Black Americans among men whose cancers were detected using PSA. In their estimates of PSA-diagnosed prostate cancer, they accounted for rising TURP-diagnosed prostate cancer rates from 1973 through about 1988, and the decline in TURP-diagnosed cancers from 1988 through 1998. The authors ran their model using average PSA-induced prostate cancer diagnosis lead times of 3, 5, and 7 yr. Five- and 7-yr lead time assumptions proved to ﬁt best with the observed SEER incidence data. Although it is useful to have estimates of the increase in prostate cancer diagnosis that resulted from the introduction of PSA testing as deﬁned and estimated by Etzioni et al. (7), the central concern for patients with respect to overdiagnosis and treatment is how many patients receive a diagnosis that is not important during their lifetime and how many patients receive a treatment they do not need. The estimates provided by Etzioni et al. based on changes in clinical diagnosis from the pre-PSA to the PSA eras should substantially underestimate the number of patients in these categories.

CONCLUSIONS Data from the pre-PSA era demonstrate substantial rates of death from non-prostate cancer causes in prostate cancer patients who were managed conservatively (5). These data demonstrate that many men who are diagnosed with prostate cancer do not need treatment. Population-based data trends strongly suggest that overdiagnosis and treatment have increased substantially in the PSA era. Given these realities, physicians need to understand and then realistically address the problem of overdiagnosis and overtreatment with their patients. It is clear that tools to predict time to death from prostate cancer and tools to predict time to death from other causes will never be sufﬁciently robust to make correct decisions consistently for each individual patient. Therefore, decisions to undertake diagnosis and treatment of prostate cancer should be made with careful assessment of the overall health and comorbidity of individual patients and with awareness of the substantially increased risk of overdiagnosis and treatment that has attended the PSA era.

REFERENCES 1. Stephenson RA. Prostate cancer trends in the era of prostate-speciﬁc antigen: an update of incidence, mortality, and clinical factors from the SEER database. Urol Clin North Am 2002;29:173. 2. http://seer.cancer.gov.

Chapter 1 / Overdiagnosis and Overtreatment of Prostate Cancer

13

3. Merrill RM, Feuer EJ, Warren JL, Schussler N, Stephenson RA. Role of transurethral resection of the prostate in population-based prostate cancer incidence rates. Am J Epidemiol 1999;150:848. 4. Stephenson RA, Smart CR, Mineau GP, James BC, Janerich DT, Dibble R. The fall in incidence of prostate cancer: on the down side of a PSA induced peak in incidence. Cancer 1996;77:1342. 5. Albertsen PC, Fryback DG, Storer BE, Kolon TF, Fine J. Long-term survival among men with conservatively treated localized prostate cancer. JAMA 1995;274:626. 6. Stanford JL, Stephenson RA, Coyle LM, et al. Prostate Cancer Trends 1973–1995. NIH Pub. No. 994543. SEER Program, National Cancer Institute, Bethesda, MD, 1999. 7. Etzioni R, Penson DF, Legler JM, et al. Overdiagnosis due to prostate-speciﬁc antigen screening: lessons from the U.S. prostate cancer incidence trends. J Natl Cancer Inst 2002;94:981.

2

Total, Complexed, and Free PSA Forms and Human Glandular Kallikrein 2 Clinical Application for Early Detection and Staging of Prostate Cancer

Alexander Haese and Alan W. Partin

INTRODUCTION In the United States, extensive use of prostate-speciﬁc antigen (PSA) for early detection of prostate cancer prostate cancer was responsible for a steady increase in the incidence of clinically and pathologically localized prostate cancer for more than a decade, with the incidence of locally advanced or metastatic disease steadily declining (1). The massive impact of PSA on the presentation of prostate cancer has caused concerns of overdetection and initiation of unnecessary treatment for so-called clinically insigniﬁcant prostate cancer. Recently, a decrease in prostate cancer incidence was noted, and today the incidence is only minimally higher than that seen in the pre-PSA era (2), suggesting that PSA is effective as a screening tool. An effective screening tool will increase the detection of a certain disease; however, the incidence should decrease over time, if signiﬁcant disease is detected through that screening method. If, however the incidence does not decline, it is possible that insigniﬁcant disease may be detected. Today, most newly diagnosed prostate cancers are detected because of an elevated PSA level, so-called clinical stage T1c cancers (3,4). The incidence of pathologically organ-conﬁned prostate cancer is higher, and hence the prognosis of such cancers is much better than in those prostate cancers detected on digital rectal examination or transrectal ultrasonography. Thus, PSA has already considerably improved early detection of prostate cancer. Still, only about 60% of all T1c prostate cancers are pathologically organ-conﬁned (5,6); therefore there is a need for improvement in the early detection of clinically signiﬁcant prostate cancer. A variety of PSA variants are immunodetectable and can be used in clinical practice. In this chapter, we describe the clinically relevant forms of PSA for early detection, staging, and surgical management of prostate cancer. From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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Haese and Partin

PSA IN THE EARLY DETECTION OF PROSTATE CANCER Total PSA Background: The diagnosis of prostate cancer requires microscopic evaluation of a biopsy specimen of the prostate, preferably obtained under ultrasound guidance. The likelihood of prostate cancer increases with increasing serum PSA concentrations, but prostate cancer is also associated with the presence or absence of a palpable prostate lesion. Retrospective studies suggest that an elevated PSA concentration owing to prostate cancer occurs a mean of 6.2 years before a palpable lesion can be identiﬁed (7). The concern that PSA for early detection of prostate cancer could be overused (leading to detection and treatment of cancers that could be clinically insignificant) is not supported by clinical experience. First descriptions of clinically insignificant cancers assessed the volume of prostate cancers found in patients who underwent cystoprostatectomy for bladder cancer (8). Other, more recent definitions take into account not only the volume but also the differentiation of the cancer (9). Insignificant cancers detected on autopsy are >90% with low volume (e.g., <0.5 mL) and of a low grade (Gleason sum <4) (10). Comparing these results with the pathologic features of prostate cancers detected through screening and removed surgically, <10% of these cancers show similar criteria of insignificance (11,12). Therefore, at present, there is only limited evidence that PSA leads to treatment of insignificant prostate cancer. Despite its positive use in prostate cancer detection, PSA is a marker for prostate tissue of malignant but also benign differentiation and hence is not a perfect cancer marker. Two other common disorders (benign prostatic hyperplasia [BPH] and chronic prostatitis) increase serum PSA concentrations. Other factors (ejaculation [13], physical activity, cystoscopy, prostate biopsy [14]) can increase serum PSA as well. On the other hand, the 5-α-reductase inhibitor Finasteride, used for treatment of symptomatic bladder outlet obstruction owing to benign prostatic hyperplasia, decreases serum PSA by approx 50%, while maintaining the ratio of free to-total PSA (15). THE MEANING OF PSA RANGES IN MEN WITH NONSUSPICIOUS FINDINGS ON DIGITAL RECTAL EXAMINATION Total PSA below 4 ng/mL. The incidence of signiﬁcant prostate cancer has been shown to be as high as 22% in men with a total PSA in the range 2.6–4 ng/mL. Moreover, the cancers removed—although still clinically signiﬁcant—were organ-conﬁned cancers in 81% (16). The European Randomized Screening Trial for Prostate Cancer (ESPRC) study results of patients with comparable characteristics demonstrated a prostate cancer detection rate of 19% in the PSA range 2.0–3.9 ng/mL and a rate of pathologically organ-conﬁned cancers of 84% as opposed to only 62% organ conﬁnement rate when total PSA was 4–10 ng/mL. Lodding et al. (17) increased the detection rate of prostate cancer by 30%, and most of the cancers detected were clinically signiﬁcant after radical prostatectomy. Total PSA range 4–10 ng/mL. The PSA range 4–10 ng/mL is commonly referred to as the diagnostic gray zone. In this range, PSA determination does not give valuable information as to the presence or absence of cancer. Analysis of screening studies of men 50 yr or older shows that up to 10% of these men have a PSA of 4 ng/mL or higher. Biopsy results showed a positive predictive value between 12 and 32% (18–21) in case of a nonsuspicious digital rectal examination (DRE). A biopsy, associated with

Chapter 2 / PSA and Human Glandular Kallikrein 2

17

costs and some degree of morbidity, would reveal no evidence of malignancy in about three of four men biopsied because of a PSA level from 4 to 10 ng/mL. Total PSA above 10 ng/mL. Patients with a total PSA > 10 ng/mL on initial evaluation and a nonsuspicious DRE have a likelihood of >40% to harbor prostate cancer (12). It is therefore accepted that a biopsy should be undertaken owing to the high likelihood of detection of a cancer. It is noteworthy, however, that the likelihood of a pathologically organ-confined cancer may be as low as 25%. It is also important to remember that PSA values are relevant only in case of a nonsuspicious DRE. If DRE shows a suspicious lesion, a prostate biopsy is mandatory.

Free PSA A predominant proportion of PSA in the extracellular ﬂuids (clinically relevant in blood) is in stable complex with antiproteases, most notably α1-antichymotrypsin (ACT). However, there are also signiﬁcant amounts of free, noncomplexed forms of PSA that are virtually nonreactive with the large excess of extracellular antiproteases (22). Clinically, the most important application of free PSA measurement is the identiﬁcation of free PSA-speciﬁc antigenic epitope structures that are unavailable when PSA forms stable covalent complexes with antiproteases such as ACT (22–23). This phenomenon forms the molecular basis for the generation of the ratio of free to total PSA (%fPSA) (24). For unknown reasons, a lower ratio of free to total PSA occurs in patients with prostate cancer than in those without (24). This is similar to the observation that the proportion of complexed PSA is higher in patients with prostate cancer than in those without (24,25). By simultaneous immunodetection of both free and total PSA, the calculated %fPSA improves the armamentarium of prostate cancer detection (24). Numerous studies have evaluated the sensitivity and specificity of %fPSA for prostate cancer detection. These studies demonstrated that, using %fPSA cutoffs between 14 and 28%, 19 to 64% of unnecessary biopsies could have been avoided at the same time maintaining a sensitivity of prostate cancer detection of 71–100% (26–27). A large, prospective, multicenter trial was able to conﬁrm retrospective studies. By applying a cutoff value for %fPSA <25%, 95% of cancers could have been detected. At the same time, it reduced the biopsy rate by 20% in the total PSA range of 4–10 ng/mL (28). The total PSA range at which %fPSA has been established and Food and Drug Administration (FDA) approved for clinical use is 4–10 ng/mL. However, an estimated 22% of men with total PSA in the 2.6–4 ng/mL range also harbor signiﬁcant prostate cancer. Evaluation of %fPSA in this PSA range demonstrated that a cutoff for %fPSA of 27% was able to detect 90% of cancers, at the same time sparing 18% of unnecessary biopsies and thus encouraging the use of %fPSA in this total PSA range as well (16). Table 1 provides an overview of selected studies on the utility of %fPSA for early detection of prostate cancer. Another feature of percent free PSA has been shown to identify those patients who will develop highly aggressive cancer in the later lifetime of the individual. Carter et al. (32) measured free and total PSA in sera collected up to 10 yr before diagnosis of prostate cancer in patients with extraprostatic extension or lymph node or bone metastases. These patients were compared to a group of patients who had prostate cancer with a more favorable pathology. They demonstrated a statistically signiﬁcant difference in %fPSA between both groups (p = 0.008) 10 yr prior to diagnosis, whereas total PSA failed to demonstrate this difference (29).

Table 1 Overview of the Literature on the Ratio of Free to Total PSA for the Discrimination of Benign vs Malignant Prostatic Disease

18

No. of patients (benign/cancer)

DRE — — Neg. —

4–20 4–10

1996

Not applicable 63/50 26/48 20/28

1997 1998

73/259 379/394

Neg. Neg.

2.6–4 4–10

Author

Year

Christensson et al. (24) Catalona et al. (28)

1993 1995

Prestigiacomo et al. (27) Catalona et al. (16) Catalona et al. (28)a

Abbreviations: DRE, digital rectal examination; PSA, prostate-speciﬁc antigen. a Multi-institutional.

tPSA range (ng/mL)

4–10

Cutoff (%) 18 20 23 23 14 27 25 22

Sensitivity (%) 71 90 90 95 95 90 95 90

Speciﬁcity (%) 95 38 31 64 56 18 20 29

Chapter 2 / PSA and Human Glandular Kallikrein 2

19

Some important concerns must be kept in mind when %fPSA is used clinically (33). First, as with total PSA, results of free PSA detection may vary because of a lack of uniform standardization of the different assay types. The results of free PSA and subsequently calculated %fPSA may be different. In addition, assays for the detection of total and free PSA can be divided in two groups based on their relative ability to detect both PSA forms. Equimolar PSA assays detect free PSA and ACT-PSA equally, and the results are largely independent of the relative amounts of free PSA and ACT-PSA in serum. Skewed response assays preferably measure the free PSA. Thus, when the proportion of free PSA increases, a higher amount of total PSA is the result. The higher amount of total PSA is the denominator in the calculation of %fPSA; therefore free PSA appears to be lower. This reduces the %fPSA ratio to a lower level, falsely suggesting prostate cancer. Hence, the use of a standard assay calibrator, preferably an equimolar assay for tPSA and fPSA detection and %fPSA calculation, is of utmost importance. Likewise, it is crucial for the clinician to be familiar with the assay applied and aware of any assay changes. Second, prostatic manipulation increases total PSA concentrations owing to an increase in free PSA. Analysis of the subfractions of total PSA in a preoperative to intraoperative comparison of radical prostatectomy patients demonstrated that essentially all increases in total PSA level during surgery are caused by the release of free PSA. %FPSA increased from a mean 11.9% preoperatively to 52.5% as a consequence of prostatic manipulation (31). The same has been observed for DRE, prostate biopsy, and urethral instrumentation, which should consequently be avoided at least 48–72 h before the testing for free PSA and %fPSA calculation. Finally, prostatic volume also affects %fPSA (32). In smaller prostates there was a statistically signiﬁcant difference in the %fPSA ratio when patients with benign disease or prostate cancer patients were compared. However, with increasing total prostate volume, differences in %fPSA between cancer and benign disease diminish, and at large volumes %fPSA concentrations may be indistinguishable. A similar result was found when prostates <35 mL and ≥35 mL were compared: cutoffs of 14% for small prostates and 25%fPSA for larger prostates detected prostate cancer with 95% sensitivity (33). The suggested cutoff value of %fPSA cannot be exactly recommended, since it is affected by multiple factors. Ranges between 14 and 25% are usually applied (24, 27, 28, 34). However, narrowing this range to an optimal, widely accepted cutoff value has not been possible. Therefore, it is the decision of the individual physician to be either more aggressive and consequently performing more unnecessary biopsies (e.g., trend to higher sensitivity) or more conservative and perform fewer biopsies revealing benign results while risking missing men with prostate cancer. In conclusion, %fPSA provides a valable improvement in speciﬁcity while maintaining a high sensitivity for prostate cancer in men with a total PSA of 2.6–10 ng/mL.

Complex PSA As outlined earlier, PSA forms stable covalent complexes with major extracellular antiproteases such as ACT (23), α2-macroglobulin (23), and protein C inhibitor (35) and to a much lesser extent and very slowly with α1-protease inhibitor (API-PSA) in blood (38). The sum of ACT-PSA, API-PSA (which corresponds to only 0.5–2% of total PSA), and other presently unknown PSA complexes is summarized as complex PSA or cPSA. This major form of PSA is also significantly influenced by prostate cancer, as initially reported by two studies in Sweden and Finland (24,25). Subse-

20

Haese and Partin

quently, commercially available immunoassays have been developed that measure cPSA without any significant nonspecific interference from other protease-ACT complexes (e.g., granulocyte-derived cathepsin G) that limit the accuracy of the specific PSA-ACT assays (37,38). Total PSA cannot reliably separate benign from malignant disease in the PSA range below 10 ng/mL. Percent fPSA is likely to be more affected by day-to-day variation, considering its signiﬁcantly shorter elimination rate in vivo, i.e., reported half-life time of 12–18 h (31), compared with the PSA-ACT complex (39). Moreover, it suffers from signiﬁcant in vitro instability (40,41). In contrast, cPSA levels are less affected than the levels of free PSA by severe renal impairment, DRE, cystoscopy, prostate biopsy, or manipulation of the prostate during surgery as is seen with free PSA (39). Several studies demonstrated that detection of cPSA in total PSA ranges of 2.5–4 ng/mL (42), 2.6–20 ng/mL (43), 0.37–117 ng/mL (44), and 4.1–10 ng/mL (45) produced cPSA speciﬁcities superior to those of total PSA. At sensitivity levels of 92–95% (which means to accept missing only 5–8% of cancers) the speciﬁcity for cPSA was 23–42%; at the same sensitivity, the speciﬁcity for tPSA was 14–18%. Details of these studies are summarized in Table 2. Complex PSA values can be obtained by two methods. They can be measured by immunoassays; the results of the previous studies all were obtained in this way. Alternatively calculated PSA levels can be generated by subtracting tPSA from fPSA. Okihara et al. (42) evaluated these calculated cPSA results in the tPSA range 2.5–4 ng/mL and concluded that results were comparable to measured cPSA with respect to sensitivity/speciﬁcity calculation. This study also conﬁrmed the improved cancer detection rate in the low PSA range 2.5–4 ng/mL achieved by cPSA in comparison with %fPSA. In conclusion, the reported data suggest that measurement of cPSA in serum is a tool that contributes a statistically signiﬁcant improved speciﬁcity at high sensitivity levels in men with suspected prostate cancer compared with conventional testing for tPSA. cPSA can be calculated from pre-existing free and total PSA assays, without any major drawback in comparison with other means of performing cPSA measurements.

Subfractions of Free PSA Subfractions of free PSA are modiﬁcations of the free, uncomplexed PSA molecule. Several types of modiﬁcations have been distinguished (Fig. 1). 1. Pro-PSA, which is enzymatically inactive and consists of 237 amino acids plus a 7amino acid polypeptide that is cleaved to activate pro-PSA into its active form. Variations in the numbers of amino acids that are clipped to activate pro-PSA occur, leading to variable sizes of the molecule. 2. Internally cleaved, nicked, or multichain PSA forms have been described, most notably an isoform showing cleavages at Lys145-Lys146 and Lys182-Ser183-position (BPSA) 3. Intact PSA, a nonreactive single-chain isoform of free PSA isolated from LnCaP-Cells. The nature of these isoforms of free PSA and whether they will improve prostate cancer detection is reviewed.

(–2)PPSA (–2)pPSA, the ﬁrst clinically evaluated pro-PSA isoform, was found as a variant of free PSA, expressed in large amounts in prostate cancer tissue (46). It is a single-chain polypeptide characterized by incomplete cleavage of the seven amino acids that normally are removed to activate pro-PSA. Two amino acid residues remain in place, yielding a

Table 2 Overview of Studies Comparing Complexed PSA, %fPSA, and Total PSA for Early Detection of Prostate Cancer No. of patients (benign/cancer)

21

Author

Year

Okegawa et al. (45)

2000

116/24

Mitchell et al. (43)

2001

109/51

Okihara et al. (42)

2001

116/37

Brawer et al. (44)a

2000

272/385

a

Multi-institutional.

Immunoassays Bayer Immuno 1 Markit M Tandem R %fPSA Bayer Immuno 1 Bayer Total Abbott %fPSA Bayer Immuno 1 %PSA Bayer Immuno 1 Tandem R %fPSA

tPSA range (ng/mL)

(complex PSA) (ACT-PSA) (total PSA)

4.1–10

(complex PSA) (total PSA)

2.6–20

(complex PSA)

2.5–4

(complex PSA) (total PSA)

0.32–117

Cutoff value (ng/mL) Sensitivity (%) 4.6 2.7 4.8 18% 3.54 3.97 30.4% 2.19 31% 2.75 3.06 23.9%

92 92 92 92 95 95 95 95 95 95 95 95

Speciﬁcity (%) 23 24 14 35 24.8 17.4 15.6 38 11 24 18 23

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Fig. 1. Isoforms of free prostate-speciﬁc antigen (PSA).

total size of 239 amino acids, hence its designation as (–2)pPSA. When serum of prostate cancer patients with a total PSA range 6–24 ng/mL was analyzed for (–2)pPSA, it could be shown that 25–95% of free PSA consisted of (–2)pPSA. Serum levels of men with no evidence of disease read an average of ﬁvefold lower (–2)pPSA-concentrations. An important aspect of (–2)pPSA is that it is detectable at tPSA concentrations typically encountered when the differential diagnosis of BPH vs prostate cancer is made. Another truncated pro-PSA isofrom currently under investigation is (–4)pPSA (after cleavage of only three amino acids of the pro-PSA). BPSA The typical feature of BPSA is a double peptide cleavage at Lys145-Lys146 and Lys182-Ser183, making it a multichain peptide isoform of free PSA. BPSA was detected in seminal plasma and nodular tissue samples of the transition zone of BPH (47). A comparison of tissue from enlarged prostates owing to BPH, normal prostates, and prostate cancer showed that BPSA was almost exclusively expressed in the transition zone. The expression of BPSA in normal prostates and in prostate cancer tissue was much less. Subsequently, the development of an immunoassay for the detection of BPSA in serum revealed a signiﬁcant concentration of BPSA in serum of men with BPH, whereas it failed to be detected in normal control males. An estimated 15–50% of all free PSA in serum was shown to be BPSA (48). Although it seems likely that BPSA reﬂects at least to some extent BPH and has potential for the monitoring of BPH under surgical or medical treatment, its role in the early diagnosis of prostate cancer remains to be clariﬁed. This is because prostate cancer and BPH are commonly found in the same organ.

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INTACT PSA Another isoform of free PSA, a potentially cancer-speciﬁc form called intact PSA, has been isolated from LnCaP cells. This isoform was evaluated to separate benign from malignant prostatic tumors (49). As opposed to multichain PSA, intact PSA is a singlechain polypeptide. A research assay for this PSA isoform was developed, and analysis of 383 men (141 with no evidence of disease and 242 patients scheduled for radical prostatectomy for prostate cancer) was performed. Determination of intact PSA and its application as the ratio of intact/free PSA improved the separation of patients with a negative systematic prostate biopsy from those with biopsy-proven prostate cancer (50). In summary, isoforms of free PSA have so far presented encouraging results; however, further evaluation is mandatory. Detection techniques need to be reﬁned, and the exact number and nature of subfractions of free PSA have to be determined.

PSA Derivates PSA derivates are permutations of total PSA developed to improve the sensitivity and speciﬁcity of early prostate cancer detection. They are PSA density, PSA velocity, and age-speciﬁc PSA ranges. PSA DENSITY PSA density (PSA-D) was introduced by Benson et al. (51). The rationale is a positive relationship between serum PSA and prostatic volume. Most prostatic enlargement is caused by benign hyperplastic tissue of the transition zone. PSA-D divides the serum PSA concentration by prostatic volume. It was created to normalize a certain PSA concentration by using the volume of the prostate, assuming that a certain volume of prostate cancer increases PSA to a greater extent than the same amount of benign tissue. However, two aspects limit the use of PSA-D: (1) the examiner and the different types of ultrasound devices used to estimate the prostatic volume; and (2) the ratio of stroma to epithelium has been shown to vary considerably between individuals. Since only prostatic epithelium produces PSA and the amount of stroma cannot be estimated from transrectal ultrasound, this inﬂuences PSA-D to an unforeseeable extent (52,53). Therefore, results of PSA-D have been discordant. A cutoff of 0.15 ng/mL for PSA-D has been reported, and it was found that PSA-D enhanced prostate cancer detection when PSA was below 10 ng/mL (54). Other studies, however, found that about 50% of all prostate cancers would have been missed when a cutoff of 0.15 ng/mL was used (55). Others could not ﬁnd any statistically signiﬁcant difference between 107 men with positive or negative biopsy results when PSA-D was used (56). Therefore, at present the role of PSA-D in the early detection of prostate cancer has not yet been proved useful when the PSA is 4–10 ng/mL and the DRE is nonsuspicious. A modiﬁcation of PSA-D, transition zone density (PSA-TZD), normalizes serum PSA to the transition zone volume (57). It focuses on the assumption that, histologically, hyperplasia occurs almost exclusively in the transition zone. PSA from the peripheral zone and central zone is assumed to be a constant and less substantial source of PSA in the absence of cancer. In an initial study with a cutoff of 0.35 ng/mL/cc, the highest positive predictive value for prostate cancer detection was found using PSATZD (74%) (58). However, methodologic problems of volume measurement and epithelial-to-stroma ratio affect PSA-TZ-density in the same way as simple PSA-D. Moreover, other centers failed to reproduce the advantage of PSA-TZD. Thus PSA-TZ density cannot be considered a routine tool for prostate cancer detection.

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PSA VELOCITY PSA velocity assesses changes in PSA level over time. It was introduced to improve the effectiveness of serial PSA measurements for more efﬁcient prostate cancer detection (59). PSA velocity is described by the formula 1/2 × (PSA2 – PSA1/time1 in years + PSA3 – PSA2/time2 in years) where PSA1 is the ﬁrst PSA measurement, PSA 2 the second, and PSA 3 the third. These three measurements should be obtained in a 2-yr period or at least 12–18 mo apart. Clinically a PSA velocity of ≥0.75 ng/mL/yr has been described to suggest the presence of prostate cancer with 72% sensitivity and 95% speciﬁcity. These signiﬁcant differences in PSA velocity between BPH and prostate cancer were detectable up to 9 yr before prostate cancer had been diagnosed (60). Disadvantages of PSA velocity are attributable to the fact that PSA is not cancerspeciﬁc and that an intraindividual day-to-day-variation of PSA concentration can be observed. A study showed that if the increase in tPSA was below 20–46%, it was more likely to be caused by biologic variation than prostate cancer development (61). Additionally, short time episodes of PSA rise (e.g., during inﬂammatory processes) interfere with the gradual natural elevation of PSA over time (60,62). Finally, PSA results are different when different assays are used, which may add some degree of imprecision to PSA velocity determinations (30). Despite these limitations, a PSA velocity >0.75 ng/mL/yr may still serve as guidance in assessing the need for a prostate biopsy in patients with a total PSA below 10 ng/mL and an unremarkable DRE. AGE-SPECIFIC PSA RANGES The upper limit of normal PSA concentration is commonly assigned to 4 ng/mL. This does not, however, compensate increasing prostatic volume with increasing age. The principle of age-speciﬁc PSA ranges has been introduced (63) to improve the sensitivity of prostate cancer detection in patients of younger age (e.g., age 50) with a PSA that might be of no concern in a patient at the age of 70 and vice versa to improve speciﬁcity by avoiding the detection of insigniﬁcant cancers in the individual at age 75. In the evaluation of almost 4600 men, age-speciﬁc PSA ranges detected 74 additional cancers in men 60 yr old or younger. Pathologic workup was favorable (organconfined or capsular penetration, Gleason score <7, no evidence of lymph node metastases or seminal vesicle invasion) in 80% of cancers. In younger men the detection of prostate cancer increased by 18% but decreased by 22% in older men (64). The comparison of age-speciﬁc PSA ranges with normal PSA cutoffs of 4 ng/mL in a screening population showed that the number of cancers detected increased by 8% using age-speciﬁc ranges in men younger than 59 yr when DRE was unremarkable. Moreover, in men older than 60 yr, 21% of biopsies were unnecessary. At the same time, only 4% of organ-conﬁned cancers were missed. Other data from Carter et al. (59) demonstrate an increased probability of curable prostate cancer when adjustments by age and PSA were performed, as shown in Table 3. In a series of 492 men with nonpalpable (T1c) prostate cancer, the likelihood of harboring curable disease (defined by organ confinement or low-grade capsular penetration, clear surgical margins, and negative lymph node or seminal vesicle) was assessed for three age and five PSA groups using logistic regression analysis. Within each PSA group, there was inverse relation of finding curable prostate cancer to increasing age, e.g., the likelihood was 89% in the PSA range 2.5–4 ng/mL at age 40–50, but 78% in the age group 61–73 yr. When the probability

Chapter 2 / PSA and Human Glandular Kallikrein 2

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Table 3 Percent Probability of Curable Prostate Cancer Adjusted by Age and Total Serum PSA Concentration Age groups (yr) PSA range (ng/mL) 2.5–4.0 4.1–6.0 6.1–8.0 8.1–10.0 >10.0

40–50

51–60

61–73

89 87 84 83 73

83 81 78 75 57

78 74 71 67 49

of curable prostate cancer was compared within PSA groups (across age) and within age groups (across PSA), it was found that the decrease in the probability of curable prostate cancer was more profound for increasing age compared with increasing PSA. Carter et al. (61) concluded that age is a strong predictor of curable disease, stronger than PSA in the range of 2.5–6.0 ng/mL, at which most cancers are detected today. It was concluded that age-specific PSA ranges improve sensitivity in the younger population (65). Other studies, however, demonstrated that the standard PSA cutoff of 4 ng/mL was the optimal and most cost-effective (66) tool for all age groups (18). Some authors have suggested the use of race-corrected age-specific PSA ranges. This was based on studies describing lower PSA levels in White or Asian compared with African-American men, even when controlled for age, Gleason grade, or clinical stage, which has been associated with a larger tumor volume in Black compared with White men (1.3–2.5 times larger). It was reported that 40% of cancers in a Black population would have been missed if traditional age-specific ranges had been used (63,67,68). Age-speciﬁc PSA ranges, however, are not to be used without careful consideration of the fact that they might lead to missed, signiﬁcant, and potentially curable cancers in the older population. Moreover, they are neither FDA- nor manufacturer-approved, and ﬁnally a single cutoff is clearly more easy to use in clinical practice.

HUMAN GLANDULAR KALLIKREIN IN THE EARLY DETECTION OF PROSTATE CANCER PSA (which is also termed human glandular kallikrein 3) and human glandular kallikrein 2 (hK2) share an extensive 80% identity in protein sequence (69). hK2 and PSA are expressed under androgen control (70). Despite a similar, prostatic, origin, some differences are noteworthy. Some immunohistochemical studies have demonstrated different tissue expression of hK2 compared with that of PSA (71,72), whereas others failed to reproduce such differences (73) hK2 concentrations in blood correspond to about 1–3% of those of PSA (74). Most hK2, in contrast to PSA, however, occurs as a free form, potentially as pro and mature isoforms. Immunoassays for hK2 detect very low concentrations of the analyte with acceptable precision (e.g., <20% coefficient of variation at hK2 levels ≥ 5–10 pg/mL). At the same time, cross-

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reactivity to different forms of PSA must be minimal (e.g., <0.05–0.1%) (75). The covariance of hK2 and tPSA concentrations has been shown to be less than 60%, suggesting an individual and independent contribution of hk2 to PSA (74–77) and suggesting the potential of hK2 as an additional tumor marker for prostate cancer. Serum concentrations of hK2, free hK2, and ACT-hK2 are elevated in patients with prostate cancer (77–81). However, after measurement of total and free PSA, Klee et al. (82) concluded that the gain in clinical information is moderate for hk2, since PSA provides similar information. However, two scenarios for early diagnosis of prostate cancer may be assumed: 1. Increase in sensitivity: Likewise of interest is the patient group with PSA levels below 4 ng/mL. In this PSA range, up to 25% of men harbor clinically signiﬁcant prostate cancer (16), which PSA fails to detect. 2. Increase in speciﬁcity: In the total PSA range between 4 and 10 ng/mL, only 25% of men have prostate cancer, and biopsy should be recommended. The speciﬁcity for cancer of the %fPSA is about 31%. Hence, unnecessary, costly, and morbid biopsies are performed in about 70% of patients (26).

Saedi et al. (80) described an increased concentration of pro-hK2 in sera of patients with cancer compared with those of BPH patients, healthy males, or females. More commonly, total hK2 concentrations in different research assays have been reported. Magklara et al. (83) analyzed hk2 and total and free PSA and merged hk2 and free PSA into the same algorithm, hK2/fPSA. On receiver operating curve (ROC) analysis, hK2/fPSA (area under the curve [AUC] = 0.69) was a stronger predictor of cancer than %fPSA (AUC = 0.64). Moreover, at 95% specificity, hK2/fPSA identified 30 and 25% of cancers when PSA was 2.5–10 and 2.5–4 ng/mL, respectively. They found the use of hK2 valuable to identify a subset of patients with low PSA but still a high likelihood of cancer In 937 serum samples of men with prostate cancer or negative biopsy and a total PSA of 2–10 ng/mL, hK2, tPSA, and fPSA were measured (78). The ratio total hK2/free PSA increased speciﬁcity for prostate cancer detection, as shown in the algoritm in Fig. 2: in the PSA range of 4–10 ng/mL, the risk of cancer was 23%, and in the PSA range of 2–4 ng/mL, it was 13%. A classiﬁcation into three risk groups was done using %fPSA (cutoff 25%), resulting in a likelihood of cancer between 10 and 43%. A further subclassiﬁcation was done using hK2/free PSA. By doing so, crude risk groups deﬁned by %fPSA could be reﬁned, yielding positive predictive values for cancer between 9 and 62%. Cumulatively, if %fPSA and hK2/fPSA were used, 40% of cancers could have been detected, requiring a biopsy in only 16.5% of men in the PSA range 2–4 ng/mL. Becker et al. (84) evaluated hK2 concentrations in a populationbased study of 604 men with a total PSA > 3 ng/mL to evaluate the discriminative power of additional hK2 measurement in prostate cancer detection. They merged hK2 and total and free PSA into an algorithm (hK2 × tPSA/fPSA). ROC analysis revealed that the AUC for hK2 × tPSA/fPSA was greater than that for total PSA and %fPSA. Additionally, at a speciﬁcity of 90%, sensitivity was 55%, compared with 41% for %fPSA (Fig. 3). Kwiatkowski et al. (85) calculated a median hK2/fPSA of 0.139 in prostate cancer patients vs 0.075 in BPH patients. At a sensitivity of almost 95%, the speciﬁcity of hK2/fPSA was 60.4% compared with 27.6% for %fPSA. A cross-sectional study of 324 men performed by Nam et al. (81) referred for prostate biopsy showed significantly higher hK2 and hK2/fPSA levels in men with

Chapter 2 / PSA and Human Glandular Kallikrein 2

27

Fig. 2. Algorithm combining human glandular kallikrein 2 and free prostate-specific antigen (PSA) to enhance specificity for the early detection of prostate cancer (PCa) based on the evaluation of 937 serum samples with a total PSA range of 2–4 (up) and 4–10 ng/mL (down). PPV, positive predictive value.

Fig. 3. Receiver operating characteristic (ROC) analysis and area under the curve (AUC) for total prostate-speciﬁc antigen (PSA), %fPSA, and human kallikrein 2 (hK2) × tPSA/fPSA in the separation of 460 men with benign prostatic biopsies compared with 144 men with prostate cancer. The pvalues illustrate the difference from the AUC of tPSA.

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cancer compared with patients with a negative biopsy. The authors found a five- to eightfold increased risk of prostate cancer with elevated hK2 and levels and elevated ratio of hK2/fPSA, hence improving selection criteria for patients referred for prostate biopsy Studies performed so far show a moderate clinical potential for hK2 but should not presently replace total and free PSA detection for early diagnosis of prostate cancer. The most efficient way to use hK2 (alone or in combination with total and/or free PSA) remains to be clarified. All restrictions of immunodetection (different research assay types, no standardization) need to be considered when hK2 is studied in a clinically meaningful setting.

PROSTATE CANCER STAGING Accurate prediction of stage in men with prostate cancer is important for selection of the appropriate therapy in clinically localized prostate cancer and for comparison of the outcome of different treatment modalities. Surgical procedures provide evaluation of the histologic specimen and therefore exact information on the stage of the tumor, whereas radiation or brachytherapy do not. Therefore, they rely to a much greater degree on accurate clinical staging of the disease. This is necessary not only to compare results of radiation therapy from different centers but also to compare radiation therapy with radical prostatectomy. However, serious limitations of transrectal ultrasonography and DRE signiﬁcantly compromise staging accuracy in patients with prostate cancer. Cancers conﬁned to the prostate have a better prognosis than those with extraprostatic extension (86,87). However, since extraprostatic extension may be detectable on microscopic evaluation only, it is evident that clinical assessment fails to detect this crucial step in cancer progression accurately. PSA provides biochemical information for staging that is less examiner-dependent.

Total PSA LOCAL STAGING PSA has outperformed DRE-based stage prediction, which showed unsuspected extraprostatic spread in up to 63% (88). Serum PSA levels in a group of patients correlated with tumor volume and advancing clinical and pathologic stage (52,89). When PSA ranges and staging results were analyzed, it was shown that PSA in ranges of <4 ng/mL or >10 ng/mL correlated reasonably well with organ-confined or extraprostatic cancer. When PSA was < 4 ng/mL, the likelihood of organ-confined cancer was 81–84% (16,17), when DRE was negative. Organ-confined rates of prostate cancer dropped to 53–67% at total PSA ranges of 4–10 ng/mL (92) and to 31–55.9% when PSA was 10–20 ng/mL (17,92). Hence, in the most frequently encountered PSA range (4–10 ng/mL), PSA does not provide valuable staging information. Moreover, on an individual basis, single PSA levels are not specific enough to permit prediction of pathologic stage. Multiparameter staging tools (nomograms and predictive algorithms) were developed to improve the accuracy of staging. These are described in a subsequent chapter. DISTANT STAGING PSA has been shown to be a good predictor of a positive bone scan in patients with prostate cancer. The combination of PSA, PAP, tumor grade, and clinical stage revealed that PSA was most accurate in predicting bone scan results, namely, if PSA was <20

Chapter 2 / PSA and Human Glandular Kallikrein 2

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Table 4 Summary of Different Studies on the Utility of %fPSA for Staging of Clinically Localized Prostate Cancer Author Graefen et al. (96) Henricks et al. (97) Bangma et al. (98) Lerner et al. (94) Pannek et al. (99) Elgamal et al. (100)c Pannek et al. (101)

No. of patients

No. of No. of No. of pT2a/b (%) ≥ pT3a (%) mets. (%)

53 28 (53%) 46 24 81 (66) 19 (15) 178b 100 (56) 301 169 (56) 37 (54) T1c 32 (46) ≥T2 263 134 (51)

25 (47) 0 23 (19) 78 (44) 121 (40) 0 (0) 119 (45)

0 (0) not applic. not applic 0 (0) 11 (4) 69 10 (4)

Mean %fPSA age (yr) useful a 62.2 No (2) No (3) 63 58.8 Yes (6) 58.9

No (1)

No (4) No (5) Yes (5)

a The numbers in parentheses refer to the following assays: 1, DPC (Diagnostic Product Corporation); 2, Dianon; 3, DELFIA; 4, research assay; 5, Hybritech; 6, Centrocor. b Of the 290 initial patients, only 178 had a relative refractory period (RRP) and were evaluated. c Of the 117 initial patients, only 69 had an RRP and were evaluated.

ng/mL, the negative predictive value was 99.7%. This has resulted in a decrease in the number of bone scans performed in patients with a PSA < 20 ng/mL (93).

Percent Free PSA Although PSA levels have been accepted for prostate cancer detection, studies that analyzed %fPSA in the staging of prostate cancer have produced conﬂicting results when the main parameter of outcome was whether or not the tumor is organ-conﬁned or not (Table 1). Although some studies reported that %fPSA provided useful staging information, others failed to demonstrate such ﬁndings. Lerner et al. (94) found statistically signiﬁcant differences only in substages of prostate cancer, which is supported by data from the University of Hamburg: no difference between organ- and non-organ-conﬁned cancers was seen. However, a signiﬁcantly lower %fPSA separated prostate cancer patient who already had seminal vesicle invasion from those who did not (95). Patient selection, study design, various immunoassays, and %fPSA cutoff values all inﬂuence the results of a single study. Because of methodologic differences among these studies, a deﬁnitive answer can only be provided by a multicenter trial. Therefore, to date no established use of %fPSA for the staging of prostate cancer exists. A summary of the utility of %fPSA for staging of clinically localized prostate cancer is given in Table 4.

ACT-PSA Complex Although ACT-PSA studies evaluating early detection of prostate cancer are numerous, only a few studies have evaluated ACT-PSA as a staging parameter. Recently, PSA, PSA density, ACT-PSA, and ACT-PSA density were assessed in 62 patients with clinically localized prostate cancer before radical prostatectomy. It was found that values for all variables increased signiﬁcantly from organ-conﬁned cancers to extraprostatic cancers and in each pathologic stage; hence ACT-PSA and ACT-PSA density only complemented PSA and PSA density. Calculation of ROC curves showed that both ACT and ACT density had a larger, but not signiﬁcantly larger, AUC compared with

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PSA and PSA density. However, at a sensitivity of 100% to detect prostate cancer, speciﬁcity was 37% and 42% for ACT-PSA and ACT-PSA density, respectively, compared with 19 and 24% for PSA and PSA density (102). This is in connection with an earlier study of 652 patients, which concluded that ACT-PSA might replace PSA as a staging tool for prostate cancer (103). However, owing to the limited amount of data available no conclusions as to the utility of ACT-PSA for staging purposes of prostate cancer can be formed.

Algorithms and Nomograms The weaknesses of PSA outlined above have led to the construction of nomograms combining a number of clinically available variables that provide independent prognostic signiﬁcance (e.g., clinical stage, PSA level, Gleason sum, or grade of prostatic biopsies) to provide a more accurate preoperative estimation of pathologic stage. PSA is an important contributing factor in predictive nomograms for lymphatic spread, pathologic stage, or outcome of clinically localized prostate cancer. A widely accepted tool for predicting pathologic stage is the Partin nomogram, which takes into account PSA, clinical stage, and the Gleason sum of the biopsy obtained. The Partin nomogram has recently been updated and validated (6). Another algorithm was developed and validated by Graefen et al. (99) based on a classiﬁcation and regression tree (CART) analysis. This model performed a side-speciﬁc prediction of a pathologically organconﬁned prostate cancer based on serum PSA levels and Gleason grade 4/5 in the prostatic biopsies (104).

Human Glandular Kallikrein 2 hK2 has been studied in the early detection of prostate cancer and has been proved to have potential to complement the information of PSA and %fPSA; at present it should not replace either parameter in terms of diagnostic accuracy. More recently, studies have evaluated the use of hK2 as a staging parameter for clinically localized prostate cancer. Detection of hK2 and total and free PSA in 68 sera samples from men scheduled for radical retropubic prostatectomy revealed that hK2 and a derived algorithm that combined hK2 with total PSA and free PSA (hK2 × tPSA/fPSA), signiﬁcantly improved the prediction of organ-confined vs non-organ-confined prostate cancer, at total PSA ranges up to 66 ng/mL (105). With an increased sample size the same group analyzed the PSA range <10 ng/mL in 161 patients and found consistent results compared with earlier observations, in that hK2 or the derived algorithm was signiﬁcantly better in the prediction of pathologic stage 2a/b prostate cancer than PSA (106). Another study conﬁrmed the improvement in staging accuracy described above. These authors found hK2 to be the only single serum analyte that highly signiﬁcantly discriminated pT2a/b prostate cancer from ≥pT3a prostate cancer (the latter involving extraprostatic extension). Moreover, hK2 separated aggressive grade 3 prostate cancer from less aggressive grade1 and 2 prostate cancer (107). These results suggest that further studies be performed to improve prostate cancer staging. As with the use of hK2 for detection of prostate cancer potential uncertainties (lack of standardization, research assays, different assay principles) have to be kept in mind when hK2 is analyzed. Therefore results from different centers, and the performance of different assays, ideally as a multicenter trial, are awaited to clarify the role of hK2 as a potential staging tool for prostate cancer.

Chapter 2 / PSA and Human Glandular Kallikrein 2

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PSA AND RADICAL PROSTATECTOMY PSA has been proved to be the most powerful tool to identify those men in whom aggressive local therapy offers the best disease control (12). It has been reported that PSA levels can stratify men in whom radical prostatectomy may result in high cure rates (6,12,104). Following radical prostatectomy, PSA displays a truly unique feature: once the prostate is removed after radical prostatectomy, contributing factors mentioned above are excluded; hence PSA, if detectable is derived from remaining prostate cancer cells. The failure to reach undetectable PSA levels is evidence for persisting prostate cancer. Undetectable PSA after radical prostatectomy is synonymous with disease-free state. In case of recurrent disease, PSA can be detected more than 5 yr earlier than any clinical symptom and as such is by far the most sensitive marker for prostate cancer relapse. Recurrence of prostate cancer typically occurs ﬁrst as a biochemical PSA recurrence, which means that PSA levels are rising from an undetectable level to levels accessible to conventional or ultrasensitive PSA assays (108–110). In the absence of clinical signs of recurrence (palpable lesion on DRE, histologic evidence of prostate cancer cells when a biopsy is taken from the former prostate location, positive bone scan, and so on), this is called biochemical recurrence. It has been shown that DRE or imagining studies in case of a biochemical failure provide little additional information as to the type of recurrence (local recurrence or distant metastatic disease). Biochemical recurrences are caused by a PSA elevation from a negative postoperative baseline PSA. The ultrasensitive PSA assays with detection limits <0.01 ng/mL PSA provide an additional lead time of almost 2 yr (109,110).

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13. Herschman JD, Smith DS, Catalona WJ. Effect of ejaculation on serum total and free prostate-speciﬁc antigen concentrations. Urology 1997;50:239. 14. Oesterling JE, Rice DC, Glenski WJ, et al. Effect of cystoscopy, prostate biopsy, and transurethral resection of prostate on serum prostate-speciﬁc antigen concentration. Urology 1993;42:276. 15. Pannek J, Marks LS, Pearson JD, et al. Inﬂuence of ﬁnasteride on free and total serum prostate speciﬁc antigen levels in men with benign prostatic hyperplasia. J Urol 1998;159:449. 16. Catalona WJ, Smith DS, Ornstein DK. Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/mL and benign prostate examination. Enhancement of speciﬁcity with free PSA measurements. JAMA 1997;277:1452. 17. Lodding P, Aus G, Bergdahl S, et al. Characteristics of screening detected prostate cancer in men 50 to 66 years old with 3 to 4 ng./ml. Prostate speciﬁc antigen. J Urol 1998;159:899. 18. Catalona WJ, Richie JP, Ahmann FR, et al. Comparison of digital rectal examination and serum prostate speciﬁc antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. J Urol 1994;151:1283. 19. Cooner WH, Mosley BR, Rutherford CL, Jr, et al. Prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal examination and prostate specific antigen. J Urol 1990;143:1146. 20. Hammerer P, Huland H. Systematic sextant biopsies in 651 patients referred for prostate evaluation. J Urol 1994;151:99. 21. Ellis WJ, Chetner MP, Preston SD, et al. Diagnosis of prostatic carcinoma: the yield of serum prostate speciﬁc antigen, digital rectal examination and transrectal ultrasonography. J Urol 1994;152:1520. 22. Lilja H, Christensson A, Dahlen U, et al. Prostate-speciﬁc antigen in serum occurs predominantly in complex with alpha 1-antichymotrypsin. Clin Chem 1991;37:1618. 23. Christensson A, Laurell CB, Lilja H. Enzymatic activity of prostate-speciﬁc antigen and its reactions with extracellular serine proteinase inhibitors. Eur J Biochem 1990;194:755. 24. Christensson A, Bjork T, Nilsson O, et al. Serum prostate speciﬁc antigen complexed to alpha 1antichymotrypsin as an indicator of prostate cancer. J Urol 1993;150:100. 25. Stenman UH, Leinonen J, Alfthan H, et al. A complex between prostate-speciﬁc antigen and alpha 1antichymotrypsin is the major form of prostate-speciﬁc antigen in serum of patients with prostatic cancer: assay of the complex improves clinical sensitivity for cancer. Cancer Res 1991;51:222. 26. Luderer AA, Chen YT, Soriano TF, et al. Measurement of the proportion of free to total prostate-speciﬁc antigen improves diagnostic performance of prostate-speciﬁc antigen in the diagnostic gray zone of total prostate-speciﬁc antigen. Urology 1995;46:187. 27. Prestigiacomo AF, Lilja H, Pettersson K, et al. A comparison of the free fraction of serum prostate speciﬁc antigen in men with benign and cancerous prostates: the best case scenario. J Urol 1996;156:350. 28. Catalona WJ, Partin AW, Slawin KM, et al. Use of the percentage of free prostate-speciﬁc antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA 1998;279:1542. 29. Carter HB, Partin AW, Luderer AA, et al. Percentage of free prostate-speciﬁc antigen in sera predicts aggressiveness of prostate cancer a decade before diagnosis. Urology 1997;49:379. 30. Semjonow A, De Angelis G, Schmidt HP. Variability of immunoassays for PSA, in Prostate-Speciﬁc Antigen, vol 1. Edited by M. K. Brawer. Dekker, New York, 2001. 31. Lilja H, Haese A, Bjork T, et al. Signiﬁcance and metabolism of complexed and noncomplexed prostate speciﬁc antigen forms, and human glandular kallikrein 2 in clinically localized prostate cancer before and after radical prostatectomy. J Urol 1999;162:2029. 32. Haese A, Graefen M, Noldus J, et al. Prostatic volume and ratio of free-to-total prostate speciﬁc antigen in patients with prostatic cancer or benign prostatic hyperplasia. J Urol 1997;158:2188. 33. Partin AW, Catalona WJ, Southwick PC, et al. Analysis of percent free prostate-speciﬁc antigen (PSA) for prostate cancer detection: inﬂuence of total PSA, prostate volume, and age. Urology 1996;48:55. 34. Bjork T, Piironen T, Pettersson K, et al. Comparison of analysis of the different prostate-speciﬁc antigen forms in serum for detection of clinically localized prostate cancer. Urology 1996;48:882. 35. Christensson A, Lilja H. Complex formation between protein C inhibitor and prostate-speciﬁc antigen in vitro and in human semen. Eur J Biochem 1994;220:45. 36. Leinonen J, Zhang WM, Paus E, et al. Reactivity of 77 antibodies to prostate-speciﬁc antigen with isoenzymes and complexes of prostate-speciﬁc antigen. Tumour Biol 1999;20(suppl 1):28. 37. Pettersson K, Piironen T, Seppala M, et al. Free and complexed prostate-specific antigen (PSA): in vitro stability, epitope map, and development of immunofluorometric assays for specific and

Chapter 2 / PSA and Human Glandular Kallikrein 2

38. 39.

40.

41. 42.

43.

44.

45.

46.

47.

48.

49.

50.

51. 52.

53. 54. 55.

56.

57. 58.

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sensitive detection of free PSA and PSA-alpha 1-antichymotrypsin complex. Clin Chem 1995;41:1480. Allard WJ, Zhou Z, Yeung KK. Novel immunoassay for the measurement of complexed prostate-speciﬁc antigen in serum. Clin Chem 1998;44:1216. Bjork T, Ljungberg B, Piironen T, et al. Rapid exponential elimination of free prostate-speciﬁc antigen contrasts the slow, capacity-limited elimination of PSA complexed to alpha 1-antichymotrypsin from serum. Urology 1998;51:57. Piironen T, Pettersson K, Suonpaa M, et al. In vitro stability of free prostate-speciﬁc antigen (PSA) and prostate-speciﬁc antigen (PSA) complexed to alpha 1-antichymotrypsin in blood samples. Urology 1996;48:81. Woodrum D, French C, Shamel LB. Stability of free prostate-speciﬁc antigen in serum samples under a variety of sample collection and sample storage conditions. Urology 1996;48:33. Okihara K, Fritsche H, Ayala A, et al. Can complexed prostate-speciﬁc antigen enhance prostate cancer detection in men with total prostate specific antigen between 2.4 and 4 ng/ml? J Urol 2001;165:1930. Mitchell IDC, Croal BL, Dickie A, et al. A. prospective study to evaluate the role of complexed prostate-speciﬁc antigen and free/total prostate-speciﬁc antigen ratio for the diagnosis of prostate cancer. J Urol 2001;165:1549. Brawer MK, Cheli CD, Neaman IE, et al. Complexed prostate speciﬁc antigen provides signiﬁcant enhancement of speciﬁcity compared with total prostate speciﬁc antigen for detecting prostate cancer. J Urol 2000;163:1476. Okegawa T, Noda H, Nutahara K, et al. Comparison of two investigative assays for the complexed prostate-specific antigen in total prostate-specific antigen between 4.1 and 10ng/ml. Urology 2000;55:700–704, 2000;55:700. Mikolajczyk SD, Millar LS, Wang TJ, et al. “BPSA”, a speciﬁc molecular form of free prostate-speciﬁc antigen is found predominantly in the transition zone of patients with nodular benign prostatic hyperplasia. Urology 2000;55:41. Mikolajczyk SD, Rittenhouse HG. BPSA and pPSA are complementary forms of PSA that are found, respectively, in the serum of men with benign and malignant prostate disease. J Clin Lig Assay, submitted, 2001. Mikolajczyk SD, Millar LS, Wang TJ, et al. A precursor form of prostate-speciﬁc antigen is more highly elevated in prostate cancer compared with benign transition zone prostate tissue. Cancer Res 2000;60:756. Nurmikko P, Vaisanen V, Piironen T, et al. Production and characterisation of novel anti-prostate-speciﬁc antigen (PSA) monoclonal antibodies that do not detect internally cleaved Lys145-Lys146 inactive PSA. Clin Chem 2000;46:1610. Steuber T, Haese A, Becker C, et al. Determination of a cancer- speciﬁc form of free PSA—intact PSA—discriminates by statistical signiﬁcance patients with a negative systematic prostate biopsy from those with biopsy proven prostate cancer. J Urol 2001;165(suppl):1162 A. Benson MC, Whang IS, Olsson CA, et al. The use of prostate speciﬁc antigen density to enhance the predictive value of intermediate levels of serum prostate speciﬁc antigen. J Urol 1992;147:817. Partin AW, Carter HB, Chan DW, et al. Prostate specific antigen in the staging of localized prostate cancer: influence of tumor differentiation, tumor volume and benign hyperplasia. J Urol 1990;143:747. Stamey TA, Kabalin JN, McNeal JE, et al. Prostate speciﬁc antigen in the diagnosis and treatment of adenocarcinoma of the prostate. II. Radical prostatectomy treated patients. J Urol 1989;141:1076. Seaman E, Whang IS, Olsson CA, et al. PSA-density (PSAD). Role in patient evaluation and management. Urol Clin North Am 1993;20:635. Catalona WJ, Richie JP, de Kernion JB, et al. Comparison of prostate-speciﬁc antigen concentration versus prostate-speciﬁc antigen density in the early detection of prostate cancer: receiver operator characteristic curves. J Urol 1994;152:2031. Brawer MK, Aramburu EAG, Chen GL, et al. The inability of prostate-speciﬁc antigen index to enhance the predictive value of prostate-speciﬁc antigen in the diagnosis of prostatic carcinoma. J Urol 1993;150:369. Djavan B, Zlotta AR, Byttebier G, et al. Prostate speciﬁc antigen density of the transition zone for early detection of prostate cancer. J Urol 1998;160:411. Djavan B, Marberger M, Zlotta AR, et al. PSA, f/tPSA, PSAD, PSA-TZ and PAS-velocity for prostate cancer prediction: a multivariate analysis. J Urol 1998;159:898(A).

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59. Carter HB, Pearson JD. PSA velocity for the diagnosis of early prostate cancer. A new concept. Urol Clin North Am 1993;20:665. 60. Nadler RB, Humphrey PA, Smith DS, et al. Effect of inﬂammation and benign prostatic hyperplasia on elevated serum prostate speciﬁc antigen levels. J Urol 1995;154:407. 61. Nixon RG, Wener MH, Smith KM. Biolgical variation of prostate speciﬁc antigen levels in serum: an evaluation of day-to-day physiological ﬂuctuations in a well-deﬁned cohort of 24 patients. J Urol 1997;157:2183. 62. Hoekx L, Jeuris W, Van Marck E, et al. Elevated serum prostate speciﬁc antigen (PSA) related to asymptomatic prostatic inﬂammation. Acta Urol Belg 1998;66:1. 63. Oesterling JE. Age-speciﬁc reference ranges for serum PSA. N Engl J Med 1996;335:345. 64. Partin AW, Criley SR, Subong EN, et al. Standard versus age- speciﬁc prostate-speciﬁc antigen reference ranges among men with clinically localized prostate cancer: a pathological analysis. J Urol 1996;155:1336. 65. Reissigl A, Pointner J, Horniger W, et al. Comparison of different prostate-speciﬁc antigen cutpoints for early detection of prostate cancer: results of a large screening study. Urology 1995;46:662. 66. Littrup PJ, Kane RA, Mettlin C, et al. Cost-effective prostate cancer detection. Reduction of lowyield biopsies. Cancer 1994;74:3146. 67. Morgan TO, Jacobsen SJ, McCarthy WF, et al. Age-speciﬁc reference ranges for prostate-speciﬁc antigen in black men. N Engl J Med 1996;335:304. 68. Oesterling JE, Kumamoto Y, Tsukamoto T, et al. Serum prostate-speciﬁc antigen in a community based population of health Japanese men: lower values than for similarly aged white men. Br J Urol 1995;75:347. 69. Schedlich LJ, Bennetts BH, Morris BJ. Primary structure of a human glandular kallikrein gene. DNA 1987;6:429. 70. Young CY, Andrews PE, Montgomery BT, et al. Tissue-speciﬁc and hormonal regulation of human prostate-speciﬁc glandular kallikrein. Biochemistry 1992;31:818. 71. Darson MF, Pacelli A, Roche P, et al. Human glandular kallikrein 2 (hK2) expression in prostatic intraepithelial neoplasia and adenocarcinoma: a novel prostate cancer marker. Urology 1997;49:857. 72. Darson MF, Pacelli A, Roche P, et al. Human glandular kallikrein 2 expression in prostate adenocarcinoma and lymph node metastases. Urology 1999;53:939. 73. Siivola P, Pettersson K, Piironen T, et al. Time-resolved ﬂuorescence imaging for speciﬁc and quantitative immunodetection of human kallikrein 2 and prostate-speciﬁc antigen in prostatic tissue sections. Urology 2000;56:682. 74. Piironen T, Lovgren J, Karp M, et al. Immunoﬂuorometric assay for sensitive and speciﬁc measurement of human prostatic glandular kallikrein (hK2) in serum. Clin Chem 1996;42:1034. 75. Becker C, Piironen T, Kiviniemi J, et al. Sensitive and speciﬁc immunodetection of human glandular kallikrein 2 in serum. Clin Chem 2000;46:198. 76. Klee GG, Goodmanson MK, Jacobsen SJ, et al. Highly sensitive automated chemiluminometric assay for measuring free human glandular kallikrein-2. Clin Chem 1999;45:800. 77. Becker C, Piironen T, Pettersson K, et al. Discrimination of men with prostate cancer from those with benign disease by measurements of human glandular kallikrein 2 (HK2) in serum. J Urol 2000;163:311. 78. Partin AW, Catalona WJ, Finlay JA, et al. Use of human glandular kallikrein 2 for the detection of prostate cancer: preliminary analysis. Urology 1999;54:839. 79. Grauer LS, Finlay JA, Mikolajczyk SD, et al. Detection of human glandular kallikrein, hK2, as its precursor form and in complex with protease inhibitors in prostate carcinoma serum. J Androl 1998;19:407. 80. Saedi MS, Hill TM, Kuus-Reichel K, et al. The precursor form of the human kallikrein 2, a kallikrein homologous to prostate-speciﬁc antigen, is present in human sera and is increased in prostate cancer and benign prostatic hyperplasia. Clin Chem 1998;44:2115. 81. Nam RK, Diamandis EP, Toi A, et al. Serum human glandular kallikrein-2 protease levels predict the presence of prostate cancer among men with elevated prostate-specific antigen. J Clin Oncol 2000;18:1036. 82. Klee GG, Young CY, Tindall DJ. Human glandular kallikrein protein, in Prostate-Speciﬁc Antigen, vol 1. Edited by M. K. Brawer. Dekker, New York, 2001, pp. 283–296. 83. Magklara A, Scorilas A, Catalona WJ, et al. The combination of human glandular kallikrein and free prostate-speciﬁc antigen (PSA) enhances discrimination between prostate cancer and benign prostatic hyperplasia in patients with moderately increased total PSA. Clin Chem 1999;45:1960.

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84. Becker C, Piironen T, Pettersson K, et al. Clinical value of human glandular kallikrein 2 and free and total prostate-speciﬁc antigen in serum from a population of men with prostate-speciﬁc antigen levels 3.0 ng/mL or greater. Urology 2000;55:694. 85. Kwiatkowski MK, Recker F, Piironen T, et al. In prostatism patients the ratio of human glandular kallikrein to free PSA improves the discrimination between prostate cancer and benign hyperplasia within the diagnostic “gray zone” of total PSA 4 to 10 ng/mL. Urology 1998;52:360. 86. Epstein JI, Pizov G, Walsh PC. Correlation of pathologic ﬁndings with progression after radical retropubic prostatectomy. Cancer 1993;71:3582. 87. Pound CR, Partin AW, Epstein JI, et al. Prostate-speciﬁc antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control. Urol Clin North Am 1997;24:395. 88. McNeal JE, Villers AA, Redwine EA, et al. Capsular penetration in prostate cancer. Signiﬁcance for natural history and treatment. Am J Surg Pathol 1990;14:240. 89. Oesterling JE, Chan DW, Epstein JI, et al. Prostate speciﬁc antigen in the preoperative and postoperative evaluation of localized prostatic cancer treated with radical prostatectomy. J Urol 1988;139:766. 90. Schroder FH, van der Cruijsen-Koeter I, de Koning HJ, et al. Prostate cancer detection at low prostate speciﬁc antigen. J Urol 2000;163:806. 91. Narayan P, Gajendran V, Taylor SP, et al. The role of transrectal ultrasound-guided biopsy-based staging, preoperative serum prostate-speciﬁc antigen, and biopsy Gleason score in prediction of ﬁnal pathologic diagnosis in prostate cancer. Urology 1995;46:205. 92. Partin AW, Yoo J, Carter HB, et al. The use of prostate speciﬁc antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 1993;150:110. 93. Chybowski FM, Keller JJ, Bergstralh EJ, et al. Predicting radionuclide bone scan ﬁndings in patients with newly diagnosed, untreated prostate cancer: prostate speciﬁc antigen is superior to all other clinical parameters. J Urol 1991;145:313. 94. Lerner SE, Jacobsen SJ, Lilja H, et al. Free, complexed, and total serum prostate-speciﬁc antigen concentrations and their proportions in predicting stage, grade, and deoxyribonucleic acid ploidy in patients with adenocarcinoma of the prostate. Urology 1996;48:240. 95. Noldus J, Graefen M, Huland E, et al. The value of the ratio of free-to-total prostate speciﬁc antigen for staging purposes in previously untreated prostate cancer. J Urol 1998;159:2004. 96. Graefen M, Hammerer P, Henke R-P, Hilz H, Huland E, Huland H. Percentage of free PSA does not correlate with pathological outcome. J Urol 1996;155:370A. 97. Henricks WH, England BG, Giacherio DA, Oesterling JE, Wojno KJ. Free total PSA-ratio does not predict extraprostatic spread of prostatic adenocarcinoma. J Urol 1996;155:369A. 98. Bangma CH, Kranse R, Blijenberg BG, Schroder FH. The free-to-total serum prostate speciﬁc antigen ratio for staging prostate carcinoma. J Urol 1997;157:544–547. 99. Pannek J, Subong EN, Jones KA, et al. The role of free/total prostate-speciﬁc antigen ratio in the prediction of ﬁnal pathologic stage for men with clinically localized prostate cancer. Urology 1996;48:51–54. 100. Elgamal AA, Comillie FJ, Van Poppel HP, Van de Voorde WM, McCabe R, Baert LV. Free-to-total prostate speciﬁc antigen ratio as a single test for detection of signiﬁcant state Tlc prostate cancer. J Urol 1996;156:1042–1049; discussiom 1047–1049. 101. Pannek J, Rittenhouse HG, Chan DW, Epstein JI, Walsh PC, Partin AW. The use of percent free prostate speciﬁc positive speciﬁc antigen for staging clinically localized prostate cancer. J Urol 1998;159;1238–1242. 102. Hara I, Miyake H, Hara S, et al. Value of the serum prostate-speciﬁc antigen-alpha 1-antichymotrypsin complex and its density as a predictor for the extent of prostate cancer. BJU Int 2001;88:53. 103. Kuriyama M, Ueno K, Uno H, et al. Clinical evaluation of serum prostate-speciﬁc antigen-alpha1antichymotrypsin complex values in diagnosis of prostate cancer: a cooperative study. Int J Urol 1998;5:48. 104. Graefen M, Haese A, Pichlmeier U, et al. A validated strategy for side speciﬁc prediction of organ confined prostate cancer: a tool to select for nerve sparing radical prostatectomy. J Urol 2001;165:857. 105. Haese A, Becker C, Noldus J, et al. Human glandular kallikrein 2: a potential serum marker for predicting the organ confined versus non-organ confined growth of prostate cancer. J Urol 2000;163:1491. 106. Haese A, Graefen M, Steuber T, et al. Human glandular kallikrein 2 levels in serum for discrimination of pathologically organ-conﬁned from locally advanced prostate cancer in total PSA-levels below 10 ng/ml. Prostate 2001;49:101.

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107. Recker F, Kwiatkowski MK, Piironen T, et al. Human glandular kallikrein as a tool to improve discrimination of poorly differentiated and non-organ-conﬁned prostate cancer compared with prostatespeciﬁc antigen. Urology 2000;55:481. 108. Lange PH, Ercole CJ, Lightner DJ, et al. The value of serum prostate speciﬁc antigen determinations before and after radical prostatectomy. J Urol 1989;141:873. 109. Haese A, Huland E, Graefen M, et al. Ultrasensitive detection of prostate speciﬁc antigen in the followup of 422 patients after radical prostatectomy. J Urol 1999;161:1206. 110. Stamey TA, Graves HC, Wehner N, et al. Early detection of residual prostate cancer after radical prostatectomy by an ultrasensitive assay for prostate speciﬁc antigen. J Urol 1993;149:787.

3

Deﬁning an Optimum PSA-Based Screening Strategy for Young Men* Judd W. Moul

INTRODUCTION Prostate cancer is the most common malignancy in American men, accounting for >29% of all diagnosed cancers and approx 13% of all cancer deaths (1). Nearly one of every six men will be diagnosed with the disease at some time in their lives (1). In 2003 alone, an estimated 221,000 US men were diagnosed with prostate cancer, and more than 28,000 died of the disease (1). Even though population-based screening for prostate cancer has yet to be deﬁnitively proved or disproved to affect the disease-speciﬁc mortality, this summary explores changes in the PSA era (deﬁned as the time in the United States when the PSA screening test came into widespread clinical use) and the prospects for testing younger men in their ﬁfth decade of life, namely, high-risk and average-risk men between the ages of 40 and 49 yr old.

PROS AND CONS OF POPULATION-BASED SCREENING IN GENERAL Early detection of prostate cancer has been attempted for many years in the form of the digital rectal examination (DRE). However, over the last 15 yr, with the advent of testing for prostate-speciﬁc antigen (PSA) levels, the topic of prostate cancer screening has become a hotly contested issue (2,3). Early detection may take the form of population-based screening or case ﬁnding. In the early 1990s, the American Cancer Society (ACS), the American Urological Association (AUA), and other organizations advocated screening for the early detection of prostate cancer (4,5). These groups recommend a DRE and PSA test for men starting at age 50 yr. Notably, however, other organizations had argued against screening, including the US Preventative Services Task Force, the American Academy of Family Physicians, and the American College of

* The opinions and assertions contained herein are the author’s private views and are not to be considered as reﬂecting the views of the US Army or the Department of Defense. From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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Physicians (6,7). Most recently, the US Preventive Services Task Force has softened its stance on screening, suggesting that physicians discuss the pros and cons of testing individual men. Several factors favor the use of screening for the early detection of prostate cancer. First, because patients do not experience symptoms during the early stages, they are unlikely to seek care until the disease has progressed. Second, improvements in detection methods have increased the prospects for identifying the disease in its early stages, when the cancer is still conﬁned to the organ and is more easily treatable and often curable. Third, early detection might mean the difference between life and death, as no cure has been found for the advanced disease. To be of value, screening must lead to treatment that has a favorable impact on prognosis. Catalona et al. (8) were one of the ﬁrst groups to examine this issue by comparing disease stages in patients with prostate cancer who had or had not undergone PSA screening. The screened group had a lower percentage of cases with advanced disease and no greater percentage with latent disease. The investigators concluded that screening reduces the incidence of advanced disease and implied that the death rate will ultimately decrease (8,9). Since these reports, there have been a multitude of studies documenting the changes in the epidemiology of prostate cancer in the PSA era.

PSA ERA CHANGES SUPPORTING GENERAL SCREENING When an effective screening tool is introduced into a population, the following events should occur. There should be a transient increase in incidence, owing to labeling of prevalent cancers. The cancers should be diagnosed in patients of a younger age. The cancer should be diagnosed at lower stages, and there should be an apparent increase in disease-speciﬁc survival (10,11). As of 2003, PSA testing has arguably fulﬁlled these criteria, and many clinicians practice screening. Furthermore, as screening has gained in popularity and public awareness of the disease has increased, there are more young men between 40 and 49 yr of age seeking evaluation. Regarding the change in prostate cancer incidence, the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute data as well as data from Mayo Clinic and other sites have documented the change (12–16). Speciﬁcally, starting in 1989 and peaking in 1992, there was a marked rise, with a subsequent decrease of approx 30%. These trends exemplify the Cull effect, that is, with the introduction of any screening tool into a population, there will be a rise in incidence, with a subsequent fall. This fall is because of the depletion of the prevalence pool of previously undiagnosed cases. The steady-state incidence of prostate cancer in the PSA era will eventually be a reﬂection both of patients aging and entering into the pool and of patients being removed from the pool as a result of dying or being diagnosed with prostate cancer (12). It is unclear whether the incidence will decrease to prescreening levels or remain higher than in previous years (16–20). Current statistics from the SEER data indicate that the steady-state incidence in the PSA era has yet to be reached (1). The mean and median age of men at diagnosis has decreased signiﬁcantly in the PSA era (20). The introduction of age-speciﬁc reference ranges for PSA screening, ﬁrst by Osterling et al. (21) and subsequently by race and age by Morgan et al. (22), has shown that prostate cancer detection and subsequent treatment is an age-dependent process. The younger the patient is at the time of diagnosis, presumably the earlier they are in the course of their disease. If curative-intent treatment is rendered at an earlier

Chapter 3 / PSA and Young Men

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age, the more likely it is that cure will occur. Chodak et al. (23) have shown that men <61 yr of age had a statistically signiﬁcant improved disease-speciﬁc survival. Smith et al. (24) from our group have also shown that younger age at diagnosis is an independent predictor of better prognosis. Age >65 yr has been demonstrated to be an independent predictor of distant metastasis (25). Carter et al. (26) have recently suggested that detection of prostate cancer in younger men is likely to lead to a decrease in prostate cancer mortality. In summary, there is strong evidence that if the diagnosis of prostate cancer is made at a younger age, disease-specific mortality can be significantly reduced, and it has now been demonstrated that in the PSA era the age at diagnosis has decreased signiﬁcantly. The decline in the age at the time of diagnosis from 72 to 69.4 yr from 1990 to 1994 has been shown by the SEER data (18). From the SEER data and other literature, a lead-time of between 3 and 5 yr is derived (13,15,18,27). In other words, with the aid of PSA, we are detecting cancers 3–5 yr earlier than prior to screening. Thus the increase in survival (time of diagnosis to time of death) in the PSA era must be at least 3–5 yr longer than the previous expected survival time to show any beneﬁt in diseasespeciﬁc survival with PSA screening. There has also been a signiﬁcant stage migration in the PSA era. Most strikingly, according to our Center for Prostate Disease Research (CPDR) database, the percentage of patients presenting with metastatic disease decreased from 14.1 and 19.8% in 1988 and 1989, respectively, to 3.3% in 1998 (20). Before a survival beneﬁt, a decrease in metastatic disease should be evident, which is clearly being shown on a national level by several studies (12–14,28). These ﬁndings are more impressive in light of the fact that no curative treatment exists for patients with metastatic disease. Similarly, we have also shown a statistically signiﬁcant decrease in the incidence of clinical T3 and T4 disease. Again, demonstrating a stage shift from disease that can merely be managed to disease that is amenable to cure. These T3 and T4, as well as T2 tumors are most likely being diagnosed several years prior to when they would previously become evident. The advent of PSA testing is reclassifying these tumors as TIc, which is associated with decreased recurrence rates and increased disease-speciﬁc survival, compared with other clinical stages (29–31). The level of PSA at the time of diagnosis is a general surrogate of tumor volume or cancer burden. A decline in PSA levels over time is further evidence of stage migration to support screening. In our CPDR studies, the median PSA at the time of diagnosis decreased from 11.8 ng/dL in 1990, to 6.3 ng/dL in 1998 (20). This is consistent with the ﬁndings of Vijayakumar et al. (32), who have recently demonstrated a statistically signiﬁcant drop in the PSA level of African-American patients presenting with prostate cancer Partin et al. (33) have shown that the lower the pretreatment PSA prior to prostatectomy, the lower the chance of extracapsular extension, seminal vesical involvement, and lymph node metastasis. Moul et al. (34) and many other investigators have shown that the PSA level is a signiﬁcant contributor in determining the risk of recurrence after treatment with radical prostatectomy. Similarly, in patients treated with external beam radiation, the lower the level of pretreatment PSA, the greater the disease-free survival (29,35). Hopefully, this continued decrease in PSA at the time of diagnosis portends more successful treatment outcomes in the future. Most of the tumors diagnosed in the PSA era are not indolent tumors by traditional grade and Gleason criteria. Multiple studies including SEER have shown that moderately differentiated or Gleason score 5–7 tumors predominate in the PSA era

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(12,13,36,37). One reason for the decrease in well-differentiated tumors is the decrease in the number of transurethreal resections of the prostate (TURPs) performed. It has been established that tumors arising in the transitional zone (area resected with a TURP) have a signiﬁcantly higher incidence of tumors with a lower Gleason score than tumors discovered in the peripheral zones by needle biopsy (38,39). Smith and Catalona (31) have shown that 97% of the tumors detected through PSA screening are medically important (deﬁned as palpable, multifocal, or diffuse, and moderately or poorly differentiated). Other recent studies conﬁrm that moderately differentiated or mid-Gleason grade tumors are clinically signiﬁcant, with higher recurrence and disease-speciﬁc mortality than lower grade tumors (23,40–42). Regarding survival, Gilliland et al. (43) showed improved survival during a period of PSA screening in New Mexico using the SEER data. The SEER 5-yr relative cancer survival rates for patients diagnosed in 1974–1977, 1980–1982, and 1989–1995 were 67, 73, and 92%, respectively; each of these changes was statistically significant (p < 0.05). Etzioni et al. (44) have determined that the improved survival is not simply owing to PSA testing, even if one considers a very short lead-time of 3 yr. It is probably related to screening and more aggressive treatment. Nevertheless, our own data from the CPDR also show significant improvements in 5-yr prostate cancer-specific survival rates as the PSA era has progressed (45). Specifically, for patients diagnosed between 1988 and 1991 at Walter Reed Army Medical Center, the cancer-specific survival was 81.7% compared with 92.5% for men diagnosed between 1992 and 1994 and 98.3% for men diagnosed between 1995 and 1998. This was based on a cohort of 2042 men, and cause of death was determined prospectively using the National Death Index, direct deaths certificate review, and Choice Point commercial service (Fig. 1). Aside from these population and database trends, screening studies by Labrie et al. (46) and Bartsch et al. (47) suggest a beneﬁt for population-based screening. Most notably, Bartsch et al. (47) recently reported early results of the Tyrolean prostate cancer screening study in Austria. By aggressively offering screening to all men in the Tyrolean state of Austria between 1993 and 1997, and testing two-thirds of eligible men between ages 45 and 75 yr, they report a 42% decline in the disease-speciﬁc mortality for prostate cancer compared with the rest of the country, where PSA testing was not commonly practiced.

ARGUMENTS AGAINST POPULATION SCREENING Opponents of screening point to the potential for side effects from treatment, the possibility that some men will be treated unnecessarily, the economic burden on the health care system, and the lack of deﬁnitive scientiﬁc evidence that the screening will reduce overall disease-speciﬁc mortality (19). Indeed, many men with prostate cancer do not die of the disease, whereas many other patients die of the disease despite our best efforts. No foolproof markers are currently available to differentiate these two groups. Therefore, a key objection to screening is that such efforts may uncover many cancers that, if left undetected, would never have caused morbidity or mortality; conversely, some cancers will cause death even though they are detected by screening (48). Some observers have further recommended that screening should be avoided in men older than 70 or 75 yr of age so as to reduce the detection of such “incidental cancers” that are unlikely to affect life expectancy.

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Fig. 1. Prostate cancer-speciﬁc survival by time period of diagnosis.

Recognizing that population screening for prostate cancer using PSA and DRE remains disputed for reducing the morbidity and mortality of the disease, authorities currently recommend that physicians and health care organizations provide the pros and cons as outlined above and let the well-informed patient decide. Many would argue that it would be wrong to mandate screening; however, it would be just as wrong not to offer the option of early detection tests for prostate cancer, especially for high-risk targeted groups, such as those with a family history of prostate cancer and those of African-American heritage. Recently the ACS and AUA have updated their prostate cancer screening guidelines to this effect (49,50). Most notably, the recommendations call for testing if the patient is undecided (49). Recognizing that these organizations recommend that testing begin at age 40 or 45 yr for high-risk men, it is critical to understand the ﬁne points of PSA testing in young men.

HIGH-RISK GROUPS THAT MAY BENEFIT FROM TESTING AT A YOUNG AGE For African-American men and those men with a family history of disease, the ACS and the AUA recommend testing for prostate cancer starting at age 45 yr. The US military services routinely offer PSA testing to military members at prescribed periodic physical examinations starting at age 40 yr. The US Army ofﬁcially recommends the PSA test at the “Over 40” physical as per Army Regulation 40-501 (January 1, 2000). Aside from these ofﬁcial recommendations, clinicians are seeing a growing population of young men who simply desire testing at a young age.

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ETHNIC PREDISPOSITION TO PROSTATE CANCER: AFRICAN-AMERICAN MEN It is widely known that men of African-American ethnicity have a high rate of prostate cancer compared with Caucasian men and in particular in relation to Asian men, who have a much lower rate. Speciﬁcally, the age-adjusted incidence of prostate cancer in African-American men is 50% higher than in White men, and Black men have the highest incidence of prostate cancer in the world (51). Difference in the probability of being diagnosed (9.6% vs 5.2%), lifetime-specific mortality (3% vs 1.4%), and 5-yr survival rates (67% vs 78%) between Blacks and Whites are all indicative of a major public health problem in the population (51). Encouraging preliminary data from the Radiation Therapy Oncology Group (52), the US Military (45), and the Veterans Administration (53), however, suggest that if Black men are afforded the same access and care as Whites, the outcome disparity may be minimized of eliminated. Despite these observed improvements in shortterm outcomes after radiation or surgery in Black and White men in the PSA era (1988–present), the long-term impact of early detection in this high-risk group is still unknown. Several recent studies point to very high cancer detection rates for African-American men. In a referral population, Fowler et al. (54) found that African-American men with a low PSA but an abnormal DRE had high rates of prostate cancer detection, speciﬁcally, 4, 15, 27, and 29% for PSAs of <1.0, 1.0–1.9, 2.0–2.9, and 3.0–3.9 ng/mL, respectively. Most recently, Bunker et al. (55), in a prospective screening of 2484 AfroCaribbeans in Tobago, found a detection rate of 10%. In the 40–49-yr age group (N = 843), 10% had a PSA above 4.0 ng/mL, and the cancer detection rate was 1% even using suboptimal sextant biopsy.

INHERITED PREDISPOSITION TO PROSTATE CANCER Many studies have demonstrated that men with ﬁrst-degree relatives with prostate cancer have an increased risk for the development of the same disease. For example, Steinberg et al. (56) obtained family histories of 691 men with prostate cancer and compared them with 640 spouse controls. They determined that men with prostate cancer had a twofold greater likelihood of having a brother or father with prostate cancer. Furthermore, prostate cancer risk increased with the total number of affected family members. A second case-control study as reported by Spitz et al. (57) using data obtained from a risk-factor questionnaire. Comparing 385 prostate cancer patients with a control population of race- and age-matched men with other forms of cancer, these investigators reported an age-adjusted relative risk of 2.4 for men having a ﬁrst-degree relative with prostate cancer. A study of twins reported a 4.5-fold higher concordance rate for prostate cancer among monozygotic compared with dizygotic twins, further supporting the importance of genetic factors in the development of prostate cancer (58). More recently, Gronberg et al. (59), using the Swedish Cancer register, demonstrated that a positive family history, deﬁned as having an affected father, is a risk factor for prostate cancer and that the effect was greatest in younger men. In our CPDR database, a study of military beneﬁciaries undergoing radical prostatectomy for clinically localized prostate cancer found that 16.5% reported a ﬁrst-degree relative who had prostate cancer (60). Family history was not associated with worse prognosis at a mean follow-up of 4.5 yr in this study. Recently, Valeri et al. (61) studied 435 ﬁrst-

Chapter 3 / PSA and Young Men

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Table 1 PSA to Predict the Future Development of Prostate Cancer: The Physicians’ Health Study Findings PSA (ng/mL)a ≤1.0 1.01–1.5 1.51–2.00 2.01–3.00 3.01–4.00 4.01–10.00 >10.00

Relative risk for prostate cancer (CI) 1.0 2.2 (1.3–3.6) 3.4 (1.9–5.9) 5.5 (3.3–9.2) 8.6 (4.7–15.6) 22.2 (12.9–38.2) 145.3 (59.1–357.0)

a

Single PSA measurement at study entry in 1982 (stored serum). Adapted from ref. 62.

degree relatives of prostate cancer patients prospectively, using PSA testing and ﬁnding 10 cancers (2.3%) in the ﬁrst screening round.

PSA LEVEL ITSELF AS A RISK FACTOR FOR FUTURE PROSTATE CANCER Aside from family history and ethnicity, the PSA value at baseline itself appears to be a risk factor for prostate cancer future development in population-based studies. Gann et al. (62) conducted a nested case-control study of 366 physicians who developed prostate cancer and 1098 age-matched control doctors who were part of the Physicians’ Health Study. Banked serum that had been collected in 1982 was used for PSA testing, and the cohort had at least a 10-yr follow-up. Table 1 shows the relative risk for prostate cancer by PSA value at entry in 1982. The study found that a single PSA measurement had a relatively high sensitivity and speciﬁcity (73% and 91%) for prostate cancer detection at 4-yr follow-up. More recently, Fang et al. (63) found similar results in young men from the Baltimore Longitudinal Study of Aging. Speciﬁcally, for 351 men enrolled when they were between 40 and 49.9 yr of age, the relative risk of prostate cancer at 25 yr was 3.75 for men who had an initial PSA above vs below the median of 0.60 ng/mL. Although more data are needed, baseline PSA measurements in young men aged 40–49 yr would appear to be appropriate in clinical practice for risk assessment. Closer follow-up would be prudent based on the value obtained; however, this risk assessment concept in young men has not yet been tested prospectively.

PSA LEVELS IN YOUNG MEN The interest in PSA levels in younger men ﬁrst surfaced in 1993 when Oesterling et al. (21) reported the ﬁrst age-adjusted or age-speciﬁc references ranges for normal PSA in healthy community-based males between the ages of 40 and 79 yr. These “normals” were based on the 95th percentile of PSA values in subjects by 10-yr age groups starting with men between 40 and 49 yr. The upper limit of normal for PSA in the Caucasian 40- to 49-yr-old cohort was 2.5 ng/mL. Since then, quite a number of groups have reported 95th percentile of PSA in this age group, as shown in Table 2 (21,22,64–71). As can be seen, the 95th percentile (the typical upper limit of normal)

44

Moul Table 2 Comparison of Age-Related PSA Values in 40- to 49-Year-Old Men Determined by Different Studiesa Race/ nationality

Study DeAntoni et al. (64) Hartzell et al. (65) Chautard et al. (66) Weinrich et al. (67) Morgan et al. (22) Morgan et al. (22) Oesterling et al. (21) Oesterling et al. (21)

CPDR database French African-American African-American Caucasian Caucasian Caucasian

Anderson et al. (69) Cooney et al. (70) Imai et al. (71)

African-American Japanese

a

Age (yr)

No.

Median

40–49 40–49 40–49 40–49 40–49 40–49 40–49 40–49 40–44 45–49 40–49 40–49

9838 757 515 400 292 196 165 147 151 225 105 68

0.7 0.54 0.7 0.7 0.7 0.7 0.65 0.6 0.6 0.74 0.8

Mean 0.83 0.96 0.63

0.91

95th percentile 2.4 2.3 1.69 1.9 2.4 2.1 2.5 2.0 1.5 1.6 2.36 2.1

PSA values are in nanograms per milliliter.

Table 3 Department of Defense Serum Repository Distribution of Serum Baseline PSA Levels According to Race and Age Group Age group (yr) Whites 20–29 30–39 40–45 20–45 Blacks 20–29 30–39 40–45 20–45

No.

Mean PSA (ng/mL)

Median PSA (ng/mL)

25th, 75th Percentiles

IQRa

95th percentile (ng/mL)

253 242 93 588

0.47 0.55 0.49 0.51

0.38 0.45 0.40 0.41

0.27, 0.57 0.28, 0.68 0.26, 0.64 0.27, 0.63

0.30 0.40 0.38 0.36

1.08 1.26 1.13 1.14

247 247 91 585

0.51 0.57 0.60 0.55

0.38 0.45 0.52 0.43

0.26, 0.61 0.32, 0.67 0.37, 0.73 0.29, 0.66

0.35 0.35 0.36 0.37

1.35 1.43 1.38 1.37

a

IQR interquartile range equals 75th percentile minus 25th percentile of PSA levels. From ref. 35.

ranges from 1.5 to 2.5 ng/mL in these studies. To explore further the normal PSA in young men, our group has reported PSA results from banked serum from the Department of Defense Serum Repository (72). Table 3 provides the data for a large cohort of Black and White men aged 20–45 yr. Of special note is the group between ages 40 and 45 yr, in which the 95th percentile of PSA was 1.13 ng/mL for White men and 1.38 ng/mL for Black men. Aside from this serum bank data, between 1997 and 2000 the author collaborated with the US Army War College and the Army Physical Fitness Research Institute (USAWC/APFRI) in

Chapter 3 / PSA and Young Men

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Table 4 PSA Testing Study 1997–2000 by the Principal Investigator and Army War College and the Army Physical Fitness Research Institute Age (yr)

No.

Mean

Median

40 41 42 43 44 45 46 47 48 49 Total

63 122 154 155 122 79 58 29 35 28 845

0.6154 0.7127 0.7981 0.7780 0.7590 0.7399 0.9067 0.8682 0.8743 0.9947 0.7770

0.5020 0.6900 0.6485 0.6650 0.6640 0.6240 0.8000 0.7000 0.6000 0.7385 0.6620

Minimum Maximum 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.20 0.10 0.10

1.90 2.64 7.82 4.40 2.90 3.47 3.27 1.84 4.74 3.30 7.82

95th PSA ≥ 1.5 ng/mL percentiles No. of patients (%) 1.30 1.50 1.56 1.51 1.65 1.80 2.20 1.80 1.62 3.20 1.81

2 7 9 13 10 6 8 5 4 5 69

3.2 5.7 5.8 8.4 8.2 7.6 13.8 17.2 11.4 17.9 8.2

Carlisle, PA to assist in the prostate cancer risk assessment of incoming military ofﬁcer students (73). During these 4 yr, 845 men between the ages of 40 and 49 yr had PSA data collected. Table 4 shows the data on PSA by age. When this study was conducted, the PSA threshold to prompt prostate biopsy was the traditional one of 4.0 ng/mL. In an analysis in 1999 of the ﬁrst 3 yr, 3 of 602 men between 40 and 49 yr old had a PSA ≥ 4.0 ng/mL and 1 man (0.17% cancer detection rate overall; 33.3% cancer detection in men with PSA ≥4.0 ng/mL) had cancer detected using a standard sextant biopsy (73).

PSA LEVELS IN AFRICAN-AMERICAN MEN Because African-American men have a higher risk of prostate cancer at a young age and testing younger men is considered appropriate, I will brieﬂy review the speciﬁc area of PSA in Black men. In 1995, our group reported on 541 consecutive men with newly diagnosed prostate cancer and showed that even with adjustment for tumor grade, age, and clinical stage, Black men had higher PSA levels (74). In the same study, we took a subsequent cohort of 91 Black and White men who underwent a radical prostatectomy and studied whole-mount specimens of their prostates with careful tumor volume assessment. Even in this study setting of a military equal-access health care system, the Black men had much higher tumor volumes overall and even within each clinical stage. This within-stage tumor volume disparity was primarily responsible for the racial difference in PSA, and PSA was a surrogate for bigger tumors in Black men. In a follow-up study in 1999 analyzing whole-mount prostatectomy specimens from 155 Caucasian and 46 African-American patients, we found that total PSA levels were higher in Black men despite rigorous covariate analysis including threedimensional measured total tumor volume (75). These studies were the ﬁrst among any research group to use multivariate analysis including measured tumor volume to demonstrate that African-American men, in general, had higher serum PSA values than Caucasian men.

46

Moul Table 5 Age-Speciﬁc Reference Ranges for the PSA Test, Based on the 5th Percentile of the Distribution of PSA Levels in the Patients, According to Race PSA (ng/mL) Age (yr)

Whites

Blacks

40–49 50–59 60–69 70–79

0.0–2.5 0.0–3.5 0.0–3.5 0.0–3.5

0.0–2.0 0.0–4.0 0.0–4.5 0.0–5.5

AGE-ADJUSTED PSA REFERENCE RANGES IN AFRICAN-AMERICAN AND CAUCASIAN MEN As an immediate follow-up to the discovery that African-American men had higher PSA values (74), we sought to better deﬁne PSA screening guidelines, particularly related to the concept of age-adjusted PSA reference ranges (21). Studying 3475 men without prostate cancer and 1783 men with prostate cancer, we reconﬁrmed that Black men had higher PSA levels, both without and with prostate cancer (22). More importantly, we were able to demonstrate that using the 95th percentile of PSA level in Black men without presumed prostate cancer was not optimal for developing PSA thresholds for early detection. We then decided to examine PSA levels in Black and White prostate cancer patients and were the ﬁrst to propose PSA early detection thresholds based on the 5th percentile of PSA in cases. Table 5 illustrates these PSA reference ranges, which are in widespread clinical use. Of note, for men between 40 and 49 yr old, the values are different for Black and White men. Speciﬁcally, up to 2.5 ng/mL is considered normal for White men and up to 2.0 ng/mL normal for Black men. The exact reason for this different screening recommendation is unknown, but it probably reﬂects a higher prevalence of disease in younger Black men in the low PSA range. The critical message in all these data is that men between 40 and 49 yr of age generally have very low PSA values. The 95th percentile in this age group is much lower than the traditional value of 4.0 ng/mL. The proper normal threshold would appear to be in the 1.5–2.5-ng/mL range. Clinicians who are testing men in this age range should be aware of this, and patients who have PSA values >1.5–2.5 ng/mL should probably be under closer surveillance. It is not unreasonable, in my opinion, to offer these men prostate biopsy if they are above this threshold. However, the full beneﬁt of this approach must await prospective population-based studies.

CANCER DETECTION RATES IN MEN WITH LOW PSA VALUES Despite the knowledge that younger men should have low PSA values, limited data exist on prostate cancer detection rates using lower thresholds. Smith et al. (76) studied 391 men 50 yr or older using a PSA threshold of >2.5 ng/mL and found a 27% cancer detection rate between 2.6 and 4.0 ng/mL, including a 45% rate in African-American and a 26% rate in White men. Similarly, Recker et al. (77) studied 168 men ≥50 yr old who had total PSA between 1.0 and 3.0 ng/mL and free PSA < 20% and found a 10.8%

Chapter 3 / PSA and Young Men

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prostate cancer detection rate. Both studies relied on sextant biopsy. Although these studies looked at lower PSA, they included only men aged 50 yr and older. It remains to be determined whether combining a lower PSA threshold and younger age (between 40 and 49 yr) will result in a meaningful cancer detection rate that ultimately improves survival rates.

OTHER FACTORS THAT MAY AFFECT PSA AND CONFOUND SCREENING IN YOUNG MEN Although it may sound good to use the PSA test to risk-assess young men for prostate cancer, certain factors (including PSA variability, ejaculation, and use of complementary and alternative medications [CAMs] and prescription medications) may affect PSA levels and make the interpretation of PSA difﬁcult.

PSA Variability Natural variation in PSA levels that occurs in healthy and diseased individuals may result in confusion and uncertainty. The literature on PSA variability is conﬂicting. Nixon et al. (78) found that the coefﬁcient of variation (CV) averaged only 7.5% for total PSA levels measured ﬁve times over 2 wk in nine men between 48 and 69 yr old. These men had a mix of diagnoses including prostate cancer (three), benign prostatic hypertrophy (BPH; three), prostatitis (one), prostatic intraepithelial neoplasia (PIN; one), and normal (one). Conversely, Prestigiacomo and Stamey (79) found a 23.5% CV in men with starting PSA levels between 4.0 and 10.0 ng/mL who had repeat testing within 2–3 wk. Morote et al. (80) found CVs of 12.9 and 18.8% for controls and cases, respectively, when testing was repeated over 1–2 mo. Ornstein et al. (81) studied 84 healthy men ≥50 yr old who had three PSA measurements taken 2 wk apart. For total PSA the CV was 15% and was unaffected by age, ejaculation, or PSA level. Most recently, Eastham et al. (82) studied multiple PSA values obtained in a cohort of 972 men enrolled in the Polyp Prevention Trial to examine variability in PSA. Looking at the thresholds of PSA >4.0 ng/mL and >2.5 ng/mL, age-speciﬁc PSA levels, and free PSA ratio, a repeat PSA was normal 26–37% of the time. Looking at a series of PSAs drawn over time, the percentage of participants with a normal test at any subsequent time after an abnormal test ranged from 40 to 55%. Furthermore, 65–83% of the time, the PSA remained normal on two consecutive further tests after one abnormal value. The conclusion was that an isolated elevation of PSA should be conﬁrmed several weeks later before proceeding with further testing including a prostate biopsy. To my knowledge, there are no published PSA variability data speciﬁcally for men between 40 and 49 yr old with a PSA in the 1.5–4.0-ng/mL range. However, the recommendations of Eastham et al. (82) to repeat the PSA several weeks later would appear prudent in this age group as well.

Effect of Ejaculation on PSA Literature regarding the effect of ejaculation on PSA levels is conﬂicting (83–89). Although some studies report that PSA levels may increase for 24–48 h after ejaculation, these were in men older than 49 yr or in whom the age was not stated. In studies of men 50–60 yr of age, or with a mean age of 60.4 yr, ejaculation had no signiﬁcant effect on PSA levels. For young men, Heidenreich et al. (85) from our group studied 100 men 25–35 yr old and found no signiﬁcant changes in serum PSA 1 and 24 h after

48

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ejaculation. Similarly, Yavascaoglu et al. (87) found no signiﬁcant change in PSA levels 1 and 5 d after ejaculation in 25 healthy volunteers 20–25 yr old. There is no literature, to our knowledge, on the effect of ejaculation on PSA for men aged 40–49 yr, so it is unknown whether we should ask men to abstain from ejaculation prior to PSA testing. A reasonable approach is not to impose any restriction on sexual activity prior to routine testing. However, if a man has an abnormal initial screening PSA, it may be reasonable to request that he avoid ejaculation for 3–5 d prior to repeat PSA.

Complementary and Alternative and Prescription Medications Effect on PSA Despite growing public interest, little is known about CAM use in young individuals and virtually nothing in men 40–49 yr old who may be at risk for prostate cancer (90–94). In older men (>50 yr), >40% take herbal supplements for lower urinary tract symptoms (LUTS) or for “prostate health” (91,95). The possible effect on serum PSA is unknown for many CAMs. For saw palmetto and Permixon®, a phytotherapy agent, two studies did not show an effect on PSA (95,96). However, it is well established that ﬁnasteride (Propecia®), the 5-α-reductase inhibitor, which has been approved by the Food and Drug Administration (FDA) for BPH and male pattern baldness, does lower PSA levels (97). Interestingly, in both normal young men (21–39 yr old) and in hypogonadal men (98,99) exogenous testosterone parenteral administration did not signiﬁcantly alter serum PSA levels. Whether any of the many health food supplements reputed to improve male sexual function and vitality affect PSA is presently unknown. Clinicians should question patients about CAM use and record it in the medical record. For patients with an abnormal or borderline PSA, it is particularly important to collect this information. It is not unreasonable, in my opinion, to ask patients to discontinue CAM use several weeks prior to repeat PSA testing.

Exercise Effect on PSA It has been suggested that exercise (bicycle riding in particular), affects PSA levels. Since younger individuals are generally more apt to be involved in these activities, it is relevant to review this issue brieﬂy here. Oremek and Seiffert (100) investigated total PSA, free PSA, and completed PSA after a 15-min bicycle ergometer test (75–100 Wt) in 301 healthy men of all age groups and found a threefold increase in total PSA, free PSA, and completed PSA. They concluded that extensive physical exercise should be avoided before blood sampling for diagnostic purposes. Crawford et al. (101) investigated 260 volunteers from a 4-d-long, 250-mile bicycle ride. In participants with normal prerace total PSA concentrations, postrace concentrations were 0.044 ng/mL higher, which is not of clinical relevance. In four athletes with a prerace PSA of more than 4 µg/L, they found a relevant total PSA increase of 1.65 ng/mL. They deduced that in men with a normal prerace total PSA there is no relevant tPSA increase after bicycle riding. Exercise has been suggested to be another disturbing factor of PSA measurement (102–104). However, only Oremek and Seiffert (100) were able to ﬁnd a signiﬁcant PSA increasing effect of physical exercise. Tymchuk et al. (103) and Leventhal et al. (104) did not ﬁnd signiﬁcant changes in PSA after different types of physical activity. Overall, three of these four studies did not ﬁnd that biking or exercise signiﬁcantly affected PSA. As with ejaculation and CAMs, it is probably not necessary to restrict activity/exercise prior to routine PSA testing. However, as with the other possible effectors, vigorous exercise or biking might be curtailed for 3–5 d prior to a repeat PSA test.

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OTHER PSA DERIVATIVES Free PSA The percent of free PSA to total PSA has become a clinically useful PSA derivative. Although free PSA is an FDA-approved laboratory test, its use in screening remains controversial. Speciﬁcally, what is the most useful cutpoint in clinical practice? At what total PSA range is precent free PSA most useful? Use of this derivative, just like total PSA, involves a balance between sensitivity and speciﬁcity. In other words, is the goal to maximize sensitivity (cancer detection) vs speciﬁcity (limiting the number of “unnecessary” prostate biopsies)? In the setting of young men, there are no speciﬁc studies on the use of percent free PSA in men aged 40–49 yr old. However, young men will be undergoing further testing at lower total PSA, and some of the literature is conﬂicting on percent free PSA in the total PSA range from 2 to 4 ng/mL. Roehl et al. (105) studied the clinical utility of percent free PSA in 965 consecutively screened men with a total PSA between 2.6 and 4.0 ng/mL and a normal DRE. A 25% free PSA cutoff detected 85% of cancers and avoided 19.1% of negative (cancer-free) biopsies, whereas a 30% free PSA threshold detected 93% of cancers while avoiding 9% of negative biopsies. The authors’ conclusion was that percent free PSA did not eliminate unnecessary biopsies and missed too many cancers. Conversely, Haese et al. (106) studied percent free PSA in 219 men with a total PSA of 2–4 ng/mL and a normal DRE. Using a percent free PSA threshold of 18–25%, the sensitivity was 46–75.6% and the speciﬁcity was 73.6–37.6%. They concluded that percent free PSA detected about 50% of cancers and spared up to 73% of “unnecessary” biopsies and could be used clinically in this total PSA range of 2–4 ng/mL. It remains to be determined how this derivative should be used in young men, particularly high-risk men in whom the sensitivity of early detection (i.e., not wanting to miss an early detection opportunity) is of paramount importance.

PSA Velocity PSA velocity is the concept of examining the rate of change of total PSA over time as a marker for the presence or absence of prostate cancer (107,108). Preliminary data from Fang et al. (107) and Ellis et al. (108) suggest that a PSA velocity ≥ 20%/yr may be predictive of prostate cancer in men with low total PSA in the 2–4-ng/mL range. However, there are no data speciﬁcally for men 40–49 yr of age. Although the traditional cutoff for normal PSA velocity has been up to 0.75 ng/mL/yr for older men, it is unknown whether this is an appropriate value to use in younger men. Most recently, interesting PSA velocity data have been presented from the National Cancer Institute sponsored Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening study (109). Table 6 shows the progression to a PSA level above 4.0 ng/mL for 27,868 men aged 55–74 yr who had had a baseline PSA exam and at least one other PSA exam within 5 yr. Although it is unknown whether these data are applicable to men 40–49 yr of age, the concept of low baseline PSA as a risk factor seems sound. For example, the median PSA for young men aged 40–49 yr is approx 0.7–0.8 ng/mL (Table 2). It may be that younger men with a baseline PSA less than or equal to the median PSA only require testing every 5 yr or even once between ages 40 and 49 yr, but further testing will be required prior to setting deﬁnitive practice guidelines. Furthermore, a low baseline PSA coupled with a PSA velocity <20%/yr may be further evidence of low risk of prostate cancer. A speciﬁc example would be a 45-yr-old man with a total PSA of

50

Moul Table 6 Prostate, Lung, Colorectal, and Ovarian Trial: Percent of Men With PSA Levels Rising Above 4 ng/mL Over 5 Years Baseline PSA (ng/mL) 0–1 1–2 2–3 3–4

Percent > 4 ng/mL Year 1

Year 2

Year 3

Year 4

Year 5

0.25 1.2 6.3 24.0

0.53 2.5 12.8 44.0

0.83 3.9 19.4 60.0

1.4 6.6 30.4 77.0

1.6 7.6 34.6 83.0

0.7–0.8 ng/mL. Using a velocity of 20%/yr would translate into a PSA of approx 0.15 ng/mL/yr as an upper limit in this young man.

REFUSAL OF PROSTATE BIOPSY IN YOUNG MEN A review of screening and the use of PSA in young men is not complete without a brief discussion of refusal of further testing for an elevated PSA or abnormal DRE. Unfortunately, there are no data/studies on the refusal to proceed to prostate biopsy speciﬁcally in young men aged 40–49 yr. However, there are some data on refusal to have prostate cancer screening in general (110,111). In the European Randomized Study of Screening for Prostate Cancer (ERSPC), Nijs et al. (110) studied men who refused to sign a consent to participate in population-based prostate screening. The main reasons for refusal were absence of urologic complaints (57%) and anticipated pain or discomfort (18%). Compared with consenting men, refusers were older, less often married, lower educated, less knowledgeable about health, and in worse general health, but they had fewer urologic complaints. In data from Prostate Cancer Awareness Week (PCAW), Crawford et al. (111) reported that only 33.2% of men with abnormal PSA and DRE actually underwent prostate biopsy. However, this was not a formal clinical trial, just a review of centers participating in free annual screening. Luhan Galen et al. (112) from Spain studied PSA velocity to prompt prostate biopsy in 986 men. There were 122 biopsies recommended and 91 (74.6%) performed; the refusal rate was 25.4%. There is a clear need to study refusal rate in young men, particularly to determine whether there are differences in high-risk men compared with average-risk men and whether other factors such as socioeconomic status affect the outcome. In the era of local anesthesia for prostate biopsy, it may be that refusal will be less of an issue, but this has not been studied (113).

THE FUTURE Aside from total PSA and free PSA, complexed PSA has recently received FDA approval for prostate cancer screening (114–120). Early data suggest that the test may be more accurate in the low total PSA range of 2–4 ng/mL than free PSA; however, as with free PSA, there is the issue of sensitivity (maximal cancer detection) vs avoiding “unnecessary” biopsies (speciﬁcity). In young men aged 40–49 yr, completed PSA has not received adequate study to date and should be evaluated further.

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Beyond PSA, future biomarkers may emerge to assess the risk of prostate cancer better. This would be particularly useful in young men in whom the prevalence of disease is lower and current screening strategies using PSA and PSA derivatives may be suboptimal. One emerging new technology is serum proteomic proﬁling. Using new high-throughput technology to analyze complex protein patterns in biologic specimens, such as blood, the testing has been employed in a variety of disease states including prostate cancer (121–123). Although it is still untested, it is hoped that serum proteomics or other molecular biomarkers will be able to risk-stratify young men accurately for prostate cancer in the future.

SUMMARY Although randomized clinical trials have yet to prove or disprove deﬁnitively the efﬁcacy of prostate cancer population-based screening, emerging data in the PSA era arguably support PSA testing in the early diagnosis of prostate cancer. Speciﬁcally, with public awareness of the disease and widespread PSA testing, smaller cancers are being detected in younger men, and 5-yr cancer-speciﬁc survivals are on the rise. Even though this lead-time effect may not translate into a long-term improvement, these changes are a necessary prerequisite to effective screening and are very promising. For high-risk patients with a family history of the disease and for African-American men, a strategy consisting of annual PSA blood test and DRE for men ≥40 yr old appears prudent. Use of age- and race-speciﬁc reference ranges for PSA based on sensitivity, or maximal cancer detection, is my favored approach in this high-risk group. Speciﬁcally for African-American men aged 40–49 yr, those with a PSA value >2.0 ng/mL should consider further evaluation. Many low/average-risk men aged 40–49 yr also request testing, and it is reasonable, in my opinion, to offer testing and risk assessment to these young men. The exact screening threshold for total PSA in these men is unknown, but 95% of them will have a PSA <1.5–2.5 ng/mL. PSA velocity (<20% year), percent free PSA (>18–25%), and perhaps complexed PSA may be used to help determine risk, but more study of young men is needed. In the future, a risk-stratiﬁed approach using molecular biomarkers and/or proteomics in young men is anticipated.

ACKNOWLEDGMENTS The author is supported by a grant from the Center for Prostate Disease Research, a program of the Henry M. Jackson Foundation for the Advancement of Military Medicine (Rockville, MD) funded by the US Army Medical Research and Material Command.

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Hereditary Prostate Cancer and Genetic Risk Phillippa J. Neville, Graham Casey, and John S. Witte

INTRODUCTION Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer-related deaths among men in the United States; in 2002, approx 189,000 men were diagnosed with—and 30,200 men died from—this disease (1). Moreover, prostate cancer is one of the most familial of common cancers. In comparison with men who have no family history of prostate cancer, those who have a ﬁrstdegree relative diagnosed with this disease have a two–fourfold greater risk, and those with three or more ﬁrst-degree relatives with prostate cancer have an approx 11-fold increased risk (2–7). A family history of prostate cancer may also increase a man’s risk of developing more biologically aggressive disease. In particular, studies have found that men with a positive family history of disease have shorter biochemical relapse-free survival following treatment (8–10), as well as increased prostate cancer mortality (11). Other studies, however, have not detected an association between family history and tumor aggressiveness (12,13). These equivocal results may reﬂect different levels of family history (e.g., single vs multiple ﬁrst-degree relatives with disease), bias in self-reports of family history (14), or heterogeneity across the different study populations. The risk of prostate cancer varies substantially across ethnic groups, with AfricanAmerican men exhibiting the highest rates worldwide (15). Furthermore, AfricanAmerican men generally present at diagnosis with more aggressive disease than men from other ethnic groups (16–18). The proportion of African-American men diagnosed with poorly differentiated tumors is nearly double that among Caucasians, and the mortality rate among African-American men is over twice as high as the rate among Caucasian men in the United States (19). Distinct biologic factors, and not simply access to medical care, appear to underlie the ethnic variation in prostate tumor aggressiveness (16–18,20–25). From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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The increased risk of prostate cancer within families and ethnic populations suggests that genetic factors play an important role in the development and aggressiveness of this disease. Two common approaches for evaluating such factors are studying candidate genes (i.e., those with strong a priori biologic rationale) and positional cloning. A number of candidate gene studies are discussed in other chapters of this text. Here we focus on genetic loci identified by positional cloning—identifying chromosomal regions that may harbor disease-causing genes solely based on their physical location. These studies generally use information from segregation and linkage analyses to help localize the regions possibly containing genes involved with familial and hereditary prostate cancer.

Segregation Analysis This approach looks at the disease inheritance patterns across generations of large pedigrees with many affected individuals to estimate the potential mode of transmission (e.g., recessive vs autosomal dominant) and frequency of putative disease-causing genes (26). Although individuals studied in segregation analyses have a family history of disease, some fulﬁll the more stringent and formal deﬁnition of exhibiting hereditary prostate cancer (HPC). In particular, families with HPC have at least one of the following: (1) three or more men with prostate cancer within a nuclear family; (2) three successive generations with affected men (maternal or paternal lineage); or (3) a cluster of two or more relatives affected before the age of 55 yr (27). Results from prostate cancer segregation analysis suggest that HPC may be inherited in an autosomal dominant manner, implying that a rare but highly penetrant risk allele(s) may cause disease (2). Other studies suggest both X-linked (4) and recessive (28) mode of prostate cancer inheritance. However, some pedigrees exhibit male-to-male transmission (29). The recessive mode of inheritance is supported by the apparent higher risk of prostate cancer among brothers of affected individuals compared with sons of affected fathers, but this increased risk may simply reflect improved screening, and therefore higher rates of diagnosis, among brothers of affected men (30).

Linkage Analysis Whereas segregation analysis looks at patterns of disease inheritance within families, linkage analysis correlates these patterns with the actual transmission of genetic markers from one generation to the next. High correlation, or linkage, between the inheritance of disease and genes helps identify genomic regions that may harbor a prostate cancercausing gene. To evaluate linkage, family members must be genotyped for a panel of highly polymorphic, microsatellite markers spanning the entire human genome (or speciﬁc regions of the genome). Genome-wide scans are generally performed in two phases by using markers broadly spaced in the initial scan (e.g., every 5–10 cM), followed by ﬁner mapping within regions showing linkage in the broad scan. Linkage analyses have most commonly used model-based methods that require assumptions about the inheritance mode and frequency of the putative disease gene (e.g., from segregation analysis). These analyses are very appropriate for the study of large multiple case families in which information can be gained from both affected and unaffected family members. Large high-risk families are quite rare, however, and the true genetic model for many diseases is often unknown. As a result, nonparametric approaches to linkage have been developed.

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A rationale underlying nonparametric methods is that affected family members will more often share identical alleles of markers surrounding the gene responsible for the inherited disease trait than they would markers from other regions of the genome. These methods are commonly applied to the affected sibling-pair design, wherein the genetic model need not be speciﬁed (31–34). Multiple sibships or small families are needed to indicate whether allele sharing is owing to common inheritance (identicalby-descent [IBD]) or other reasons (such as low variability of alleles) and to allow for different alleles to segregate with disease in different families.

PROSTATE CANCER SUSCEPTIBILITY LOCI As discussed below, several research groups have performed genome-wide scans or undertaken linkage replication studies using multiple case families or affected sibling pairs. These studies have detected a number of locations on chromosomes (loci) that may contain prostate cancer genes. Identifying the corresponding causal genetic mutations or variants, however, has proved difﬁcult for a number of reasons (35–39). First, prostate cancer is generally diagnosed at later ages, and the lack of any signiﬁcant distinguishing features of hereditary prostate cancer make it difﬁcult to separate hereditary from nonfamilial disease. This can lead to the inclusion of nonfamilial phenocopies within pedigrees and a weakening of linkage. Second, prostate cancer is a heterogeneous disease, with several genes probably contributing to an individual’s risk. Third, many of these genes may have modest or incomplete penetrance (35–37,39). Finally, different studies use varying ascertainment criteria and analytical approaches. Nevertheless, additional work suggests that speciﬁc genes within some of these linkage regions may play a role, either causal or modifying, in the development of prostate cancer.

HPC2/ELAC2 The HPC2/ELAC gene on chromosome 17p11 was originally identiﬁed as a candidate prostate cancer-susceptibility gene in a linkage analysis of families with multiple affected men from Utah (40). In addition to localizing the chromosomal region, this study detected in HPC2/ELAC two disease-segregating mutations, 1641insG (truncating) and R781H, as well as several other common mis-sense alterations. Two of the latter, Ser217Leu and Ala541Thr, were associated with risk of prostate cancer, irrespective of family history. Several additional studies have shown the 217Leu/541Thr variants to be associated with increased risk of prostate cancer, although not the more stringently deﬁned HPC (41–43). However, other studies have not detected linkage to this region or associations between variants in HPC2 and prostate cancer (42,44,45). This evidence was recently evaluated in a meta-analysis of the 217Leu/541Thr variants, which detected an overall positive association between 541Thr and prostate cancer; however, 217Leu had only a moderate effect, suggesting that it may act in concert with 541Thr (46). This is supported by the observation that the relative risk estimate for the multilocus analysis (541Thr and 217Leu) was slightly higher than that for the individual 541Thr analysis. Findings from the meta-analysis suggest that these two common ELAC2 variants could be involved with the development of approx 2% of all prostate cancers (46).

HPC1/RNASEL The HPC1 locus on chromosome 1q24-q25 was initially identiﬁed from a genomewide linkage analysis of 91 families, each with at least three men diagnosed with

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prostate cancer (47). Some studies have not conﬁrmed linkage to HPC1 (30,48–50), although others have (51–54). These equivocal results may reﬂect heterogeneity of the disease, whereby linkage to HPC1 may occur primarily among families with early-onset disease (6,55), advanced prostate cancer (56), or African-American ethnicity (51). A strong candidate for the HPC1 gene is RNASEL. Two of eight families linked to HPC1 have germline mutations that ablate RNASEL enzyme activity (57). In these families, a mutation in the initiation codon (M1I) and a truncating mutation (E265X) of RNASEL were found to segregate with disease (57). RNASEL is an ubiquitously expressed, latent endoribonuclease shown to mediate the antiviral and antiproliferative effects of the interferon-regulated 2′-5′-oligoisoadenylate (2–5A) pathway (58), implicating the immune response in prostate cancer etiology. Moreover, RNASEL has previously been proposed to function as a tumor suppressor gene (59), and a founder mutation (471delAAAG) was recently reported in Ashkenazi Jewish men with prostate cancer (60). Several polymorphisms were originally reported in RNASEL, including the common variant R462Q (Gln462Arg) (57). A family-based study from Finland detected a weak positive association between R462Q and prostate cancer (p = 0.07) (61). Another family-based study found an even stronger positive association between this variant and disease (p = 0.01) and showed that the in vitro enzymatic activity of the variant R462Q had approx one-third the activity of the wild-type enzyme (62,63). This association was slightly strengthened when the subjects were restricted to Caucasians only (p = 0.007), and the corresponding odds ratios suggest that carrying one copy of the variant increases the risk of prostate cancer approx 50%, whereas carrying two copies of the variant approx doubles a man’s risk of this disease. However, another study detected an inverse association between the R462Q variant and prostate cancer (p = 0.02) (64). This result was strengthened among men diagnosed at ≤64 yr (p = 0.0008) (64).

Macrophage Scavenger Receptor 1 (MSR1) on Chromosome 8p22-p23 Multiple lines of evidence suggest that chromosome 8p harbors one or more prostate cancer genes. In particular, loss of heterozygosity (LOH) (65–68) and comparative genomic hybridization (69,70) studies have identiﬁed several consistently deleted regions across chromosome 8p in prostate tumors. One of these loci, 8p22-p23, has also been linked to HPC in a study of 159 multiple-case families, with the highest linkage seen in families with older age at onset (≥65 yr) and ﬁve or more affected members (71). Linkage of this region to prostate cancer was recently conﬁrmed by an independent study of 57 Swedish multiple-case families (72); however, in contrast to the previous study, the strongest linkage was seen in families with early-onset disease (<65 yr old) and less than ﬁve affected members. This linked region contains several genes previously implicated as putative tumor suppressor genes, including the MSR1 (macrophage scavenger receptor 1) gene (70,73–75). One nonsense and six rare missense germline alterations were identiﬁed in MSR1 and were strongly associated with prostate cancer (71,76). MSR1 functions as a transmembrane homotrimeric receptor for a number of polyanionic ligands including a variety of bacteria, and MSR1 shows increased expression in inflammation following oxidative stress (73). Furthermore msr1–/– mice have a reduced capacity to eradicate certain pathogens effectively, perhaps reﬂecting a compromised immune response (74,75).

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Common MSR1 sequence variants have also been reported in HPC probands, and three of these have been associated with prostate cancer in a study of 301 prostate cancer patients and 250 unaffected controls (77). One haplotype contained all of the risk alleles, and thus was strongly associated with prostate cancer (p = 0.004). This haplotype did not include any of the rare mutations identiﬁed in the previous study (71,76), suggesting that any association between the common and rare MSR1 variants and prostate cancer may be independent.

HPCX The HPCX locus on chromosome Xq27-q28 was predicted to account for up to 16% of HPC cases (78). Here, linkage analysis detected a maximum two-point lod score of 4.6 at marker DXS1113, 153cM from Xpter in a study of 360 multiple case families recruited from sites in the United States, Finland, and Sweden. Several other studies have replicated this linkage, with the strongest finding in families showing no male-to-male transmission, as one might expect (79–82). However, some studies detected increased linkage among men with early age of disease onset (≤65 yr old) (79,82), whereas another found stronger linkage for men with a later age of onset (>65 yr old) (80). Both physical and transcript maps of the region surrounding HPCX have recently been published and show that >50 known and predicted genes exist within the region (83).

HPC20 Another locus identified by linkage analysis is on chromosome 20q13, termed HPC20 (84). Linkage to HPC20 was detected in a study of 162 North American families with three or more members affected with prostate cancer. Families showing the highest linkage to this region were those with less than five affected members, later age at disease onset, and absence of male-to-male transmission. As with other loci, these findings suggest that this candidate susceptibility locus may be involved in a distinct subset of HPC families. Although an independent study failed to replicate these findings, it did show slight linkage to 20q13 in smaller families with later age at onset (85).

PCAP The prostate cancer-susceptibility locus, predisposing for cancer of the prostate (PCAP), on chromosome 1q42.2-q43 (approx 60 cM telomeric to HPC1) was identiﬁed in a study of French and German families (48). Linkage was strongest in families with an earlier age of disease onset (diagnosed at <60 yr) giving a multipoint lod scores of 3.31. Using an expanded pedigree set, an overall maximum multipoint nonparametric lod score of 2.8 was detected (86). Again, families with earlier onset disease (≤65 yr old) contributed substantially to the overall linkage observed, with a maximum multipoint non-parametric linkage (NPL) score of 2.03. The authors of this work hypothesized that PCAP may be the major known prostate cancer predisposing locus in families from south and west Europe. Other groups have reported marginal linkage to this region, with the strongest evidence seen in those families with early-onset disease (87,88) or greater family history (89) or when Gleason score and/or male-to-male transmission was taken into account (53). Conversely, no evidence of linkage was observed in families from Iceland (90) or from other North American pedigrees (91,92).

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CAPB A cancer of the prostate and brain (CAPB) locus has been linked to the chromosome 1p36 region. Here, a genome-wide scan of high-risk prostate cancer families found that the chromosome 1p36 locus may be involved in a subset of high-risk prostate cancer families in which at least one member developed brain cancer (93). This is consistent with epidemiologic studies showing increased rates of brain (27) and central nervous system (CNS) (94) tumors in families with HPC and with studies reporting frequent LOH across chromosome 1p36 in brain and CNS tumors (95–98).

Chromosome 16q23 A genome-wide scan of 504 affected brothers from 230 multiplex sibships identiﬁed several regions linked to prostate cancer, with the strongest at chromosome 16q23 (99). The region of linkage covered approx 7.5 cM between markers D16S3049 and D16S3040, with the peak linkage at marker D16S3096 (multipoint Z score = 3.15). This result was recently replicated in two independent sets of affected sibling pairs (100; J. Witte, personal communication). A high frequency of LOH was also identiﬁed on chromosome 16q23 in prostate tumors, when studying the markers that showed peak linkage in this region (101). These markers are within intron 8 of the WW oxidoreductase (WWOX) gene. This large intron is the site of the second most common fragile site in the human genome (FRA16D) (102,103) and is the site of frequent translocations in multiple myelomas (104). WWOX is a putative oxidoreductase that is expressed in hormonally regulated tissues (i.e., testis, prostate, breast, and ovary) (105) and may play a role in activating and deactivating hormones involved in prostate cell division, implicating it as a strong candidate for the 16q23 gene. Furthermore, WWOX has been shown to function as a tumor suppressor gene in breast cancer cells, and homozygous deletions within this gene have been reported in several tumor cell lines (103,106,107).

BRCA1 and BRCA2 Prostate and breast cancer appear to cluster within some families (108), and relatives of breast cancer patients have an increased incidence of prostate cancer (109) and vice versa (110). The increased risk of breast cancer is further elevated among women with a family history of early-onset prostate cancer (111,112). Germline mutations in the BRCA1 and BRCA2 genes are thought to result in the development of many familial breast and ovarian cancers (113). Moreover, in a study of breast/ovarian cancer families linked to BRCA1, comparing men carrying a BRCA1 mutation with the general population gave a relative risk of prostate cancer equal to 3.33 (95% conﬁdence interval = 1.78–6.20) (113). Similarly, the Breast Cancer Linkage Consortium recently reported evidence of an increased risk of prostate cancer in carriers of BRCA1 mutations <65 yr (RR = 1.82; 95% CI = 1.01–3.29) (114). An earlier study by the Breast Cancer Linkage Consortium suggested that BRCA2 mutation carriers also have an increased risk of prostate cancer (115). The relative risk of prostate cancer in men from 173 breast-ovarian cancer families with BRCA2 mutations was 4.65 (95% CI = 3.48–6.22) and rose to 7.33 (95% CI = 4.66–11.52) in men <65 yr of age (115). The relative risk of developing prostate cancer at early age (<56 yr old) for men carrying BRCA2 mutations has been estimated as being 23-fold higher than in noncarriers (116). LOH studies have also implicated both BRCA1 and BRCA2, with

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prostate tumors frequently demonstrating LOH at 17q (BRCA1) (117,118) and 13q (BRCA2) (119,120). Furthermore, speciﬁc BRCA2 mutations have been associated with an increased risk of developing prostate cancer. Carrying the 999del5 BRCA2 mutation appears to confer an increased risk of more aggressive prostate cancer (121,122), and risk of disease is increased in ﬁrst- and second-degree relatives of breast cancer patients carrying this mutation, although not in relatives of probands without the mutation (123). Further evidence for increased risk of prostate cancer in BRCA2 mutation carriers comes from a recent study of a Swedish family in which the father and four sons were all diagnosed with prostate cancer at very early ages (124). A truncating mutation, 6051delA, was identiﬁed in three of the affected sons and three daughters, two of whom had been diagnosed with breast cancer at an early age. Contrary to these ﬁndings, several reports have shown that BRCA1 and BRCA2 founder mutations (185delAG and 5382InsC in BRCA1 and 6174delT in BRCA2) do not occur more frequently in Ashkenazi Jewish men with prostate cancer than would be expected in the general population (125–129). This is in stark contrast to the well-documented increased frequency of BRCA1 and BRCA2 founder mutations in affected members of Ashkenazi Jewish breast and ovarian cancer families (113,130,131). It is possible that this disparity is associated with the position of the mutations. In particular, the BRCA2 mutation 6174delT lies within the ovarian cancer cluster (OCCR), which has previously been associated with an increase in ovarian cancer risk (RR = 1.88) and a decrease in both prostate (RR = 0.48) and breast cancer risk (RR = 0.63) (132). The proportion of familial prostate cancer cases attributable to BRCA2 mutations has been estimated to be between 5 and 33% in different populations (115,116,133,134). This proportion may be signiﬁcantly higher among early-onset (≤55 yr of age) prostate cancer families (116).

PROSTATE CANCER AGGRESSIVENESS LOCI The aggressiveness of prostate cancer varies considerably; some tumors progress to life-threatening disease, and others remain indolent for many years. Furthermore, as discussed earlier, aggressiveness may depend in part on family history or ethnic populations, suggesting that there may be a genetic basis for how quickly a tumor progresses (12,13). Although most segregation and linkage analyses have focused on prostate cancer susceptibility loci, a few studies have investigated linkage to tumor aggressiveness.

Chromosome 7q32-q33 and 19q12-q13.1 A genome-wide linkage analysis of affected brothers’ Gleason scores identiﬁed three chromosomal regions potentially harboring prostate cancer aggressiveness loci: chromosome 5q31–q33 (p = 0.0002); chromosome 7q32 (p = 0.0007); and chromosome 19q12 (p = 0.0004) (135). These regions were not identiﬁed when the data were analyzed irrespective of Gleason score (99), implying that at least some loci linked to tumor aggressiveness are distinct from those linked to prostate cancer incidence. Independent studies have replicated the linkage of tumor aggressiveness to chromosomes 7q32 and 19q12 (100,136,137; J. Witte, personal communication). Moreover, a report of frequent LOH within the 7q32 (138) and 19q12 (139) regions in unselected prostate cancer cases supports the mapping of tumor suppressor gene(s) to these regions.

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Patients showing interstitial LOH at 7q32 marker D7S1804 (the marker showing peak linkage) were more likely to have been diagnosed at a younger age (<65 yr old) and to have a higher combined Gleason score and tumor stage, markers for tumor aggressiveness. Several genes have been mapped to the 7q32 region, including two biologically plausible candidates for tumor aggressiveness, muskelin (MKLN1) and podocalyxinlike (PODXL).

CONCLUSIONS AND GENETIC RISK Substantial progress has been made toward identifying genes involved in prostate cancer risk and aggressiveness. A number of genetic loci linked to prostate cancer are reviewed here, some of which contain strong candidates, including HPC2/ELAC, HPC1/RNASEL, and MSR1. Additional studies will undoubtedly help to clarify the potential roles of these loci and genes in prostate cancer. One noteworthy ﬁnding is that both MSR1 and RNASEL are involved in innate immunity. Future studies should determine whether there is any evidence of a viral or bacterial etiology to prostate cancer, or whether the impact of these genes on prostate cancer is independent of their innate immunity function. Prostate cancer appears to be a heterogeneous disease, with multiple genes each possibly accounting for only a small percentage of prostate cancer cases. Nevertheless, some of the ﬁndings reported here (e.g., for HPC1/RNASEL) support the hypothesis that common, low-penetrance variants may play an important role in prostate cancer risk. Although the increase in risk attributable to each such variant may be relatively small, the overall effect on the public’s health may be large owing to the relatively high frequency of some of the variants in the population. The heterogeneity of prostate cancer complicates not only the identiﬁcation of causal genes but also future screening for prostate cancer-causing genes. In particular, to undertake such a test may require developing a panel that screens for multiple genes. Furthermore, although screening men for genetic variants may be justiﬁed in future risk assessment of prostate cancer, the clinical implications of the additional knowledge gained from such tests remains unclear. Nevertheless, screening for aggressiveness genes may have near-term beneﬁts, providing important information about the most appropriate recommended course of treatment among men already diagnosed with prostate cancer.

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35. Eeles RA. Genetic predisposition to prostate cancer. Prostate Cancer Prostatic Dis 1999;2:9–15. 36. Nwosu V, Carpten J, Trent JM, Sheridan R. Heterogeneity of genetic alterations in prostate cancer: evidence of the complex nature of the disease. Hum Mol Genet 2001;10:2313–2318. 37. Ostrander EA, Stanford JL. Genetics of prostate cancer: too many loci, too few genes. Am J Hum Genet 2000;67:1367–1375. 38. Simard J, Dumont M, Soucy P, Labrie F. Perspective: prostate cancer susceptibility genes. Endocrinology 2002;143:2029–2040. 39. Singh R, Eeles RA, Durocher F, et al. High risk genes predisposing to prostate cancer developmentdo they exist? Prostate Cancer Prostatic Dis 2000;3:241–247. 40. Tavtigian SV, Simard J, Teng DH, et al. A candidate prostate cancer susceptibility gene at chromosome 17p. Nat Genet 2001;27:172–180. 41. Rebbeck TR, Walker AH, Zeigler-Johnson C, et al. Association of HPC2/ELAC2 genotypes and prostate cancer. Am J Hum Genet 2000;67:1014–1019. 42. Wang L, McDonnell SK, Elkins DA, et al. Role of HPC2/ELAC2 in hereditary prostate cancer. Cancer Res 2001;61:6494–6499. 43. Suarez BK, Gerhard DS, Lin J, et al. Polymorphisms in the prostate cancer susceptibility gene HPC2/ELAC2 in multiplex families and healthy controls. Cancer Res 2001;61:4982–4984. 44. Rokman A, Ikonen T, Mononen N, et al. ELAC2/HPC2 involvement in hereditary and sporadic prostate cancer. Cancer Res 2001;61:6038–6041. 45. Xu J, Zheng SL, Carpten JD, et al. Evaluation of linkage and association of HPC2/ELAC2 in patients with familial or sporadic prostate cancer. Am J Hum Genet 2001;68:901–911. 46. Camp NJ, Tavtigian SV. Meta-analysis of associations of the Ser217Leu and Ala541Thr variants in ELAC2 (HPC2) and prostate cancer. Am J Hum Genet 2003;71:1475–1478. 47. Smith JR, Freije D, Carpten JD, et al. Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 1996;274:1371–1374. 48. Berthon P, Valeri A, Cohen-Akenine A, et al. Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2-43. Am J Hum Genet 1998;62:1416–1424. 49. Goode EL, Stanford JL, Chakrabarti L, et al. Linkage analysis of 150 high-risk prostate cancer families at 1q24-25. Genet Epidemiol 2000;18:251–275. 50. McIndoe RA, Stanford JL, Gibbs M, et al. Linkage analysis of 49 high-risk families does not support a common familial prostate cancer-susceptibility gene at 1q24-25. Am J Hum Genet 1997;61:347–353. 51. Cooney KA, McCarthy JD, Lange E, et al. Prostate cancer susceptibility locus on chromosome 1q: a conﬁrmatory study. J Natl Cancer Inst 1997;89:955–959. 52. Hsieh CL, Oakley-Girvan I, Gallagher RP, et al. Re: prostate cancer susceptibility locus on chromosome 1q: a conﬁrmatory study. J Natl Cancer Inst 1997;89:1893–1894. 53. Goddard KA, Witte JS, Suarez BK, Catalona WJ, Olson JM. Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4. Am J Hum Genet 2001;68:1197–1206. 54. Xu J, Zheng SL, Chang B, et al. Linkage of prostate cancer susceptibility loci to chromosome 1. Hum Genet 2001;108:335–345. 55. Gronberg H, Smith J, Emanuelsson M, et al. In Swedish families with hereditary prostate cancer linkage to the HPC1 locus on chromosome 1q24-25 is restricted to families with early-onset prostate cancer. Am J Hum Genet 1999;65:134–140. 56. Goode EL, Stanford JL, Peters MA, et al. Clinical characteristics of prostate cancer in an analysis of linkage to four putative susceptibility loci. Clin Cancer Res 2001;7:2739–2749. 57. Carpten J, Nupponen N, Isaacs S, et al. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nat Genet 2002;30:181–184. 58. Hassel BA, Zhou A, Sotomayor C, Maran A, Silverman RH. A dominant negative mutant of 2-5Adependent RNase suppresses antiproliferative and antiviral effects of interferon. EMBO J 1993;12:3297–3304. 59. Lengyel P. Tumor-suppressor genes: news about the interferon connection. Proc Natl Acad Sci USA 1993;90:5893–5895. 60. Rennert H, Bercovich D, Hubert A, et al. A novel founder mutation in the RNASEL gene 471delAAAG, is associated with prostate cancer in Ashkenazi Jews. Am J Hum Genet 2002;71:981–984. 61. Rokman A, Ikonen T, Seppala EH, et al. Germline alterations of the RNASEL gene a candidate HPC1 gene at 1q25 in patients and families with prostate cancer. Am J Hum Genet 2002;70:1299–1304. 62. Casey G, Neville PJ, Plummer SJ, et al. RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases. Nat Genet 2002;32:581–583.

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63. The SAS System, release 6.12. SAS, Carey, NC, 1996. 64. Wang L, McDonnell SK, Elkins DA, et al. Analysis of the RNASEL gene in familial and sporadic prostate cancer. Am J Hum Genet 2002;71:116–123. 65. MacGrogan D, Levy A, Bostwick D, Wagner M, Wells D, Bookstein R. Loss of chromosome arm 8p loci in prostate cancer: mapping by quantitative allelic imbalance. Genes Chromosomes Cancer 1994;10:151–159. 66. Macoska JA, Trybus TM, Benson PD, et al. Evidence for three tumor suppressor gene loci on chromosome 8p in human prostate cancer. Cancer Res 1995;55:5390–5395. 67. Vocke CD, Pozzatti RO, Bostwick DG, et al. Analysis of 99 microdissected prostate carcinomas reveals a high frequency of allelic loss on chromosome 8p12-21. Cancer Res 1996;56:2411–2416. 68. Prasad MA, Trybus TM, Wojno KJ, Macoska JA. Homozygous and frequent deletion of proximal 8p sequences in human prostate cancers: identiﬁcation of a potential tumor suppressor gene site. Genes Chromosomes Cancer 1998;23:255–262. 69. Bova GS, Carter BS, Bussemakers MJ, et al. Homozygous deletion and frequent allelic loss of chromosome 8p22 loci in human prostate cancer. Cancer Res 1993;53:3869–3873. 70. Kagan J, Stein J, Babaian RJ, et al. Homozygous deletions at 8p22 and 8p21 in prostate cancer implicate these regions as the sites for candidate tumor suppressor genes. Oncogene 1995;11:2121–2126. 71. Xu J, Zheng SL, Hawkins GA, et al. Linkage and association studies of prostate cancer susceptibility: evidence for linkage at 8p22-23. Am J Hum Genet 2001;69:341–350. 72. Wiklund F, Jonsson BA, Goransson I, Bergh A, Gronberg H. Linkage analysis of prostate cancer susceptibility: conﬁrmation of linkage at 8p22-23. Hum Genet 2003;112:414–418. 73. Mietus-Snyder M, Glass CK, Pitas RE. Transcriptional activation of scavenger receptor expression in human smooth muscle cells requires AP-1/c-Jun and C/EBPbeta: both AP-1 binding and JNK activation are induced by phorbol esters and oxidative stress. Arterioscler Thromb Vasc Biol 1998;18. 74. Suzuki H, Kurihara Y, Takeya M, et al. A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection. Nature 1997;386:292–296. 75. Thomas CA, Li Y, Kodama T, et al. Protection from lethal gram-positive infection by macrophage scavenger receptor-dependent phagocytosis. J Exp Med 2000;191:147–156. 76. Xu J, Zheng SL, Komiya A, et al. Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Nat Genet 2002;32:321–325. 77. Xu J, Zheng SL, Komiya A, et al. Common sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Am J Hum Genet 2003;72:208–212. 78. Xu J, Meyers D, Freije D, et al. Evidence for a prostate cancer susceptibility locus on the X chromosome. Nat Genet 1998;20:175–179. 79. Lange EM, Chen H, Brierley K, et al. Linkage analysis of 153 prostate cancer families over a 30-cM region containing the putative susceptibility locus HPCX. Clin Cancer Res 1999;5:4013–4020. 80. Schleutker J, Matikainen M, Smith J, et al. A genetic epidemiological study of hereditary prostate cancer (HPC) in Finland: frequent HPCX linkage in families with late-onset disease. Clin Cancer Res 2000;6:4810–4815. 81. Peters MA, Jarvik GP, Janer M, et al. Genetic linkage analysis of prostate cancer families to Xq27-28. Hum Hered 2001;51:107–113. 82. Bochum S, Paiss T, Vogel W, Herkommer K, Hautmann R, Haeussler J. Conﬁrmation of the prostate cancer susceptibility locus HPCX in a set of 104 German prostate cancer families. Prostate 2002;52:12–19. 83. Stephan DA, Howell GR, Teslovich TM, et al. Physical and transcript map of the hereditary prostate cancer region at xq27. Genomics 2002;79:41–50. 84. Berry R, Schroeder JJ, French AJ, et al. Evidence for a prostate cancer-susceptibility locus on chromosome 20. Am J Hum Genet 2000;67:82–91. 85. Bock CH, Cunningham JM, McDonnell SK, et al. Analysis of the prostate cancer-susceptibility locus HPC20 in 172 families affected by prostate cancer. Am J Hum Genet 2001;68:795–801. 86. Cancel-Tassin G, Latil A, Valeri A, et al. PCAP is the major known prostate cancer predisposing locus in families from south and west Europe. Eur J Hum Genet 2001;9:135–142. 87. Gibbs M, Chakrabarti L, Stanford JL, et al. Analysis of chromosome 1q42.2-43 in 152 families with high risk of prostate cancer. Am J Hum Genet 1999;64:1087–1095. 88. Berry R, Schaid DJ, Smith JR, et al. Linkage analyses at the chromosome 1 loci 1q24-25 (HPC1) 1q42.2-43 (PCAP) and 1p36 (CAPB) in families with hereditary prostate cancer. Am J Hum Genet 2000;66:539–546.

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89. Suarez BK, Lin J, Witte JS, et al. Replication linkage study for prostate cancer susceptibility genes. Prostate 2000;45:106–114. 90. Bergthorsson JT, Johannesdottir G, Arason A, et al. Analysis of HPC1 HPCX and PCaP in Icelandic hereditary prostate cancer. Hum Genet 2000;107:372–375. 91. Whittemore AS, Lin IG, Oakley-Girvan I, et al. No evidence of linkage for chromosome 1q42.2-43 in prostate cancer. Am J Hum Genet 1999;65:254–256. 92. Hsieh CL, Oakley-Girvan I, Balise RR, et al. A genome screen of families with multiple cases of prostate cancer: evidence of genetic heterogeneity. Am J Hum Genet 2001;69:148–158. 93. Gibbs M, Stanford JL, McIndoe RA, et al. Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36. Am J Hum Genet 1999;64:776–787. 94. Isaacs SD, Kiemeney LA, Baffoe-Bonnie A, Beaty TH, Walsh PC. Risk of cancer in relatives of prostate cancer probands. J Natl Cancer Inst 1995;87:991–996. 95. Bello MJ, Vaquero J, de Campos JM, et al. Molecular analysis of chromosome 1 abnormalities in human gliomas reveals frequent loss of 1p in oligodendroglial tumors. Int J Cancer 1994;57:172–175. 96. White PS, Maris JM, Beltinger C, et al. A region of consistent deletion in neuroblastoma maps within human chromosome 1p36.2-36.3. Proc Natl Acad Sci USA 1995;92:5520–5524. 97. Smith JS, Alderete B, Minn Y, et al. Localization of common deletion regions on 1p and 19q in human gliomas and their association with histological subtype. Oncogene 1999;18:4144–4152. 98. Bauer A, Savelyeva L, Claas A, Praml C, Berthold F, Schwab M. Smallest region of overlapping deletion in 1p36 in human neuroblastoma: a 1 Mbp cosmid and PAC contig. Genes Chromosomes Cancer 2001;31:228–239. 99. Suarez BK, Lin J, Burmester JK, et al. A genome screen of multiplex sibships with prostate cancer. Am J Hum Genet 2000;66:933–944. 100. Witte JS, Suarez BK, Theil B, et al. Genome-wide scan of brothers: replication and ﬁne mapping of prostate cancer susceptibility and aggressiveness loci. The Prostate, in press. 101. Paris PL, Witte JS, Kupelian PA, et al. Identiﬁcation and ﬁne mapping of a region showing a high frequency of allelic imbalance on chromosome 16q23.2 that corresponds to a prostate cancer susceptibility locus. Cancer Res 2000;60:3645–3649. 102. Mangelsdorf M, Ried K, Woollatt E, et al. Chromosomal fragile site FRA16D and DNA instability in cancer. Cancer Res 2000;60:1683–1689. 103. Paige AJ, Taylor KJ, Stewart A, et al. A 700-kb physical map of a region of 16q23.2 homozygously deleted in multiple cancers and spanning the common fragile site FRA16D\. Cancer Res 2000;60:1690–1697. 104. Chesi M, Bergsagel PL, Shonukan OO, et al. Frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma. Blood 1998;91:4457–4463. 105. Bednarek AK, Laﬂin KJ, Daniel RL, Liao Q, Hawkins KA, Aldaz CM. WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1, a region frequently affected in breast cancer. Cancer Res 2000;60:2140–2145. 106. Paige AJ, Taylor KJ, Taylor C, et al. WWOX: a candidate tumor suppressor gene involved in multiple tumor types. Proc Natl Acad Sci USA 2001;98:11417–11422. 107. Bednarek AK, Keck-Waggoner CL, Daniel RL, et al. WWOX, the FRA16D gene, behaves as a suppressor of tumor growth. Cancer Res 2001;61:8068–8073. 108. Sellers TA, Potter JD, Rich SS, et al. Familial clustering of breast and prostate cancers and risk of postmenopausal breast cancer. J Natl Cancer Inst 1994;86:1860–1865. 109. Tulinius H, Egilsson V, Olafsdottir GH, Sigvaldason H. Risk of prostate, ovarian, and endometrial cancer among relatives of women with breast cancer. BMJ 1992;305:855–857. 110. Anderson DE, Badzioch MD. Breast cancer risks in relatives of male breast cancer patients. J Natl Cancer Inst 1992;84:1114–1117. 111. Gronberg H, Bergh A, Damber JE, Emanuelsson M. Cancer risk in families with hereditary prostate carcinoma. Cancer 2000;89:1315–1321. 112. Valeri A, Fournier G, Morin V, et al. Early onset and familial predisposition to prostate cancer significantly enhance the probability for breast cancer in first degree relatives. Int J Cancer 2000;86:883–887. 113. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 1998;62:676–689. 114. Thompson D, Easton DF. Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 2002;94:1358–1365.

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115. Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 1999;91:1310–1316. 116. Edwards SM, Kote-Jarai Z, Meitz J, et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet 2003;72:1–12. 117. Brothman AR, Steele MR, Williams BJ, et al. Loss of chromosome 17 loci in prostate cancer detected by polymerase chain reaction quantitation of allelic markers. Genes Chromosomes Cancer 1995;13:278–284. 118. Gao X, Zacharek A, Salkowski A, et al. Loss of heterozygosity of the BRCA1 and other loci on chromosome 17q in human prostate cancer. Cancer Res 1995;55:1002–1005. 119. Gudmundsson J, Johannesdottir G, Bergthorsson JT, et al. Different tumor types from BRCA2 carriers show wild-type chromosome deletions on 13q12-q13. Cancer Res 1995;55:4830–4832. 120. Hyytinen ER, Frierson HF Jr, Boyd JC, Chung LW, Dong JT. Three distinct regions of allelic loss at 13q14, 13q21-22, and 13q33 in prostate cancer. Genes Chromosomes Cancer 1999;25:108–114. 121. Thorlacius S, Olafsdottir G, Tryggvadottir L, et al. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet 1996;13:117–119. 122. Sigurdsson S, Thorlacius S, Tomasson J, et al. BRCA2 mutation in Icelandic prostate cancer patients. J Mol Med 1997;75:758–761. 123. Tulinius H, Olafsdottir GH, Sigvaldason H, et al. The effect of a single BRCA2 mutation on cancer in Iceland. J Med Genet 2002;39:457–462. 124. Gronberg H, Ahman AK, Emanuelsson M, Bergh A, Damber JE, Borg A. BRCA2 mutation in a family with hereditary prostate cancer. Genes Chromosomes Cancer 2001;30:299–301. 125. Hubert A, Peretz T, Manor O, et al. The Jewish Ashkenazi founder mutations in the BRCA1/BRCA2 genes are not found at an increased frequency in Ashkenazi patients with prostate cancer. Am J Hum Genet 1999;65:921–924. 126. Lehrer S, Fodor F, Stock RG, et al. Absence of 185delAG mutation of the BRCA1 gene and 6174delT mutation of the BRCA2 gene in Ashkenazi Jewish men with prostate cancer. Br J Cancer 1998;78:771–773. 127. Nastiuk KL, Mansukhani M, Terry MB, et al. Common mutations in BRCA1 and BRCA2 do not contribute to early prostate cancer in Jewish men. Prostate 1999;40:172–177. 128. Vazina A, Baniel J, Yaacobi Y, et al. The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel. Br J Cancer 2000;83:463–466. 129. Wilkens EP, Freije D, Xu J, et al. No evidence for a role of BRCA1 or BRCA2 mutations in Ashkenazi Jewish families with hereditary prostate cancer. Prostate 1999;39:280–284. 130. Abeliovich D, Kaduri L, Lerer I, et al. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet 1997;60:505–514. 131. Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with speciﬁc mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 1997;336:1401–1408. 132. Thompson D, Easton D. Variation in cancer risks by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 2001;68:410–419. 133. Gayther SA, de Foy KA, Harrington P, et al. The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators. Cancer Res 2000;60:4513–4518. 134. Thorlacius S, Struewing JP, Hartge P, et al. Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet 1998;352:1337–1339. 135. Witte JS, Goddard KA, Conti DV, et al. Genomewide scan for prostate cancer-aggressiveness loci. Am J Hum Genet 2000;67:92–99. 136. Paiss T, Worner S, Kurtz F, et al. Linkage of aggressive prostate cancer to chromosome 7q31–33 in German prostate cancer families. Eur J Hum Genet 2003;11:17–22. 137. Slager SL, Schaid DJ, Cunningham JM, et al. Conﬁrmation of linkage of prostate cancer aggressiveness with chromosome 19q. Am J Hum Genet 2003;72:759–762. 138. Neville PJ, Conti DV, Paris PL, et al. Prostate cancer aggressiveness locus on chromosome 7q32-q33 identiﬁed by linkage and allelic imbalance studies. Neoplasia 2002;4:424–431. 139. Neville PJ, Conti DV, Krumroy LM, et al. Prostate cancer aggressiveness locus on chromosome segment 19q12-q13.1 identiﬁed by linkage and allelic imbalance studies. Genes Chromosomes Cancer 2003;36:332–339.

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Strategies for the Chemoprevention of Prostate Cancer Ronald Lieberman, Jacob Kagan, Margaret G. House, Joseph Kelaghan, David J. Kansal, and Howard L. Parnes

INTRODUCTION Carcinogenesis Carcinogenesis is a multistep process driven by genetic and epigenetic alterations that disrupt the regulatory pathways controlling cellular proliferation, programmed cell death (apoptosis), angiogenesis, and differentiation (1–3). The age-dependent incidence of most cancers and the recognition that precursor lesions, representing intermediate stages between normal and malignant cells, may precede invasive cancer by 20 yr or more, suggests that malignant transformation generally occurs over decades (4–10) (Fig. 1). The protracted nature of this process provides an opportunity to intervene before the malignant phenotype is established. This may be done with life-style changes such as diet and exercise, or by chemoprevention, the administration of natural or synthetic agents to reverse, inhibit, slow, or prevent the development of cancer (11).

Genetic and Epigenetic Changes in Cancer Alterations in nucleotide sequence (genetic mutations) are associated with the initiation and progression of speciﬁc cancers. These alterations are considered nonrandom mutations, to distinguish them from the random mutations found throughout the genome that generally do not result in malignant transformation. Genetic alterations range from simple point mutations to deletions, insertions, ampliﬁcations, and allelic losses, to abnormalities in chromosome number (ploidy), chromosomal rearrangements, translocations, and inversions (12–15). Epigenetics is the study of mitotically heritable changes in gene expression that occur without a change in DNA sequence. Epigenetic changes tend to be global, affecting the expression of many genes within the cell genome or within a large chromosomal From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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Fig. 1. Genetic alteration associated with prostate cancer development and progression. Stages of cancer development and progression are correlated with speciﬁc chromosomal regions with allelic losses, gene ampliﬁcation, and inactivation of candidate tumor suppressor genes (TSGs). TP53, tumor protein p53, is located on chromosome 17p13.1; KLF-6, kruppel-like factor 6 (also known as core promoter element-binding protein [COPEB] and transcription factor ZF9) is located on chromosome 10p15; PTEN, phosphatase and tensin homolog (also known as mutated in multiple advanced cancers 1 [MMAC1]) is located on chromosome 10q23.3; AR, androgen receptor (also known as dihydrotestosterone receptor [DHTR]), is located on chromosome Xq11-12. Inactivation of listed TSGs and ampliﬁcation of speciﬁc chromosomal regions and genes are highly associated with characteristic features of advanced prostate cancer.

region or regions. Epigenetic gene silencing may occur both at the chromatin level (e.g., deacetylation and methylation of histones, resulting in chromatin compaction and repression of gene expression) and at the DNA level (e.g., cytosine methylation of CpG islands). CpG islands are associated with at least half of all cellular genes and are normally methylation-free. Hypermethylation of cytosine residues within these islands causes transcriptional silencing. Such silencing normally occurs at genes subject to genomic imprinting or to X-chromosome inactivation. Conversely, hypomethylation of a chromosomal region may activate gene transcription. Epigenetic changes in gene expression may affect a variety of genes associated with carcinogenesis (16). These changes include DNA methylation, which is under the control of enzymes known as DNA methyl transferases (e.g., DMMT1) and histone modiﬁcations, such as acetylation and deacetylation. Proteins, such as MBD1–4 and MeCP2, may bind to methylated CpGs and recruit histone deacetylases (HDACs), thus repressing transcription. Conversely, histone-acetylases (HATs) generally activate transcription. An additional family of proteins that facilitates gene transcription via chromatin modiﬁcation (in this case by modifying promoter chromatin regions) is the SWI/SNF family (16,17). Although genetic mutations are generally irreversible, epigenetic changes are potentially reversible. Inhibitors of DNA methylation and histone deacetylation are available

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that can alter gene transcription, in vitro and in vivo. 5-Aza-2′-deoxycytidine is a very potent, speciﬁc inhibitor of DNA methylation. Although it has been used experimentally in the treatment of leukemia, its usefulness for treatment as well as for prevention is limited by its toxicity (18,19). Histone deacetylase inhibitors (e.g., trichostatin A) can reactivate a range of epigenetically silenced genes, in vitro. Several of these agents are being tested in clinical trials (20); however, a major drawback of this approach is its lack of speciﬁcity and the potential of HDAC inhibitors to affect a large number of genes not associated with cancer. Future research will be required to develop more reﬁned strategies to reactivate or inactivate epigenetically modiﬁed expression of speciﬁc genes.

Oncogenes and Tumor Suppressor Genes Speciﬁc genetic and epigenetic alterations may affect gene expression and/or the structure and function of speciﬁc gene products associated with carcinogenesis. The two major classes of such genes are oncogenes and tumor suppressor genes, both of which are essential components of many regulatory circuits. Oncogenes, some of which are the human homologs of viral genes, promote tumorigenesis upon activation by a single event, such as a point mutation, chromosomal translocation, or ampliﬁcation. Tumor suppressor genes (TSGs) are genes whose inactivation is associated with tumor development. In contrast to oncogenes, both alleles of a TSG must be affected to promote tumorigenesis (21). Inactivation of a TSG can occur through a combination of genetic and epigenetic mechanisms. Activation of oncogenes and inactivation of TSGs may result in uncontrolled cell growth and acquisition of tumorigenic phenotypes (22).

Signal Transduction Pathways (Regulatory Circuits) Cell growth, proliferation, apoptosis, angiogenesis, and differentiation are controlled by complex signal transduction pathways (regulatory circuits) (22). These pathways are typically activated by the binding of a ligand (an extracellular protein or small molecule, such as a steroid hormone) to a speciﬁc cell surface or nuclear receptor. Activation and transmission of the signal frequently depends on serine or tyrosine kinases associated with the cytoplasmic portion of the receptor. The signal is then relayed into the nucleus by cytoplasmic proteins, resulting in a change in intracellular gene and protein expression patterns. Alterations of critical proteins in these regulatory pathways may have an oncogenic effect. For example, the genes encoding the epidermal growth factor receptor (EGFR2) and the platelet-derived growth factor receptor (PDGFR) are known oncogenes that are overexpressed or mutated in a number of human malignancies (23,24). Similarly, intracellular kinases that are intermediate effectors in relaying intracellular signals are frequently targets for oncogenic activation (25,26). Inactivation of TSGs involved in cell signaling may result in malignant transformation as well. For example, the inactivation of phosphatase and tensin homolog (PTEN), which normally promotes apoptosis by inhibiting the Akt cell survival signaling pathway, may promote carcinogenesis in the prostate, breast, ovary, endometrium, and brain (27–29).

PROSTATE CARCINOGENESIS Prostate cancer is the most common nondermatologic malignancy and remains the second leading cause of cancer death in American men (30), despite advances in early detection and local therapy (31,32). Death from prostate cancer is usually associated with the development of hormone-refractory disease (31,32).

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The most important risk factors for the development of prostate cancer are age, race, family history, and androgen exposure. In addition, environmental factors, in particular diet, have been implicated in the etiology of this disease. It has been hypothesized that these factors contribute to a favorable microenvironment for the development and progression of prostate cancer (33,34). Age is a major risk factor, with approx 75% of prostate cancers diagnosed in men over 60 yr of age (35). In the United States, AfricanAmerican men have the highest incidence of prostate cancer. In addition, they tend to be diagnosed at a younger age and have higher prostate cancer mortality rates than Caucasions (36). Age-adjusted epidemiologic studies indicate that the incidence of prostate cancer is lower among Asian Americans than among Caucasians and African Americans (107 vs 173 vs 275 per 100,000, respectively) (30). However, the incidence is approx twice as high for Asian-American men born in the United States than for those born in Asia (37). These observations suggest an important role for environmental factors in prostate carcinogenesis. Several histologic changes within the prostate epithelium have been proposed as risk factors and/or biomarkers for the development of prostate cancer. These include atypical adenomatous hyperplasia (AAH), proliferative inflammatory atrophy (PIA) and prostatic intraepithelial neoplasia (PIN). AAH is characterized by architectural atypia with proliferation and crowding of small gland and acini that are usually located at the edges of a hyperplasic nodule in the transition zone (TZ) of the prostate gland (38,39). PIA is a term used to describe a variety of lesions characterized by focal atrophy accompanied by inflammation and immunohistochemical evidence of proliferation (40). The possibility that PIA may represent a true precursor of prostate cancer is currently an area of active research (see Epigenetics and Prostate Carcinogenesis below). PIN is characterized by progressive abnormalities of cellular differentiation (from low to high grade). This lesion (high-grade variant) coexists with cancer in >85% of cases and is generally considered to represent a true precursor of invasive prostate cancer (41). Approximately 30–50% of men with high-grade PIN, and no evidence of cancer will be found to have invasive prostate cancer on subsequent biopsy (41–43). The observation that PIN occurs with similar frequencies in populations with different risks of invasive prostate cancer, e.g., Japan and the United States (44,45), suggests that this lesion may be amenable to chemoprevention intervention. In addition, autopsy data indicate that PIN generally precedes prostate cancer by at least a decade (46), providing ample opportunity to implement such strategies.

Epigenetics and Prostate Carcinogenesis Epigenetic changes may affect a variety of genes associated with prostate carcinogenesis. For example, methylation of the promoter region of glutathione S-transferase-π1 (GSTP1) is commonly observed in both prostate cancer and high-grade PIN (47,48). GSTP1 encodes an enzyme that detoxiﬁes electrophilic compounds (including carcinogens and cytotoxic drugs) by glutathione conjugation (49,50) and may protect DNA from oxidative damage (51). The expression of GSTP1 in prostate epithelium and in PIA and its inactivation in high-grade PIN and prostate cancer suggest that epigenetic silencing of GSTP1 might be an important early event in prostate carcinogenesis and that PIA may represent an early precursor of invasive prostate cancer (52). As epigenetic changes are potentially reversible, reactivation of genes such as GSTP1, silenced by promoter region methylation, may represent a viable chemopreventive strategy.

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Familial and Hereditary Prostate Cancer Although there may be a familial component for up to 20% of men with prostate cancer, only 5–10% of cases can be linked through segregation analysis to mendalian inherited susceptibility (53–56). Nevertheless, the importance of hereditary genetic factors in prostate cancer may be as significant as in hereditary cases of colon and breast cancers (57). Prostate cancer susceptibility genes may be passed in either an autosomal dominant (53,55) or an X-linked, recessive fashion (54,58). The calculated lifetime risk for the development of prostate cancer increases two- to threefold in men with a single ﬁrst-degree relative with prostate cancer. If both ﬁrst- and second-degree relatives are affected, the risk may be as much as eightfold higher than in men without such a family history (53). Patients with familial prostate cancer are also more likely to develop the disease at a younger age. Although several putative loci for susceptibility genes have been identiﬁed (59–63), as of today there is only one conﬁrmed hereditary prostate cancer gene (HPC1). This gene codes for RNase L, a ribonuclease that may inhibit prostate carcinogenesis at several steps (64–67). Furthermore, a speciﬁc variant of this gene appears to be associated with sporadic cases of prostate cancer (67).

Nonrandom Genetic Alterations in Sporadic Prostate Cancer The precise molecular genetic mechanisms underlying the onset and development of sporadic prostate cancer are unknown. However, the most frequently detected genetic alterations in prostate cancer are allelic losses in speciﬁc chromosomal regions (see Table 1). Chromosomal regions with frequent allelic losses are thought to be the sites of TSGs that are inactivated during tumor development or progression. The most common abnormality is the loss of alleles on the short arm of chromosome 8 (8p). 8p allelic losses are considered an early event because they are frequently detected in high-grade PIN and in organ-conﬁned cancers (68,69). Additional frequent allelic losses and gene ampliﬁcations in prostate cancer are summarized in Tables 1 and 2 and in Fig. 1. Genetic alterations in TSGs, such as p53, are most commonly associated with advanced prostate cancer (70–72) and with the transition from androgen-dependent to androgen-independent disease (73,74). Although numerous candidate TSGs have been proposed, currently only PTEN appears to play a substantial role in prostate carcinogenesis (see above) (75–79). Recently, Narla et al. (80) identiﬁed a promising candidate TSG, Kruppel-like factor 6 (KLF6) on chromosome 10p. KLF6 is a ubiquitously expressed transcription factor that directly interacts with DNA through a GC box promoter element (80). Although frequent allelic losses and mutations were identiﬁed, these ﬁndings will require independent conﬁrmation.

PROSTATE CANCER PREVENTION CLINICAL TRIALS Cancer prevention agent development requires the systematic conduct of welldesigned clinical trials. Chemoprevention trials pose unique challenges with regard to accrual, selection of study endpoints, and the identiﬁcation of cohorts. Successful accrual to cancer prevention studies requires a coordinated, multidisciplinary effort and the active participation of surgeons, internists, family practitioners, and pathologists.

Endpoints The long natural history of prostate cancer requires that intermediate endpoint biomarkers (IEBs) be utilized for preliminary evaluation of chemoprevention agents

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Lieberman et al. Table 1 Frequent Allelic Alterations in Prostate Cancer: Allelic Losses and Decrease in Gene Copy Numbera

Chromosome

Allelic losses (% of specimens)

1p 2q 3p 5q 6p 6q 7q 8p 9p 10p 10q 11q 13q 15q 16p 16q 17p 18q 19 22

Ref.

89

219

8 25 33–75 50–69

221 221 223,224 69,224,225

17 14–37

226 224,226,227

21–33

228,229

0 51 50 35

230 230 231 224,232

Decrease in gene copy by CGH (% of specimens)

Ref.

50 42

217 218

18–39 18 22–39

217,220 220 217,220,222

32–72 16 20 40 29 32–50 16–39 22 19–42 16 19 45 45

217,220,222 222 220 217,220 220 217,222 217,220 220 217,220,222 220 222 217 217

a Allelic losses are presented as a percent of specimens showing loss of allele. CGH, comparative genomic hybridization; chromosomal regions with decrease in gene copy number are presented as percent of specimens showing decrease in gene copy number at speciﬁc chromosomal regions. The best correlation between measured allelic losses and the decrease in gene copy by CGH appears to be on chromosomes 6q, 8p, 10p, 10q, 13q, 16q, and 18q. Chromosomal regions with frequent allelic losses are suspected to harbor candidate tumor suppressor genes.

Table 2 Frequent Allelic Alterations in Prostate Cancer: Frequent Increases in Gene Copy Number (Ampliﬁcation) Detected by CGHa Chromosome 1q 2p 3q 7q, 7 8q 11p 18q Xq a

Increase in gene copy number (% of specimens) 52 42 52 20–56 72–89 52 32 18–56

Ref. 218 218 218 217,220,222 217,222 218 217 217,220,222

Chromosomal regions with increase in gene copy number, gene ampliﬁcation, detected by comparative genomic hybridization (CGH). The most frequent ampliﬁcations are reported on chromosomes 7, 8q and Xq. Gene ampliﬁcation is highly associated with advanced prostate cancer.

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(81). The categories of IEBs commonly used in chemoprevention trials include histopathologic markers, tissue-based markers, and serum markers (52). The leading histopathologic IEB used in the assessment of potential prostate cancer prevention agents is high-grade PIN. Given the substantial evidence that this lesion is a precursor of prostate cancer (45), low-toxicity agents that reduce the extent of high-grade PIN would warrant further evaluation in this regard. Another histopathologic marker of interest is PIA. The hypothesis that this lesion may represent an even earlier precursor than high-grade PIN is the subject of ongoing research (40,82). The major serum marker for prostate cancer is PSA. However, its usefulness as an IEB for prostate cancer is limited by its relatively low specificity for cancer and the fact that some agents are known to affect the production of PSA in both benign and malignant tissue (83). In addition, there is no evidence that reductions in PSA are either necessary or sufficient for an agent to have chemopreventive efficacy. Other serum markers include markers of angiogenesis (vascular endothelial growth factor) (84) and growth factors and their binding proteins (insulin-like growth factor 1 [IGF1] and IGF binding protein-3) (85,86). Another potentially useful category of IEBs for chemoprevention agent development is that of tissue-based markers. Examples include markers of cellular proliferation, e.g., Ki-67 and proliferating cell nuclear antigen (PCNA) (87), markers of apoptosis, e.g., TUNEL/apoptotic bodies (terminal deoxynucleotidyl transferase-mediated dUTP in situ nick end-labeling) (88) and Bcl-2 (89,90), markers of angiogenesis, e.g., microvascular density (91), and markers of oxidative damage, e.g., oxidized DNA base adducts (92). In addition, drug-speciﬁc markers can be useful to determine whether an agent is having the desired effect at the tissue level, e.g., prostaglandin levels for cyclo-oxygenase inhibitors, such as celocoxib (93) and polyamine levels for ornithine decarboxylase inhibitors, such as diﬂuoromethylornithine (DFMO) (94). This use of intermediate endpoints requires that studies be well controlled, and preferably placebo-controlled, since comparisons of intermediate endpoints before and after an uncontrolled intervention are difﬁcult to interpret. For example, in a placebo-controlled study of 4-Hydroxyphenylretinamide (4-HPR) in preprostatectomy patients, biomarker levels ﬂuctuated before and after-intervention among patients receiving placebo as well as among those randomized to 4-HPR. This suggests that factor(s) unrelated to 4-HPR, such as the prostate biopsy itself, were responsible for the observed changes in the biomarker endpoints (95). A summary of the endpoints currently in use in National Cancer Institute (NCI)-sponsored chemoprevention trials is shown in Table 3.

Cohorts Another important factor is the identiﬁcation of appropriate cohorts for prostate cancer prevention studies. Cohorts of interest for prostate cancer chemoprevention clinical trials range from the general population, i.e., all men over a certain age with a “normal” PSA, to men with stage D0 prostate cancer, i.e., PSA relapse following deﬁnitive therapy for localized prostate cancer. The general population cohort is appropriate for large-scale prevention studies of low-toxicity agents such as ﬁnasteride, selenium, and vitamin E. At the other end of the spectrum, treatment trials in men with biochemical evidence of relapse following local therapy may provide useful information with regard to an agent’s potential chemopreventive efﬁcacy. The most promising example in this regard is sulindac sulfone, which was shown to increase PSA doubling time in men with biochemical relapse following deﬁnitive therapy for localized prostate cancer

Table 3 National Cancer Institute-Sponsored Prostate Cancer Chemoprevention Trials Cohort

Agent/dose Selenium yeast 200 or 400 µg qd

Elevated PSA, negative biopsy

Soy protein 25 g qd plus isoﬂavones 52 mg qd

High-grade PIN

Flutamide 250 mg qd

78

Elevated PSA, negative biopsy

Study design

Endpoints

Randomized, placebo-controlled, Primary endpoint phase II Prostate cancer incidence, PSA velocity Other endpoints Serologic biomarkers Prostate cancer progression: alkaline phosphatase, CgA Randomized, placebo-controlled, Primary endpoint Tissue-based biomarkers phase II Proliferation: Ki67 Other endpoints Histologic biomarkers High-grade PIN Tissue-based biomarkers Apoptosis: apoptotic cells Hormone receptors: ER-α, ER-β, PR, AR Phase 2 detoxiﬁcation enzyme: GSTP Serologic biomarkers PSA Quality of life Urinary and sexual function Randomized, placebo-controlled, Primary endpoint phase II Prostate cancer incidence Other Endpoints Histologic biomarkers DNA ploidy, nuclear morphometry Tissue-based biomarkers Proliferation: PCNA, Ki67 Apoptosis: apoptotic bodies Angiogenesis: MVD Oncogene: c-erbB-2 (Her-2/neu) Genetic: FISH for chromosome 8 Serologic biomarkers AR, PSA, hK2

High-grade PIN

Selenomethionine 200 µg qd

Positive family history DFMO 500 mg qd (brothers/ﬁrst-degree cousins < 70 yr of age)

79 Preprostatectomy

1α-hydroxyvitamin D2 10 µg qd

Randomized, placebo-controlled, Primary endpoint phase III Prostate cancer incidence Other endpoints Histologic biomarkers Degradation of the basal cell layer of prostatic ducts and glands; chromatin patterns Tissue-based biomarkers Proliferation: Ki67 Apoptosis: TUNEL Randomized, placebo-controlled, Primary endpoint phase II Drug-speciﬁc biomarkers Drug effect marker: prostatic polyamine levels— putrescine, spermidine, spermine Other endpoints Histologic biomarkers MMPs: matrilysin (MMP-7), gelatinase-A (MMP-2), membrane metallaproteinase 1, cathepsin-D, integrins α6 and β4, basement membrane components (laminin subchains α, β3, and γ4, collagen VII) Serologic biomarkers Free/total PSA Randomized with observation Primary endpoints arm, phase II Histologic biomarkers Nuclear morphology evaluation in normal, PIN, and cancerous tissue before and after treatment Tissue-based biomarkers Proliferation: MIB-1 Angiogenesis: MVD, factor VIII, VEGF Apoptosis: TUNEL, apoptotic bodies Hormone receptors: AR, vitamin D receptor Other endpoints Serologic biomarkers Drug effect markers: PSA, PSMA, PTH, growth factors: IGF-1, IGFBP-3, TGF-β, β-FGF, VEGF Drug speciﬁc marker: vitamin D metabolites Hormones: testosterone (table continues)

Table 3 (Continued) Cohort

Agent/dose

Study design

Bicalutamide 50 mg qd Randomized, placebo-controlled, DFMO 500 mg qd phase II (2 × 2 Factorial) (alone or in combination)

Preprostatectomy

Celecoxib 400 mg bid

80

Preprostatectomy

Randomized, placebo-controlled, phase II

Endpoints Primary endpoints Drug-speciﬁc biomarkers Drug effect markers: prostatic polyamine levels— putrescine, spermidine, spermine Other endpoints Histologic biomarkers Cytomorphometric indices Tissue-based biomarkers Proliferation: PCNA, Ki67, TGF-α Apoptosis: ICH-PARP, TUNEL Serologic biomarkers PSA Primary endpoints Drug effect biomarkers Prostatic prostaglandins: PGD2, PGE2, PGF2α, TXB2, 6KF1α; quantitative RT-PCR of COX (1 and 2) expression Other endpoints Tissue-based biomarkers Proliferation: PCNA, Ki67 Angiogenesis: MVD, factor VIII, VEGF, KDR Apoptosis: TUNEL, PARP-3 Cell cycle: p27Kip1, p21Waf1 Oxidative DNA damage: 8-OhdG Serologic biomarkers PSA levels on treated/untreated tissue specimens Pharmacokinetic/pharmacodynamic measures

Preprostatectomy

Genistein 2 mg/kg/d

Randomized with observation arm, phase II

Preprostatectomy

Genistein 150, 300, or 600 mg qd

Randomized, placebo-controlled, phase II

81

Primary endpoint Serologic biomarkers Circulating prostate cancer cells: RT-PCR analysis for PSA Histologic biomarkers Nuclear morphometry Other endpoints Tissue-based biomarkers Proliferation: PCNA Apoptosis: apoptotic index Cell cycle: p27Kip1 Gene expression: FAK, endoglin, gene array-based gene proﬁling Serologic biomarkers PSA, testosterone Primary endpoint Tissue-based biomarkers Oxidative DNA damage: 5-OHmdU, 8-isoprostane Serologic biomarkers Oxidative DNA damage: 5-OHmdU, 8-isoprostane Other endpoints Histologic biomarkers PIN, prostate cancer grade/volume/extent Tissue-based biomarkers Proliferation: MIB-1 Angiogenesis: MVD, VEGF Apoptosis: Bcl-2, Bax Cell cycle: cyclin D, CDK (5 and 6) Cell-cell communication: Cx43 Tumor suppressor gene: p53 Drug effect biomarkers IGF-1, IGFBP-3, PSA, testosterone Drug-speciﬁc biomarkers Plasma/prostate isoﬂavone levels (table continues)

Table 3 (Continued) Cohort

Agent/dose

Preprostatectomy

Lycopene 15, 30, or 45 mg qd; or soy isoﬂavone 40, 60, or 80 mg qd

Preprostatectomy

L-Selenomethionine

Preprostatectomy

L-Selenomethionine

200 µg

82 200 µg qd and/or α-tocopherol 400 IU qd

Study design

Endpoints

Randomized, controlled pilot study; Primary endpoints Tissue-based biomarkers six experimental groups, one control group, phase II Proliferation: PCNA, Ki67 Apoptosis: TUNEL Other endpoints Serologic biomarkers PSA Hormones: testosterone, SHBG, estradiol Drug-speciﬁc biomarkers Plasma/tissue levels of lycopene, isoﬂavones Randomized with observation Primary endpoints arm, phase II Drug-speciﬁc biomarkers Measurement of prostate tissue selenium levels in the two groups Other endpoints Tissue-based biomarkers Apoptosis: TUNEL Oxidative damage: 8-OHdG, prostate tissue levels of selenoprotein glutathione peroxidase, selenoprotein thioredoxin reductase in normal and cancer tissue Randomized, placebo-controlled, Primary endpoints Drug-speciﬁc biomarkers phase II (2 × 2 Factorial) Measure prostate tissue for differential distribution of biologic activity of selenomethionine/α-tocopherol Other endpoints Tissue-based biomarkers Proliferation: Ki67 Apoptosis: TUNEL Tumor suppressor gene: p53 Oxidative markers: lipid peroxidation, glutathione peroxidase, NF-κB, prostaglandins, COX-2

Preprostatectomy

Sulindac sulfone 200 mg bid

Preprostatectomy

GTX-006 (antiestrogen) 40 mg qd

83

Drug-speciﬁc biomarkers Measurable differential zonal prostatic tissue accumulation of selenomethionine Prospective, nonrandomized, Primary endpoints controlled trial (historic Tissue-based biomarkers and concurrent controls) phase II Apoptosis: bcl-2, Bax, Par-4, M30, TUNEL in pre-/post-treatment prostate tissue Other endpoints Histologic biomarkers PSA, high-grade PIN, DNA ploidy Tissue-based biomarkers Proliferation: MIB-1 Tumor suppressor gene: PTEN in pre-/post-treatment prostate tissue Serologic biomarkers PSA Primary endpoints Randomized with observation arm, phase II Histologic biomarkers Percent of radical prostatectomy tissue volume (excluding luminal area) with high-grade PIN Other endpoints Histologic biomarkers DNA ploidy, nuclear morphology, NMP, PIN, cancer Tissue-based biomarkers Proliferation: Ki-67 Apoptosis: apoptotic bodies, bcl-2 Angiogenesis: MVD Hormones: Intraprostatic testosterone, dihydrotestosterone, estradiol Serologic biomarkers Hormones: PSA, testosterone, dihydrotestosterone, estradiol, DHEA, SHBG, androstenedione, androstanediol-glucuronide Drug-speciﬁc marker: NdemethylGTX-006 CAG repeats: AR germline CAG repeat length polymorphism (table continues)

Table 3 (Continued) Cohort

Agent/dose

Study design

84

PCPT Men aged ≥ 55 yr, no prior history of prostate cancer, normal DRE Total PSA ≤ 3 ng/ml

Finasteride 5 mg qd

Randomized, placebo-controlled, phase III

SELECT Men aged ≥ 55 yr (African-American men ≥ 50 yr), no prior history prostate cancer, normal DRE, total PSA ≤ 4 ng/mL

L-Selenomethionine

Randomized, placebo-controlled, phase III (2 × 2 Factorial)

200 µg qd and/or α-tocopherol 400 mg qd

Endpoints Primary endpoints Biopsy-proven prevalence of prostate cancer over 7 yr Other endpoints Assess effect of ﬁnasteride on stage and grade of prostate cancer at diagnosis; assess toxicity of ﬁnasteride; estimate difference in total and prostate cancer-speciﬁc mortality between the two groups; estimate sensitivity, speciﬁcity, predictive values of DRE and PSA; estimate effects of ﬁnasteride on self-reported urinary/sexual function symptoms and other quality of life dimensions Primary endpoints Assess effects of selenium and vitamin E alone and in combination on clinical incidence of prostate cancer Other endpoints Assess effects of selenium and vitamin E alone and in combination on clinical incidence of lung cancer, colorectal cancer, and all cancers combined; assess effects of selenium and vitamin E alone and in combination on prostate cancer-free survival, lung cancer-free survival, colorectal cancer-free survival,

cancer-free survival, overall survival, and serious cardiovascular events; assess the effect of selenium and vitamin E on health-related quality of life; evaluate the association of molecular markers with the risk of prostate, lung, and colon cancer; explore the relationship between the effects of selenium and vitamin E on prostate cancer risk and genetic factors; evaluate cellular and molecular markers from banked tissue on the biology of prostate carcinogenesis and correlate with efﬁcacy of selenium and vitamin E.

85

Abbreviations: PSA, prostate-speciﬁc antigen; CgA, chromogranin A; Ki67/MIB-1, monoclonal antibody to Ki67/MIB-1 recognizes a human nuclear antigen expressed in the S, G2, and M phases of the cell cycle; PIN, prostatic intraepithelial neoplasia; ER-α, estrogen receptor-α; ER-β, estrogen receptor-β; PR, progesterone receptor; AR, androgen receptor; GSTP, glutathione S-transferase-π; PCNA, proliferating cell nuclear antigen; MVD, microvessel density; c-erbB-2 (Her-2/neu), an oncogene located at chromosome 17q21 encoding for a transmembrane growth factor receptor; FISH, ﬂuorescence in situ hybridization; hK2, human kallikrein 2; TUNEL, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling; MMP, matrix metalloproteinase; VEGF, vascular endothelial growth factor; PSMA, prostate-speciﬁc membrane antigen; PTH, parathyroid hormone; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; TGF, transforming growth factor; FGF, ﬁbroblast growth factor; ICH-PARP; ICH-polyA-ribose polymerase; PGD2, prostaglandin D2; PGE2, prostaglandin E2; PGF2, prostaglandin F2; TXB2, thromboxane B2; 6KF1α, 6-keto-PGF1 α; RT-PCR, reverse transcriptase-polymerase chain reaction; COX, cyclooxygenase; KDR, knock-down resistance, also known as VEGFR-2 (vascular endothelial growth factor receptor-2); p27Kip1, cyclin-dependent kinase inhibitor; p21Waf1-cyclin-dependent kinase inhibitor; 8-ohdG, 8hydroxy-2-deoxy-guanosine; FAK, focal adhesion kinase; 5-OHmdU, 5-hydroxymethyl-2′-deoxyuridine; Bcl-2, an antiapoptotic proto-oncogene; Bax, a proapoptotic gene; CDK, cyclin-dependent kinase; Cx43, connexin 43 (a protein involved in cell-cell communication); SHBG, sex hormone binding globulin; NF-κB, Nuclear factorκB (an antiapoptotic transcription factor); Par-4, protease-activated receptor 4; M30, a marker of apoptosis; PTEN, phosphatase and tensin homolog deleted on chromosome 10; NMP, nuclear matrix protein; DHEA, dehydroepiandrosterone; DRE, digital rectal examination

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(96). Further evaluation of this agent is currently ongoing (see COX-Independent Proapoptotic Agents below). Given the importance of tissue-based intermediate endpoint biomarkers in the evaluation of putative cancer prevention agents, the ideal candidate for a prostate cancer chemoprevention trial would be a man in whom prostate tissue will be obtained during the course of standard management. Examples include men with (1) high-grade PIN, (2) a positive family history, (3) an elevated PSA and a negative biopsy, (4) prostate cancer being followed expectantly, i.e., watchful waiting, and (5) prostate cancer scheduled for radical prostatectomy. The NCI is currently supporting prostate cancer chemoprevention studies in each of these cohorts, as shown in Table 3. HIGH-GRADE PIN COHORT Men with high-grade PIN are at increased risk of being diagnosed with prostate cancer (97). In a recent study, repeat biopsies identiﬁed cancer in 32.2% of 245 men with a prior diagnosis of high-grade PIN (98). The number of cores with high-grade PIN proved to be the only independent predictor of a cancer diagnosis: 30.2% with 1 or 2 cores, 40% with 3 cores, and 75% with >3 cores. Although the precise schedule of subsequent prostate biopsies varies, follow-up biopsies are routinely performed in this group of patients, making them ideal candidates for prostate cancer chemoprevention studies. A major obstacle to accruing men with high-grade PIN to these trials is that most high-grade PIN occurs in the setting of prostate cancer. The reported frequency of high-grade PIN in biopsies without cancer varies considerably, although most large biopsy series report a prevalence of about 5–10% (7,41). Nevertheless, given the large number of prostate biopsies performed each year in the United States, men with highgrade PIN represent a cohort of great potential for the study of chemopreventive agents. The NCI is currently sponsoring a phase III, placebo-controlled trial of selenium in the form of selenomethionine in men with high-grade PIN. POSITIVE FAMILY HISTORY COHORT Epidemiologic studies indicate that dominantly inherited susceptibility genes with high penetrance may cause as much as 5–10% of all prostate cancer cases, and as much as 30–40% of early-onset disease (99). Having a brother with prostate cancer may confer a greater risk than a father (100), possibly because the gene for the androgen receptor is located on the X chromosome (101). The NCI is currently sponsoring a trial of DFMO in men with a positive family history (brothers and ﬁrst cousins). ELEVATED PSA, NEGATIVE BIOPSY COHORT Another important cohort for the study of chemoprevention agents is that of men with an elevated PSA and a negative biopsy. Although such men may or may not be at increased risk of prostate cancer, depending on how many biopsies (and how many cores) have been previously examined, most of these men will have repeat prostate biopsies and thus represent good candidates for prostate chemoprevention studies, especially those addressing biomarker endpoints. The NCI is currently sponsoring trials of high-selenium yeast and soy in this cohort. WATCHFUL WAITING COHORT Men with prostate cancer who are being followed expectantly, i.e., watchful waiting, represent another informative cohort for chemoprevention agent development, since such patients routinely undergo follow-up biopsies to monitor for disease progression. In addi-

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Table 4 Leads for Agent Development Lead

Agents

Epidemiology

Treatment studies Secondary analyses of Phase 3 cancer prevention studies Biology and carcinogenesis

Experimental animal models

Soy (136), lycopene (131,132), selenium (203), vitamins D (152), and E (213), nonsteroidal anti-inﬂammatory agents (170) Flutamide (108), bicalutamide, sulindac sulfone (96), lycopene (134), vitamin D and analogs (154,233) Selenium (214), vitamin E (216) Antiandrogens (106), antiestrogens (43), antioxidants (125), anti-inﬂammatory agents (166), antiproliferative agents (164,165), proapoptotic agents (234), differentiating agents (233), signal transduction inhibitors (141) MNU + testosterone WU rat model Flutamide (113), soy isoﬂavones (113) Human xenograft model (mice) Flutamide, soy isoﬂavones, SERMs (119), DFMO (162), sulindac sulfone (96), vitamins D (233) and E (235) TRAMP model (mice) Flutamide (115), soy isoﬂavones (113), toremifene (122), DFMO (236)

Abbreviations: DFMO, diﬂuoromethylornithine; SERM, selective estrogen receptor modulator.

tion, this cohort provides an important group in whom to evaluate the ability of genomic and proteomic proﬁling technologies to predict the natural history of this heterogeneous disease. The NCI is currently sponsoring a trial of high-selenium yeast in this cohort. PREPROSTATECTOMY COHORT Men with localized prostate cancer scheduled to undergo prostatectomy represent the most important cohort for phase II prostate cancer chemoprevention drug development. (Table 3) In this model, men generally receive the investigational agent or a matching placebo for 3–6 wk, the period of time between the diagnostic biopsy and deﬁnitive surgery. The major advantage that this cohort provides is that the entire prostate gland will become available at the time of surgery, permitting the most comprehensive analyses of intermediate endpoints and the most complete assessment of drug distribution in the target tissue. The primary limitation of this model is the relatively short duration of exposure to the investigational agent.

LEADS FOR PROSTATE CANCER CHEMOPREVENTION AGENT DEVELOPMENT The identiﬁcation of promising agents (and their molecular targets) for prostate cancer prevention is guided by data derived from a variety of sources (102). These evidence-based leads come from (1) epidemiologic observations, (2) prostate cancer treatment trials, (3) secondary analyses from large, randomized, controlled cancer prevention trials, (4) an understanding of cancer biology and prostate carcinogenesis, and (5) experimental animal models (Table 4).

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Lieberman et al. Table 5 Biology and Carcinogenesis: Agent, Target, and Process

Agent Antiandrogens Flutamide, bicalutamide Finasteride, dutasteride Antiestrogens Genistein Toremifene Antioxidants Vitamin E, selenium Lycopene Anti-inﬂammatory (selective COX-2 Inhibitor) Celecoxib Soy-derived Genistein Soy isoﬂavones Antiproliferative DFMO Differentiation inducer (Vitamin D analog) 1-α-OH D2 Apoptosis inducer Sulindac sulfone

Major targets

Process

AR 5-α-reductases

Androgen signaling T to DHT

ER-β ER-α/β

Estrogen signaling Estrogen signaling

ROS ROS

Oxidative DNA damage Oxidative DNA damage

COX-2

Inﬂammation (PIA)

PTK PTK

Signal transduction Signal transduction

ODC

Polyamine synthesis

VDR/RXR

Differentiation

PDE-2/5

Apoptosis

Abbreviations: AR, androgen receptor, COX, cyclo-oxygenase; DHT, dihydrotestosterone; DFMO, diﬂuoromethylornithine; ER, estrogen receptor, ODC, ornithine decarboxylase; PDE, phosphodiesterase, PIA, proliferative inﬂammatory atrophy; PTK, protein tyrosine kinase, ROS, reactive oxygen species; RXR, retinoic acid X receptor, T, testosterone, VDR, vitamin D receptor.

For most agents in development, multiple lines of evidence have contributed to the rationale for advancing to clinical evaluation in prostate cancer prevention cohorts. In addition, novel molecular targets are being elucidated through technology-driven approaches, such as the NCI Cancer Genome Anatomy Project (CGAP), which seeks to catalog the array of expressed genes and sequences in normal epithelium, intraepithelial neoplasia, and invasive cancer including adenocarcinoma of the prostate (103,104).

AGENTS IN DEVELOPMENT FOR PROSTATE CANCER PREVENTION The NCI is currently evaluating the clinical and biologic effects of more than a dozen promising agents in phase I, II, and III clinical trials (102,105). Although presented below in the context of their major mode of action (e.g., mechanistic class), experimental models suggest that many of these agents affect a variety of molecular targets and may also modulate or interact with multiple processes involved in prostate biology and carcinogenesis (Table 5).

The Androgen Hypothesis The classic studies of Huggins et al. (106) in the 1940s demonstrated the importance of androgens to the growth of metastatic prostate cancer. Subsequent biologic, experi-

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mental, and clinical studies have conﬁrmed the importance of androgens in normal prostate development and in prostate carcinogenesis. Most recently, the central role of the androgen receptor (AR) and associated coregulatory proteins (coactivators and corepressors), in both androgen-independent and androgen-dependent prostate cancer, has been elucidated (107). The basic premise underlying the effect of antiandrogens is that prostatic epithelium, i.e., normal epithelium, intraepithelial neoplasia, and invasive cancer, responds in varying degrees to disruption of androgen signaling (108,109). DEPLETION OF TESTICULAR ANDROGENS The depletion of testicular androgens by medical (e.g., luteinizing hormone-releasing hormone [LHRH] agonists) or surgical castration remains the cornerstone of therapy for patients with metastatic prostate cancer. The possibility that LHRH agonists (e.g., leuprolide) could represent an effective chemopreventive strategy is suggested by the observation that high-grade PIN, as well as invasive prostate cancer, responds dramatically to approaches that include an LHRH agonist and an AR antagonist (110–112). However, the toxicities associated with LHRH agonists (osteoporosis, impotence, gynecomastia, hot ﬂashes, asthenia, and anemia) make this approach generally unfeasible for prostate cancer prevention. ANDROGEN RECEPTOR ANTAGONISTS Androgen receptor antagonists (ARAs), such as the nonsteroidal antiandrogens ﬂutamide, bicalutamide, and nilutamide, appear to represent a more feasible chemoprevention strategy of androgen deprivation than LHRH agonists. However, toxicities such as reduced potency and painful gynecomastia may limit their applicability for chemoprevention. Along with soy-derived agents (see Soy Isoﬂavones below), ARAs have shown consistent treatment and chemopreventive activity in prostate cancer animal models, such as the MNU and testosterone carcinogen model in WU Wistar rats, the human xenograft model in immunodeﬁcient mice and the transgenic adenocarcinoma of mouse prostate (TRAMP) model (113–115). In addition to their established role in the treatment of metastatic disease (stage D2) and in combination with LHRH agonists as an adjunct to radiation therapy for localized prostate cancer (stages B2 and C), recent studies suggest that ARAs may slow the progression of prostate cancer, when given in the adjuvant setting or to patients managed by watchful waiting. However, the data for objective clinical response (e.g., radiologic evidence) was considered too premature to recommend approval for these indications (ODAC, December 18, 2002, Bethesda, MD). A randomized, placebo-controlled phase II trial of low-dose ﬂutamide (250 mg/d) was recently conducted in 60 men with high-grade PIN and no evidence of cancer. Analysis after 1 yr of ﬂutamide administration showed no decrease in the incidence of biopsyproven prostate cancer (116). Another ARA, bicalutamide, is currently being evaluated in combination with DFMO in men with localized prostate cancer in the preprostatectomy period. (see Rational Combinations below). The objectives of this trial are to assess the effect of the combination on prostate cancer, high-grade PIN, and intermediate endpoint biomarkers such as proliferation, apoptosis, angiogenesis, and polyamine levels. 5-α-REDUCTASE INHIBITORS Since a favorable beneﬁt-to-risk proﬁle is a major consideration for chronic administration of an ideal chemopreventive intervention, agents such as LHRH agonists and

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(ARAs), with their notable systemic toxicities, may not be suitable for the general population of men at risk for prostate cancer. Therefore, less toxic antiandrogen strategies have been sought. One of the most promising approaches is the use of the novel class of steroidal agents known as 5-α reductase inhibitors (5-ARIs), such as ﬁnasteride and dutasteride, which exhibit an acceptable safety proﬁle (low incidence of diminished libido and impotence). These promising agents, which signiﬁcantly reduce circulating levels of dihydrotestosterone (DHT), have become a “lead” class for deﬁnitive phase III prostate cancer chemoprevention trials in low- to average-risk men (see the Prostate Cancer Prevention Trial below).

Antiestrogens and the Estrogen Hypothesis There is also evidence to support a role for estrogens in prostate carcinogenesis. Estrogens are important for prostate growth, and estrogen receptors (ERs) are found in the prostatic stroma (ER-α) and epithelium (ER-β) (117–119). Although expressed during prostate carcinogenesis, the precise role of these ER subtypes in normal, precancerous, and malignant prostate cell biology is under active investigation. An increase in the ratio of estrogens (e.g., estradiol) to androgens (e.g., DHT) appears to be a critical factor in the development of PIN and cancer in the dog, and estradiol promotes PIN and prostate cancer development in the Noble rat (120,121). In man, the incidence of prostate cancer peaks around the age when the concentration of estradiol in the serum and prostate is increasing relative to that of DHT. SELECTIVE ESTROGEN RECEPTOR MODULATORS Selective estrogen receptor modulators (SERMs), such as toremifene, arzoxifene, and raloxifene, are nonsteroidal compounds that have either estrogen agonist or antagonist activity depending on the target organ. Besides opposing the effects of estrogens, these agents may affect multiple peptide growth factors, including transforming growth factorα and -β, IGF-1, and epidermal growth factor, as well as coregulatory factors associated with SERM-ER binding complexes (119). Given their broad range of putative targets and favorable toxicity proﬁles, SERMs are candidate chemopreventive agents. Arzoxifene and raloxifene have been shown to increase time to tumor progressions in human xenograft models using LNCAP cells in immunodeﬁcient mice, a model that may be relevant to the phenotype of early hormone-dependent prostate cancer in man (119). Another SERM, toremifene (GTX-006), a chlorinated derivative of tamoxifen, increased the tumor latency period by up to 12 wk and reduced the incidence of high-grade PIN and palpable prostate cancer in the TRAMP mouse model (122). GTX-006 is currently being evaluated in an NCI-sponsored phase II preprostatectomy trial (Table 3) and in a pharmaceutical industry-sponsored phase II/III trial in men with high-grade PIN. Recent data from an industry-sponsored, uncontrolled pilot study of GTX-006 (60 mg/d) in men with high-grade PIN suggested a reduction in the expected rate of persistent high-grade PIN after 4 mo of therapy, i.e., 72% of the 18 men who completed the trial compared with 17.9% of historical controls had no high-grade PIN on subsequent prostate biopsies (123).

Antioxidants Evidence from epidemiologic studies, experimental systems, and large clinical prevention trials suggests that oxidative stress and DNA damage play an important role in prostate carcinogenesis. Reactive oxygen species (ROS) may cause oxidative damage to lipids, proteins, and DNA, as reﬂected by markers of oxidative stress, such as F2-

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isoprostanes, protein carbonyls, and oxidized DNA bases, respectively, and by the expression of stress-responsive genes, such as c-fos, c-jun, NFκB, and GSTP1 (124–126). There is also evidence that androgens may promote carcinogenesis by altering the pro-oxidant-oxidant balance of prostate cells and that antioxidants can block this androgen-mediated oxidative stress process (127). Several antioxidants are currently being evaluated in phase II and phase III prostate cancer prevention trials (Table 3). At supraphysiologic doses, agents such as selenium, vitamin E, and lycopene have been shown to exhibit novel or enhanced activities, such as cell cycle arrest, inhibition of cell growth, modulation of inﬂammatory cytokines, reduction in DNA strand breaks, and activation of apoptosis, in experimental model systems (128,129). Efforts are currently under way to translate these ﬁndings into clinical beneﬁt. For example, selenium (selenomethionine, 200 µg/d), and vitamin E (d/lα-tocopherol acetate, 400 IU/d), at doses well above their recommended daily allowances, are being evaluated in a large, population-based phase III chemoprevention trial (see The Selenium and Vitamin E Cancer Prevention Trial below). LYCOPENE Lycopene, the carotenoid that gives tomatoes, watermelon, and red grapefruit their red color, is a potent antioxidant (at least twice the singlet oxygen-quenching capacity of β-carotene) and the most abundant carotenoid in the prostate gland (130). Epidemiologic studies suggest that lycopene may protect against prostate cancer, although the results of these trials are mixed: ﬁve showed a signiﬁcant decrease in prostate cancer among high-lycopene consumers, three showed a nonsigniﬁcant decrease, and seven did not support an association. The largest of these trials, a prospective study in male health professionals, found that consumption of two to four servings of tomato sauce per week was associated with a signiﬁcant 35% risk reduction of total prostate cancer incidence and a 50% reduction in cases of stage C/D extraprostatic cancer (131,132). In addition to its antioxidant activity, lycopene may inhibit prostate carcinogenesis by other mechanisms, such as interfering with growth factor receptor signaling and promoting cell cycle arrest (133). Kucuk et al. (134) recently reported the results of a small, randomized controlled trial of lycopene supplementation (30 mg/d) for 3 wk in 26 patients with early prostate cancer scheduled for radical prostatectomy (RP). They observed a reduction in positive surgical margins and a decrease in the extent of high-grade PIN among men randomized to receive lycopene during the prostatectomy period (134). However, apparent imbalances in the randomization involving key prognostic factors, i.e., grade and stage of disease, may have confounded the results, and conﬁrmatory trials will be needed to verify these ﬁndings. Furthermore, in a nonrandomized clinical study of 32 men with localized prostate cancer scheduled for RP, daily administration for 3 wk of a tomato sauce-based food preparation (30 mg/d of lycopene) was associated with a reduction in serum PSA levels, oxidized DNA bases in the serum and prostate gland, and increased serum and prostate lycopene concentrations (135). Currently, several different formulations of lycopene-enriched products (pharmaceutical grade and commercial preparations) are being evaluated in NCI-sponsored phase I and II trials in prostate cohorts, such as men with high-grade PIN, men with an elevated PSA and a negative biopsy, and patients with prostate cancer scheduled for RP (see table). SELENIUM See Selenium and Vitamin E Cancer Prevention Trial below.

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VITAMIN E See Selenium and Vitamin E Cancer Prevention Trial below. SOY-DERIVED AGENTS Epidemiologic evidence suggests that environmental factors, in particular differences in the consumption of dietary soy, may contribute to the lower prostate cancer and breast cancer incidence and mortality rates observed in Southeast Asia compared with Western countries (136). A typical Japanese diet contains about 1 mg/kg/d of genistein (the predominant soy isoﬂavone), resulting in serum levels 10–100-fold greater than those typically observed in US males (136). Of note, the chemopreventive activity for a variety of soy-derived agents has been demonstrated in several rodent models of prostate cancer (113). Currently, several soy-derived products, e.g., pharmaceutical grade genisteinenriched formulations, commercial nutriceutical soy isoﬂavone formulations, pharmaceutical grade Bowman-Birk inhibitor (BBI), and commercial soy protein isolate admixed with soy isoﬂavones are being evaluated in NCI-sponsored phase I and II clinical trials. For example, the NCI is currently supporting three phase II trials using this soy protein formulation in prostate cohorts including subjects with elevated PSA/negative biopsy and patients at risk for recurrence and progression following surgery (137). Soy Isoﬂavones. Soy isoﬂavones (e.g., genistein, daidzein) are weak plant estrogens (phytoestrogens) found in soybeans that concentrate in prostate tissue (138). Soy isoﬂavones may inhibit carcinogenesis through a variety of mechanisms and processes. One hypothesis is that these weak estrogens occupy estrogen receptors in the prostatic epithelium (e.g., ER-β), thereby protecting prostate cells from the cancer-promoting effects of more potent endogenous estrogens, e.g., estradiol (139). Another hypothesis is that soy isoflavones, such as genistein, inhibit signal transduction pathways mediated by protein tyrosine kinases (PTKs) (140). These pathways, which are aberrantly expressed during inflammation and carcinogenesis, promote cell proliferation, cell survival, angiogenesis, adhesion, and metastases (141). For example, by inducing the formation of a complex between focal adhesion kinase (a PTK) and β1-integrin, genistein may reduce the metastatic potential of prostate cancer cells (140,142). A recent clinical study suggests that daily exposure to 160 mg/d of dietary isoflavones derived from red clover may induce apoptosis in lowto moderate-grade prostate cancers (143). Furthermore, soy isoﬂavones may also protect cells from oxidative stress, as evidenced by upregulation of glutathione peroxidase gene expression (144). Proprietary formulations enriched for genistein and developed by Protein Technologies Inc. (also known as Solae), have undergone single- and multiple-dose pharmacokinetic and pharmacodynamic evaluation by the NCI in normal subjects (1–16 mg/kg/d), in patients with solid tumors (2–8 mg/kg/d), and in patients with prostate cancer. Pharmacodynamic effects of genistein, such as increases in tyrosine phosphorylation, have been observed in peripheral blood lymphocytes of patients in these phase I studies (145). Furthermore, doses as high as 300 and 600 mg/d of genistein were evaluated for 28 and 84 d, respectively, in patients with advanced prostate cancer (stage C and D) per recommendations of the Food and Drug Administration (FDA) and were well tolerated, without evidence of genotoxicity or chromosomal/DNA damage (146). Potential concerns regarding genotoxicity and an interaction between soy isoﬂavones and normal thyroid physiology have been raised by the FDA and are now included in the informed consent of patients in NCI-sponsored studies that use soy isoﬂavones.

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Bowman-Birk Inhibitor. Another soy-derived product with chemopreventive potential under development by the NCI is BBI, a natural protease inhibitor with anticarcinogenic, anti-inﬂammatory, and antiangiogenic properties (147). BBI has shown cancer-preventive activity in a variety of epithelial tumors and model systems. In a study of men with benign prostatic hyperplasia, a statistically signiﬁcant decrease in serum PSA and triglyceride levels was observed without evidence of dose-limiting toxicity (148).

Differentiating and Antiproliferative Agents DIFFERENTIATING AGENTS (VITAMIN D ANALOGS) Among the agents currently in the clinic with both antiproliferative and differentiating activity, vitamin D and its analogs appear to be very promising. The vitamin D endocrine system is characterized by the sequential, two-step activation of the prohormone (vitamin D) to the active hormone (1,25 dihydroxyvitamin D or D3) (149). The activity of D3 is mediated by the vitamin D receptor (VDR), which interacts with speciﬁc DNA repeat sequences, binding as either a homodimer or as a heterodimer with retinoid X receptors (RXRs) (150). Microarray analyses (cDNA) of normal and malignant prostate epithelial cells indicate that D3 regulates many target genes, expanding the possible mechanisms of its anticancer activity and suggesting new potential therapeutic targets. For example, D3 upregulates the expression of the cell cycle inhibitor p21, leading to growth arrest, as well as genes that are involved in protection from oxidative stress (151). A major impetus for evaluating vitamin D as a potential chemopreventive agent comes from the epidemiologic observation that prostate cancer mortality is associated with states of relative vitamin D deﬁciency, such as advanced age (vitamin D deﬁciency is more common in the elderly), African-American race (melanin inhibits vitamin D synthesis), and men living at northern latitudes (less exposure to ultraviolet radiation, a major source of vitamin D) (152,153). Furthermore, normal prostate epithelium expresses the enzyme 1-α hydroxylase, which converts circulating 25hydroxyvitamin D to the active 1,25-hydroxyvitamin D. Interestingly, prostate cancer epithelial cells express signiﬁcantly reduced amounts of this enzyme. Phase II clinical trials suggest that vitamin D can slow the rate of rise of PSA in prostate cancer patients with biochemical failure following deﬁnitive local therapy (154,155). However, hypercalcemia was observed in patients receiving daily D3 (154). Since the clinical utility of vitamin D may be limited by its potential to cause hypercalcemia and renal calculi, there has been an active search for noncalcemic vitamin D analogs (149,156). One of the most promising of these analogs is 1-α-hydroxyvitamin D2, which has been approved by the FDA for the treatment of secondary hyperparathyroidism associated with end-stage renal disease. In a phase I trial in patients with hormone-refractory prostate cancer, measurable soft tissue responses and PSA decreases were reported (157). This agent is currently under investigation in an NCI-sponsored phase II trial in a preprostatectomy cohort. ANTIPROLIFERATIVE AGENTS (POLYAMINE SYNTHESIS INHIBITORS) DFMO was first synthesized in the 1970s as an antitumor agent but was subsequently found to be active in several animal prevention models of epithelial cancers including colon, skin, breast, bladder, and prostate. DFMO is a noncompetitive irreversible inhibitor of ornithine decarboxylase (ODC), which catalyzes the rate-limiting step in polyamine biosynthesis. Elevated levels of polyamines have been

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associated with premalignant and malignant epithelial lesions (158,159), and ODC activity and polyamine content (spermine and spermidine) are higher in prostate tissue than in other mammalian tissues (160,161). Marked polyamine suppression by DFMO has been observed in rodent prostates (162). In the TRAMP model, DFMO prevented the development of distant metastases and restored protein expression of E-cadherin and α/β-catenin, biomarkers associated with loss of the metastatic phenotype (163). DFMO appears to have an acceptable toxicity profile for chemoprevention, although it can cause both reversible and mild irreversible ototoxicity (NCI Alert Letter, 2002). Leads from carcinogenesis, experimental animal models, and clinical studies support the development of DFMO for prostate cancer chemoprevention. Two published clinical trials show that DFMO (0.5 g/m2) administered for 2–4 wk signiﬁcantly reduces prostate polyamine levels (164,165). These encouraging results have stimulated two NCI-sponsored chemoprevention trials of DFMO in high-risk prostate cohorts (Table 3). One is a phase II randomized, placebo-controlled trial of DFMO (0.5 g/d) administered for 12 mo in individuals with a family history of prostate cancer (brothers and ﬁrst cousins). The other is a phase II trial of DFMO (0.5 g/d) and bicalutamide (50 mg/d) in a preprostatectomy cohort (see Rational Combinations below). In both of these trials, the primary endpoint is change in prostatic polyamine levels.

Anti-inﬂammatory Arachidonic Acid Signaling Agents SELECTIVE CYCLO-OXYGENASE-2 INHIBITORS Experimental, biologic, and epidemiologic studies support an important linkage among exposure to nonsteroidal anti-inﬂammatory drugs (NSAIDs), the arachidonic acid metabolic pathway, and decreased incidence and progression of prostate cancer. Products of cyclo-oxygenase-2 (COX-2) metabolism, such as prostaglandin E2, are believed to promote carcinogenesis through modulation of inﬂammation, angiogenesis, and apoptosis, and the antineoplastic effect of most NSAIDs is thought to involve inhibition of arachidonic acid/COX-2 signaling pathways (166). Clinically, inhibition of COX-2 is also associated with increased adverse effects such as edema, hypertension, and renal failure. Whether some selective COX-2 inhibitors increase or decrease the risk for cardiovascular thrombotic events remains an important issue that is under active investigation (167). Although overexpression of COX-2 in high-grade PIN and prostate cancer has been reported (168), other investigators have found that COX-2 upregulation in prostatic epithelium occurs primarily in inﬂammatory lesions, such as PIA (169). PIA is also associated with overexpression of GSTP1, a gene that codes for a critical oxidant detoxiﬁcation phase II enzyme. As cells progress from PIA to high-grade PIN and eventually to cancer, there is progressive loss of GSTP1 expression owing to promoter region hypermethylation, leading to gene silencing (125). This has given rise to a new model of prostate cancer carcinogenesis focusing attention on the role of oxidative stress and inﬂammation. Recent epidemiologic studies suggest that there is an inverse relationship between prostate cancer risk and the use of NSAIDs (170,171). Roberts et al. (170) reported a statistically significant, 55% overall reduction in prostate cancer incidence among NSAID users vs nonusers, in a prospective cohort study of 1362 men. An even more profound effect of NSAIDS on prostate cancer risk (80% reduction) was observed among older men, i.e., 70–79 yr old, suggesting that NSAIDs may prevent the progression of prostate cancer from latent to clinical disease (170).

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Several selective COX-2 inhibitors (celecoxib, rofecoxib, and others), originally approved for arthritis and pain management, are being investigated as potential preventive agents in a variety of epithelial cancers including prostate cancer (172). The NCI is currently sponsoring a phase II randomized, placebo-controlled trial of celecoxib (400 mg twice a day for 3–6 wk) in preprostatectomy patients. This is the same dose recommended for patients with familial adenomatous polyposis (FAP) and twice the FDAapproved dose for the management of arthritis. The primary endpoint of this study is modulation of COX-2-dependent prostate prostaglandins (Table 3). COX-INDEPENDENT PROAPOPTOTIC AGENTS There is evidence from experimental models that many NSAIDs have non-COX-2 mediated proapoptotic activity. For example, celecoxib has potent apoptotic effects on prostate, breast, colon, and hematopoietic cell lines independent of COX-2 expression. Furthermore, non-COX-2 targets for celecoxib include the AKT cell survival pathway and ERK2 (173,174). Another example of an agent with COX-independent apoptotic activity is sulindac sulfone, an active metabolite of the prodrug sulindac (175). This agent lacks both COX-1- and COX-2-inhibiting activity yet shows a consistent ability to induce apoptosis in a wide variety of cancer cell lines and in various animal models, including prostate cancer models (176). Sulindac sulfone has a novel mechanism of action that involves inhibition of the cyclic GMP phosphodiesterases (PDE)-2 and 5 and upregulation of protein kinase G, both of which promote apoptosis (177). This agent has been shown to increase the PSA doubling time in a phase II randomized, placebo-controlled trial in patients with rising PSA after radical prostatectomy (96) and is currently under investigation in an NCI-sponsored phase II trial in patients scheduled for radical prostatectomy.

Rational Combinations The administration of two chemopreventive agents with different mechanisms of action and non-overlapping toxicities has the potential to improve efficacy while maintaining an acceptable safety profile. For example, the NCI is currently supporting a definitive, phase III, placebo-controlled prostate cancer prevention trial in >32,000 men to determine whether selenium and vitamin E, either alone or in combination, can decrease the incidence of prostate cancer in average-risk men (see SELECT, below) (178). The NCI is also supporting a complementary, small phase II trial of this regimen in a preprostatectomy cohort of 40 patients to identify potential surrogate endpoint biomarkers (SEBs) that could subsequently be validated in the Selenium and Vitamin E Cancer Prevention Trial (179). Another rational combination currently being evaluated in an NCI-sponsored trial is that of bicalutamide, an ARA, and DFMO, a polyamine synthesis inhibitor. There is strong mechanistic and preclinical evidence in animal models of prostate cancer supporting this combination (180). This phase II, factorial design, randomized, placebocontrolled study in 40 patients scheduled for prostatectomy or brachytherapy will assess the effect of these agents, alone and in combination, on prostatic polyamine levels, biomarkers of proliferation, apoptosis, high-grade PIN, prostate cancer, and clinical tolerability (102). An example of a combination for which there are strong preclinical supporting data is that of NSAIDs with DFMO. This combination has shown striking additivity/synergy in several animal models (181). However, many factors must be addressed before combina-

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tions of agents can be advanced into clinical cancer prevention trials. These include questions of dose, duration, potential pharmacokinetic and pharmacodynamic interactions, and the inherent difﬁculty in obtaining industry support when more than one pharmaceutical company is involved. Hopefully, progress will be made toward developing rational combinations of agents for the prevention of prostate cancer in the coming years.

PHASE III PROSTATE CANCER PREVENTION TRIALS Two phase III, NCI-sponsored, prostate cancer prevention trials are currently being conducted under the auspices of the Southwest Oncology Group. These trials are known as PCPT (the Prostate Cancer Prevention Trial) and SELECT (the Selenium and Vitamin E Cancer Prevention Trial). Both are large, prospective, randomized, placebocontrolled studies with deﬁnitive prostate cancer endpoints, as well as a variety of secondary endpoints (178,182). In addition, biorepositories consisting of serum, white blood cells, and tissue have been created for these studies to foster basic research addressing the molecular basis of prostate cancer and prostate cancer prevention (183).

The Prostate Cancer Prevention Trial PCPT is a randomized, placebo-controlled, phase III trial of finasteride, 5 mg/d, in men ≥55 yr old with a baseline PSA ≤ 3 ng/mL and a normal digital rectal exam. In all, 18,882 men were accrued to this trial between 1993 and 1997. All patients are requested to have an end-of-study prostate biopsy after 7 yr on study, and thus the primary endpoint is the period prevalence of prostate cancer. Finasteride, a competitive inhibitor of 5-α-reductase, the enzyme that converts testosterone to the more potent DHT (184), became available for the treatment of benign prostatic hyperplasia (BPH) in the early 1990s. At doses of 5 mg/d, finasteride decreases circulating and prostatic DHT by up to 70%, decreases prostate gland size by 20%, and decreases circulating PSA by 50% (185,186). Epidemiologic evidence suggesting that 5-α-reductase activity is directly associated with prostate cancer risk (187–189), coupled with its favorable safety profile (186,190), supported the development of this agent for prostate cancer prevention. Results of this landmark trial showed a 24.8% reduction (p<0.001) in the 7-yr period prevalence of prostate cancer in men randomized to the finasteride group compared to placebo (190a). Whether the apparent increase in high-grade (Gleason 7–10) tumors observed in the finasteride group compared to placebo (6.4% vs 5.1%, p=0.005) is an histologic artifact is under intense investigation (190b). Unlike ﬁnasteride, which mainly inhibits the type II 5-α-reductase enzyme, dutasteride inhibits both the type I and type II isoforms and produces even more profound suppression of serum DHT levels, i.e., 93% vs 70% suppression (191). Serum concentrations of testosterone remain in the normal range on these agents, whereas both agents decrease serum concentrations of PSA by about 50%. An industry-sponsored, randomized, placebo-controlled prostate cancer prevention (REDUCE) trial of dutasteride in men with PSA values 2.5–10 ng/mL and a negative prostate biopsy was recently initiated. This study has an accrual goal of 8000 men (192).

The Selenium and Vitamin E Cancer Prevention Trial SELECT is a large, randomized, phase III, placebo-controlled study of selenium (Se), 200 µg/d, and/or vitamin E, 400 mg/d, for the prevention of prostate cancer in

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healthy men aged 55 yr or older (≥50 yr old for African-American men) with a PSA of ≤4 ng/mL (193). The primary endpoint is the incidence of prostate cancer as determined by routine clinical practice. Therefore, unlike PCPT, there are no planned biopsies, and yearly PSAs and digital rectal examinations (DREs) are suggested rather than required. SELECT opened to accrual in July 2001 and enrolled approx 20,000 men during the ﬁrst 20 mo. At this rate, the study will reach its target sample size of 32,000 men in 2004. All men are requested to remain on their study agents (vitamin E + selenium, vitamin E + placebo, selenium + placebo, or placebo + placebo) until the last men randomized have been on study for 7 yr. This study will have 96% power to detect a difference of approx 25% in the detection of prostate cancer in any treatment arm vs placebo, and 89% power to detect a difference of 25% in the detection of prostate cancer in the combined treatment arm compared with a single effective supplement. Secondary endpoints to be addressed by this study are total, lung, and colorectal cancer incidences, cancer-free survival, cardiovascular events, and quality of life (193). Results are anticipated by 2015, although planned interim analyses may permit earlier reporting. SELENIUM Se is an essential trace element with anticarcinogenic activity in vitro and in vivo (194). One mechanism by which Se may reduce cancer risk is by providing the catalytic center of antioxidant enzymes, such as the glutathione peroxidases (195). Alternatively, Se may serve as a source of antitumorigenic Se metabolites that cause cell cycle arrest and apoptosis, enhance DNA repair, and inhibit signal transduction (128,129,196,197). For example, Menter et al. (128) have shown that selenomethionine inhibits proliferation and promotes apoptosis in prostate cancer cell lines, and Waters et al. (129) have shown that both selenomethionine and high-selenium yeast increase DNA repair and promote apoptosis in the dog prostate gland. Recent evidence also suggests that Se, as well as other antioxidants, may inhibit protein kinase C, a major cell survival signal molecule (198). Several prospective epidemiologic studies conducted between 1983 and 1991 were unable to relate prostate cancer incidence to selenium status (199–202). However, these were all small studies, i.e., from 6 to 51 prostate cancer cases, and were based on serum Se levels, an unreliable measure of chronic Se intake. In contrast, the Health Professional Follow-Up Study utilized toenail Se levels, a more reliable measure of Se intake over time, to evaluate the selenium status of 181 men with prostate cancer vs matched controls. This large (n = 52,529), cohort study found that men in the highest quintile of toenail Se levels had an approx 35% decrease in prostate cancer incidence compared with those in the lowest quintile (203). VITAMIN E Vitamin E is an essential fat-soluble vitamin and functions as an antioxidant in cell membranes. Although best known as an antioxidant, vitamin E may also inhibit angiogensis (204) and protein kinase C activity (205,206), reduce serum androgen concentrations (207), and affect differentiation and proliferation (208). Epidemiologic studies are inconsistent with regard to the potential prostate cancer chemopreventive beneﬁts of this vitamin (209–213). Notably, in the Health Professional Follow-up Study, a trend toward decreased risk of metastatic or fatal prostate cancer was observed among smokers taking supplemental vitamin E (213).

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RATIONALE FOR SELECT Epidemiology and mechanistic data not withstanding, the major rationale for conducting SELECT was the need to verify secondary ﬁndings from recently conducted clinical trials suggesting that Se and vitamin E could signiﬁcantly reduce the risk of developing prostate cancer. These trials are the Nutritional Prevention of Cancer Study (NPC) (214) and the Alpha-Tocopherol Beta-Carotene Study (ATBC) (215), respectively. The Nutritional Prevention of Cancer Study. The NPC was a randomized, placebo-controlled trial of selenium for the prevention of recurrent nonmelanoma cell skin cancers in 1312 participants living in the southeastern United States, an area of the country with low soil Se levels. Although a decrease in skin cancer recurrence was not observed, secondary ﬁndings showed a signiﬁcant reduction in total cancer mortality, total cancer incidence, and prostate, lung, and colorectal cancer incidence was observed among the men randomized to receive 200 µg/d of selenium-enriched yeast (214). Alpha-Tocopheral, Beta-Carotene Study. ATBC was a randomized, placebo-controlled trial of α-tocopherol (vitamins E), 50 mg daily, and/or β-carotene, 20 mg daily, for the prevention of lung cancer in 29,133 Finnish male smokers, age 50–69 yr. After a median follow-up of 6.1 yr, neither agent was shown to decrease the incidence of lung cancer, and unexpectedly a 16% increase (p = 0.02) in lung cancer incidence was observed among the men randomized to β-carotene (215). In addition, a signiﬁcant 32% decrease in prostate cancer incidence and a 41% decrease in prostate cancer mortality were observed among the men randomized to vitamin E (216). Since neither the ATBC nor the NPC was primarily designed to assess prostate cancer risk, these results must be considered hypothesis-generating, rather than deﬁnitive. Therefore, SELECT is being conducted to conﬁrm or refute these provocative ﬁndings.

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188. Imperato-McGinley J, Miller M, Wilson JD, Peterson RE, Shackleton C, Gajdusek DC. A cluster of male pseudohermaphrodites with 5 alpha-reductase deficiency in Papua New Guinea. Clin Endocrinol (Oxf) 1991;34:293–298. 189. Imperato-McGinley J, Gautier T, Zirinsky K, et al. Prostate visualization studies in males homozygous and heterozygous for 5 alpha-reductase deficiency. J Clin Endocrinol Metab 1992;75:1022–1026. 190. Stoner E. Three-year safety and efﬁcacy data on the use of ﬁnasteride in the treatment of benign prostatic hyperplasia. Urology 1994;43:284–292; discussion 292–294. 190a. Thompson IM, Goodman PJ, Tangen CM, et al. The inﬂuence of ﬁnasteride on the development of prostate cancer. N Engl J Med 2003;349:213–222. 190b. Lippman SM. Personal comunication. 191. Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G. Efﬁcacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002;60:434–441. 192. Andriole G. Personal communication. 193. Klein EA, Thompson IM, Lippman SM, et al. SELECT: the Selenium and Vitamin E Cancer Prevention Trial: rationale and design. Prostate Cancer Prostatic Dis 2000;3:145–151. 194. Ip C, Thompson HJ, Zhu Z, Ganther HE. In vitro and in vivo studies of methylseleninic acid: evidence that a monomethylated selenium metabolite is critical for cancer chemoprevention. Cancer Res 2000;60:2882–2886. 195. McKenzie RC, Arthur JR, Beckett GJ. Selenium and the regulation of cell signaling, growth, and survival: molecular and mechanistic aspects. Antioxid Redox Signal 2002;4:339–351. 196. Chigbrow M, Nelson M. Inhibition of mitotic cyclin B and cdc2 kinase activity by selenomethionine in synchronized colon cancer cells. Anticancer Drugs 2001;12:43–50. 197. Gasparian AV, Yao YJ, Lu J, et al. Selenium compounds inhibit I kappa B kinase (IKK) and nuclear factor-kappa B (NF-kappa B) in prostate cancer cells. Mol Cancer Ther 2002;1:1079–1087. 198. Gopalakrishna R, Gundimeda U. Antioxidant regulation of protein kinase C in cancer prevention. J Nutr 2002;132:3819S–3823S. 199. Willett WC, Polk BF, Morris JS, et al. Prediagnostic serum selenium and risk of cancer. Lancet 1983;2:130–134. 200. Coates RJ, Weiss NS, Daling JR, Morris JS, Labbe RF. Serum levels of selenium and retinol and the subsequent risk of cancer. Am J Epidemiol 1988;128:515–523. 201. Knekt P, Aromaa A, Maatela J, et al. Serum selenium and subsequent risk of cancer among Finnish men and women. J Natl Cancer Inst 1990;82:864–868. 202. Criqui MH, Bangdiwala S, Goodman DS, et al. Selenium, retinol, retinol-binding protein, and uric acid. Associations with cancer mortality in a population-based prospective case-control study. Ann Epidemiol 1991;1:385–393. 203. Yoshizawa K, Willett WC, Morris SJ, et al. Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. J Natl Cancer Inst 1998;90:1219–1224. 204. Woodson K, Triantos S, Hartman T, Taylor PR, Virtamo J, Albanes D. Long-term alpha-tocopherol supplementation is associated with lower serum vascular endothelial growth factor levels. Anticancer Res 2002;22:375–378. 205. Mahoney CW, Azzi A. Vitamin E inhibits protein kinase C activity. Biochem Biophys Res Commun 1988;154:694–697. 206. Chatelain E, Boscoboinik DO, Bartoli GM, et al. Inhibition of smooth muscle cell proliferation and protein kinase C activity by tocopherols and tocotrienols. Biochim Biophys Acta 1993;1176:83–89. 207. Hartman TJ, Dorgan JF, Woodson K, et al. Effects of long-term alpha-tocopherol supplementation on serum hormones in older men. Prostate 2001;46:33–38. 208. Traber MG, Packer L. Vitamin E: beyond antioxidant function. Am J Clin Nutr 1995;62:1501S–1509S. 209. Hsing AW, Comstock GW, Abbey H, Polk BF. Serologic precursors of cancer. Retinol, carotenoids, and tocopherol and risk of prostate cancer. J Natl Cancer Inst 1990;82:941–946. 210. Knekt P, Aromaa A, Maatela J, et al. Serum vitamin E and risk of cancer among Finnish men during a 10-year follow-up. Am J Epidemiol 1988;127:28–41. 211. Comstock GW, Helzlsouer KJ, Bush TL. Prediagnostic serum levels of carotenoids and vitamin E as related to subsequent cancer in Washington County, Maryland. Am J Clin Nutr 1991;53:260S–264S. 212. Eichholzer M, Stahelin HB, Gey KF, Ludin E, Bernasconi F. Prediction of male cancer mortality by plasma levels of interacting vitamins: 17-year follow-up of the prospective Basel study. Int J Cancer 1996;66:145–150.

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213. Chan JM, Stampfer MJ, Ma J, Rimm EB, Willett WC, Giovannucci EL. Supplemental vitamin E intake and prostate cancer risk in a large cohort of men in the United States. Cancer Epidemiol Biomarkers Prev 1999;8:893–899. 214. Clark LC, Combs GF Jr, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 1996;276:1957–1963. 215. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994;330:1029–1035. 216. Heinonen OP, Albanes D, Virtamo J, et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst 1998;90:440–446. 217. Nupponen NN, Kakkola L, Koivisto P, Visakorpi T. Genetic alterations in hormone-refractory recurrent prostate carcinomas. Am J Pathol 1998;153:141–148. 218. Cher ML, Bova GS, Moore DH, et al. Genetic alterations in untreated metastases and androgen-independent prostate cancer detected by comparative genomic hybridization and allelotyping. Cancer Res 1996;56:3091–3102. 219. Dahiya R, McCarville J, Hu W, et al. Chromosome 3p24-26 and 3p22-12 loss in human prostatic adenocarcinoma. Int J Cancer 1997;71:20–25. 220. Chu LW, Troncoso P, Johnston DA, Liang JC. Genetic markers useful for distinguishing between organ-conﬁned and locally advanced prostate cancer. Genes Chromosomes Cancer 2003;36:303–312. 221. Cooney KA, Wetzel JC, Consolino CM, Wojno KJ. Identiﬁcation and characterization of proximal 6q deletions in prostate cancer. Cancer Res 1996;56:4150–4153. 222. Visakorpi T, Kallioniemi AH, Syvanen AC, et al. Genetic changes in primary and recurrent prostate cancer by comparative genomic hybridization. Cancer Res 1995;55:342–347. 223. Zenklusen JC, Thompson JC, Troncoso P, Kagan J, Conti CJ. Loss of heterozygosity in human primary prostate carcinomas: a possible tumor suppressor gene at 7q31.1. Cancer Res 1994;54:6370–6373. 224. Latil A, Baron JC, Cussenot O, et al. Genetic alterations in localized prostate cancer: identiﬁcation of a common region of deletion on chromosome arm 18q. Genes Chromosomes Cancer 1994;11:119–125. 225. Bova GS, Carter BS, Bussemakers MJ, et al. Homozygous deletion and frequent allelic loss of chromosome 8p22 loci in human prostate cancer. Cancer Res 1993;53:3869–3873. 226. Trybus TM, Burgess AC, Wojno KJ, Glover TW, Macoska JA. Distinct areas of allelic loss on chromosomal regions 10p and 10q in human prostate cancer. Cancer Res 1996;56:2263–2267. 227. Ittmann M. Allelic loss on chromosome 10 in prostate adenocarcinoma. Cancer Res 1996;56:2143–2147. 228. Cooney KA, Wetzel JC, Merajver SD, Macoska JA, Singleton TP, Wojno KJ. Distinct regions of allelic loss on 13q in prostate cancer. Cancer Res 1996;56:1142–1145. 229. Yin Z, Spitz MR, Babaian RJ, Strom SS, Troncoso P, Kagan J. Limiting the location of a putative human prostate cancer tumor suppressor gene at chromosome 13q14.3. Oncogene 1999;18:7576–7583. 230. Osman I, Scher H, Dalbagni G, Reuter V, Zhang ZF, Cordon-Cardo C. Chromosome 16 in primary prostate cancer: a microsatellite analysis. Int J Cancer 1997;71:580–584. 231. Gao X, Zacharek A, Grignon DJ, et al. Localization of potential tumor suppressor loci to a < 2 Mb region on chromosome 17q in human prostate cancer. Oncogene 1995;11:1241–1247. 232. Yin Z, Babaian RJ, Troncoso P, et al. Limiting the location of putative human prostate cancer tumor suppressor genes on chromosome 18q. Oncogene 2001;20:2273–2280. 233. Walczak J, Wood H, Wilding G, Williams T Jr, Bishop C, Carducci M. Prostate cancer prevention strategies using antiproliferative or differentiating agents. Urology 2001;57:81–85. 234. Myers C, Koki A, Pamukcu R, Wechter W, Padley RJ. Proapoptotic anti-inﬂammatory drugs. Urology 2001;57:73–76. 235. Fleshner N, Fair WR, Huryk R, Heston WD. Vitamin E inhibits the high-fat diet promoted growth of established human prostate LNCaP tumors in nude mice. J Urol 1999;161:1651–1654. 236. Gupta S, Srivastava M, Ahmad N, Bostwick DG, Mukhtar H. Over-expression of cyclooxygenase-2 in human prostate adenocarcinoma. Prostate 2000;42:73–78.

6

The Special Problems of Prostate Cancer Among African Americans Clinical and Molecular Factors

Isaac J. Powell

INTRODUCTION In 2003, approx 1.3 million Americans will be diagnosed with invasive cancer. Racial/ethnic minorities are expected to account for a disproportionate number of these cancers. African Americans in particular have a 10% higher incidence rate and a 30% higher death rate from all cancers combined than Whites (1). African-American incidence rates for all cancers combined increased from the early 1970s to the early 1990s in both males and females, although the incidence rates were higher and increased fasters in males than in females. During the 1990s, however, rates decreased in African-American males while stabilizing in African-American females. The decrease in incidence rates in men largely involved cancers of the lung and prostate. The mortality rate for all cancers combined increased among African Americans from 1973 to 1992 but decreased after 1992, by 1.2% a year on average. The decline for African-American males (2.1% a year since 1993) was larger than the decline for African-American females (0.4% a year since 1991). Prostate cancer accounts for most of the dynamic changes of cancer among African-American men since it is by far the most commonly diagnosed cancer among men (1).

PROSTATE CANCER STATISTICS Prostate cancer accounts for 39% of all cancer cases diagnosed in African-American males. In 1999, the prostate cancer incidence rate was 58% higher among African Americans than among White men. From 1989 to 1992, prostate cancer incidence rates increased by 20.6% a year, but between 1992 and 1996, the incidence rate declined by approx 5.7% a year. The incidence rate stabilized in the time period between 1996 and 1999. The dramatic short-term increase in prostate cancer incidence rate between 1989 From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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and 1992 was probably owing to earlier and more complete diagnosis through use of prostate-speciﬁc antigen (PSA) blood testing (1). Prostate cancer ranks as the second most common cause of cancer death among African-American males. Among ethnic/racial groups in the country, African Americans have the highest mortality rate, approx 2.5 times greater than Whites (2). The death rate from prostate cancer among African-American men has been decreasing by 2.5% a year since 1993, Some of the decrease in mortality appears to be owing to screening and aggressive treatment. The decline in prostate cancer began later in African Americans than in Whites and has occurred more gradually. Current 2003 statistics report the estimated prostate cancer incidence as 220,900, which is higher than the 2002 estimate of 189,000. However, the 2003 deaths are estimated to be 28,900, which is less than the 2002 estimate of 30,000. This decreasing trend of deaths started in 1992. The current deaths per 100,000 for African Americans is 75.1, that of Whites is 32.9, and that of Hispanics is 22.6 (2). The cause of this disproportionate death rate among African Americans compared with other ethnicities is unclear but will be explored later in the chapter. The disparity in incidence is intriguing as well and may be more a difﬁcult question to answer than the disproportionate mortality. The 2003 incidence rate per 100,000 is 275.3 for African Americans, 172.9 for Whites, and 127.6 for Hispanics (2). Although it has been reported that African Americans have the highest incidence of prostate cancer in the world, a recent study of Blacks in Jamaica noted a higher rate than African Americans. The study reported that the Black Jamaican incidence of prostate cancer was 304 per 100,00 in 1994 compared with 224,000 per 100,000 for African Americans during that same year (3). The reason for the high incidence among Black Jamaicans as well as African Americans is unclear. However, it raises several questions about similar genetic components and/or similar diet or other factors as a cause for these high incidence rates among these population of similar origin. Some unreported observations have suggested that Black Jamaicans of sub-Saharan West African descent have a diet high in fat content similar to that of African Americans (also of sub-Saharan West African descent). It has been reported that saturated fat causes prostate cancer to progress (4). Recent reports from Nigeria suggest that the incidence rates there are much higher than previous reports suggested. In fact, prostate cancer in Nigeria is the most commonly diagnosed cancer (5,6). The amount of fat content in the Nigerian diet is unclear, but there is much less obesity among Nigerians compared with African Americans. A recent report from Brazil found that men of sub-Saharan African descent have a higher incidence of high-grade prostate intraepithelial neoplasia (PIN) than men of European descent. High-grade PIN has been reported to be associated with aggressive prostate cancer (7). All the above ﬁndings of prostate cancer incidence and high-grade PIN among men of sub-Saharan African descent from different parts of the world and different environments suggest that a genetic component is at least partially causal for these ﬁndings and outcomes. This will be discussed later in the chapter.

AGE, PROSTATE CANCER, AND ETHNICITY Age is one of the established risk factors for prostate cancer. The age-speciﬁc mortality rate of patients diagnosed with prostate cancer from 1996 to 2000 between ages 45 and 69 yr is three times greater among African-American men compared with European Americans (8). Data based on the outcome of men treated for clinically localized prostate cancer demonstrated more advanced disease and more frequent recurrence

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among young African-American men than among European-American men, young and of advanced age (9). Examination of 759 consecutive radial prostatectomy specimens from African Americans and European Americans was performed from January 1991 to June 1996 at Wayne State University, Harper University Hospital, Detroit, Michigan. International, salvage prostatectomy, and neoadjuvant hormonal therapy patients were excluded, as were patients with lymph node metastasis. Univariate analysis of contingency tables was performed, using chi-squared-tests to assess the correlation between stage and race after stratiﬁcation of patients by age group. Biochemical recurrence was analyzed using the Kaplan-Meier method and the log rank test. African-American men aged 50–69 yr had higher PSA levels, worse Gleason scores, more advanced stage of disease, and a higher recurrence rate than men of European descent. However, among men aged 70–79 yr, there were no difference in these parameters between African-American and European-American men (9). Austin et al. (10) examined survival rates of African-American and European-American patients who were treated by primary radiation therapy for carcinoma of the prostate. When survival for each race was analyzed individually by age, they noted that younger African-American patient (<60 yr) tended to do worse than older AfricanAmerican patients (36% vs 41%, 5-yr survival). The younger European Americans tended to do better than older European Americans (62% vs 45%, 5-yr survival). They noted that the difference in grade between African-American and European-American patients was even more pronounced in the younger African-American age group. They concluded that younger African-American males, in fact, may be predisposed to a more virulent tumor (10). In a predominately European-American population, Stamey et al. (11) sought to determine whether increasing age at the time of diagnosis is related to morphologic and clinical predictors of cancer progression. The result of that study showed that the percentage Gleason grade 4/5 cancer and cancer volume showed the most statistically signiﬁcant changes with aging. They concluded that since percentage Gleason grade for 4/5 cancer and cancer volume are also associated with primary determinance of failure to cure prostate cancer by radical prostatectomy, these age-related changes suggest that detection of prostate cancer later in life will be accompanied by an increased amount of high-grade cancer and larger tumor volumes (11). These findings appear to contrast with the findings among African Americans reported by Austin and others. These ﬁndings suggested that there may be different survival curves based on age secondary to morphologic and biologic predictors of prostate cancer progression and survival. In a study in an equal-access institution to examine survival among African-American and European-American men, we identiﬁed a racial “crossover” effect in survival occurring around age 70 yr. European-American men demonstrated better survival under age 70 yr, and African-American men 70 yr and older tended to have better survival (12). This further suggests that there may be different biologic factors driving prostate cancer between these two populations. This consideration will be discussed later in the chapter.

SIGNIFICANCE OF STAGE AT DIAGNOSIS OF PROSTATE CANCER It has been reported that the biochemical progression of prostate cancer by stage is greater among African-American than European-American men with advanced disease

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but not organ-conﬁned disease. A recent study examined 848 consecutive patients who underwent radical prostatectomy at Wayne State University, Karmanos Cancer Institute between 1991 and 1995. The mean follow-up of this cohort was 34 mo. African-American and European-American men diagnosed with organ-confined prostate cancer demonstrated similar PSA levels, Gleason grade, and biochemical recurrence. However, African-American men diagnosed with non-organ-conﬁned disease demonstrated higher PSA levels and a higher incidence of recurrence than European-American men with non-organ-conﬁned disease. There was a trend toward African-American men having a greater proportion of high-grade lesions than European Americans when prostate cancer was not organ-conﬁned. The evidence suggests that the difference in recurrence among African-American vs European-American men is based on pretreatment PSA, grade, extracapsular extension, and positive surgical margins. Seminal vesicle invasion predicted a worse prognosis for both African-American and European-American men equally in this study (13). It was hypothesized from the study that African-American men have a more rapid growth rate of prostate cancer, which may be responsible for the clinical ﬁndings. Pettaway et al. (14) recently reported a higher incidence of seminal vesicle involvement and cancers with a Gleason score of 8 or more (p = 0.02), as well as a trend toward decreased margin-negative disease among 40 African-American men compared with 148 European-American men. More importantly, the mean prostate tumor volume, total gland weight, and serum PSA level among African-American and EuropeanAmerican men with pathologic stage PT2, PT2+, and PT3 cancer were not signiﬁcantly different. However, with advancing pathologic stage (PT3+ and PT3c) disease, African-American men had higher preoperative serum PSA levels on univariate and multivariate analysis, despite similar total gland weight and tumor volume (14). Moul et al. (15) reported that Black race was an adverse prognostic factor for recurrence after radical prostatectomy, after multivariable adjustment for pretreatment PSA and acid phosphatase, organ-conﬁned status, and tumor grade in an equal-access health care setting. African-American and European-American men had 39.1 and 40.65% orgainconﬁned prostate cancer, respectively (15). It is clear that most of their cohort were diagnosed with pathologically locally advanced prostate cancer among both AfricanAmericans and European-American men. This study was reported in the early 1990s. However, Freedland et al. (16) reported that race was not a signiﬁcant predictor of biochemical failure after radical prostatectomy by multivariate analysis (p = 0.199); their study was also done in a equal-access system. Mean follow-up was 29 mo. In their population, African-American and European-American men had 80 and 81% organ-conﬁned prostate cancer, respectively. Both the Freedland and the Moul studies are consistent with the conclusions of the Wayne State University report. A recently reported Southwest Oncology Group Study found that African-American men had a poorer survival when diagnosed with metastatic prostate cancer and treated similarly in a well-controlled protocol compared with European Americans (17). In summary, stage-for-stage, pathologically organ-conﬁned disease shows no difference in progression-free survival, but locally advanced and metastatic prostate-cancer in African-Americans demonstrates a worse progression-free survival and disease-speciﬁc survival, respectively, than in European Americans. It has been hypothesized that biologic/genetic instability is more highly expressed and may be more pronounced with time in prostate cancer among African-American men than European-American men. More importantly, these data suggest that if prostate cancer is diagnosed early and

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treated aggressively, we can eliminate the disparity between African-American and European-American men even though prostate cancer may be more biologically aggressive among African Americans than among European-American men. Results from a multivariate analysis conducted at Wayne State University revealed that, among men with organ-conﬁned prostate cancer, race was not a signiﬁcant predictor of disease-free survival after adjusting for Gleason grade and PSA. In fact, Gleason grade was the only signiﬁcant predictor of outcome within organ-conﬁned pathologic stage. However, among non-organ-conﬁned patients, race was a predictor of outcome, even after adjusting for Gleason grade and PSA (18). The initiation of PSA testing has led to increased public awareness, early detection, and a stage shift in prostate cancer. As previously stated, African-American men have a worse disease-free survival independent of pathologic and clinical factors from locally advanced and metastasic disease. We tested the stage shift effects on disease-free survival in our cohort of patients treated with radical prostatectomy. A total of 1042 consecutive patient underwent radical prostatectomy, performed at Wayne State University by full-time faculty. The cohort was divided by the year of surgery. Group 1 (585 patients) underwent surgery from June 1990 to December 1995, and group 2 (457 patients) underwent surgery January 1997 to December 1999. Improvements in clinical stage, preoperative PSA, and biopsy Gleason score were observed in group 2 (p = 0.0001). Pathologically organ-conﬁned disease increased in group 2 vs group 1 in the two races, an increase of 89 of 153 (58%) from 66 of 178 (37%) in African-American men and 189 of 304 (62%) from 194 of 470 (48%) in European-American men (p = 0.003 and 0.001, respectively). The calculated cancer recurrence-free median probabilities in group 1 at 42 mo were 81 and 68% in European-American and African-American men, respectively (log rank test = 0.001). These differences became insigniﬁcant in group 2 patients at 42 mo, with median probabilities of 90 and 88% in European-American and AfricanAmerican men, respectively (log rank test = 0.39), representing a net increase in diseasefree survival of 20% in African-American men. Specimen Gleason score, PSA, and pathologic stage were independent predictors of survivals in the two groups. In contrast, race was an independent predictor only in group 1. The conclusion of this study was that an increased rate of pathologically organ-conﬁned disease translates into an improved survival rate. These data suggest that the survival gap in African-American and European-American men who undergo radical prostatectomy is narrowing and becoming stastically insigniﬁcant (19). These ﬁndings validate the recent results of Paquette et al. (20), who observed a 35% decrease in extracapsular extension in African-American men between 1990 and 1999.

PROSTATE CANCER GRADE AT DIAGNOSES Pathologic grade of radical prostatectomy specimens among ethnic groups (AfricanAmerican and European-American men) has been examined by only a few investigators. An initial review of two studies demonstrated no difference in grade between the two races; however, in those series most patients of both races examined had a pathologic grade of VII (out of 10) (15,21). Recently, Sakr et al. (22) examined the components of Gleason score 7 (3 + 4 vs 4 + 3) and stratiﬁed these components by race. They reported that African-American men had a greater percentage of the 4+3 component in radical prostatectomy specimens than European-American men, whereas EuropeanAmerican men had a greater percentage of the 3+4 component. These differences are

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particularly evident among younger patients (<55 yr old). Differences in overall outcome have been reported, and patients with a 4 + 3 component have been identiﬁed as having worse outcomes than those with a 3 + 4 (22). At Wayne State University, men were grouped into cohorts that consisted of Gleason score 8–10 plus 7 (4+3) and Gleason score ≤6 plus 7 (3+4). It was reported that African-American men aged 50–59 yr had a trend toward higher Gleason scores by group (8–10, 4+3) than European-American men (21 of 71 patients [30%] vs 26 of 130 patient [20%], respectively; p = 0.12). However, among men aged 60–69 yr, AfricanAmerican men had higher Gleason grades than European-American men (39% vs 29%; p = 0.03). Analysis of the age group 70–79 yr old among African-American men vs European-men demonstrated high Gleason grade in 20 of 47 patients (43%) vs 15 of 50 patients (30%), respectively (p = 0.20) (9). In a recent study, Freeman et al. (23) collected data on the histologic grade, stage, and age at diagnosis of more than 4000 patients diagnosed with prostate cancer in the Chicago area. The patient cohort studied included approximately one-third African Americans, and the tumors were classified into high and low histologic grade categories (poorly or undifferentiated vs well or moderately differentiated, respectively). After adjusting for tumor stage (localized, regional, or distant), the authors used logistic regression to assess the correlation between race and tumor histologic grade. They found that the relative risk of high histologic grade prostate cancer in African-American patients compared with Caucasian patients was 1.7 (95% CI [1.4, 2.0], p < 0.0001). The authors suggested that the grade discrepancies within fairly well-defined stage categories may contribute to the higher mortality rate from prostate cancer in African Americans (23). Land et al. (24) reported that African-American men had a higher percentage of prostate cancer Gleason grade 8–10, and, as mentioned above, Pettaway et al. (14) reported a higher proporation of Gleason score 8 or more among African-American men compared with European-American men. If Gleason grade is a reﬂection of biologic potential, then these ﬁnding suggest that prostate cancer exhibits more aggressive biologic behavior and perhaps more rapid growth among African-American men vs European-American men.

ETHNIC VARIATIONS IN PROSTATE SPECIFIC ANTIGEN Serum PSA is considered a powerful prognostic indicator of prostate cancer volume. African-American men have been reported to have a signiﬁcantly higher mean pretreatment PSA than European-American men (25). It has also been reported that for similar prostate volumes, PSA levels are higher among African Americans diagnosed with prostate cancer than among European Americans (26). The cause of this difference is unclear. One study found that among men with benign prostatic hyperplasia, the percent of PSA secreted per prostate volume was greater among African-American men than among other ethnic groups (27). These ﬁndings raise the question of whether the production of PSA per prostate cell differs among ethnic groups, or whether some other mechanism accounts for the difference, such as cell leakage. This question offers opportunity for further research. However if the grade is a reﬂection of biologic activity and African Americans have a higher grade and thus more active biology or physiology of the prostate cell, one might assume that there would be greater production of PSA among African-American vs European-American men.

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It has also been reported that PSA level has a greater predictive value for detection of prostate cancer among African-American men (42–45%) than among EuropeanAmerican men (30–35%) (28–30). These findings may indicate that PSA-driven prostate cancer detection is more cost-effective among African-American than European-American men.

EPIDEMIOLOGY OF AUTOPSY STUDIES Recent autopsy studies have demonstrated no statistical difference between the two races in prevalence and initiation of latent forms of prostate cancer (31). The terms latent, incidental, histologic, and autopsy cancer have all been used to describe tumors identiﬁed at autopsy. A more recent term that has been used is subclinical prostate cancer. There is an exceedingly high prevalence of this form of prostate cancer compared with the relatively smaller fraction of clinically diagnosed prostate cancers. This suggests that most of these autopsy cancers are low-grade, slowly growing tumors. In an early study by Guileyardo et al. (32), the authors reported on the frequency and characteristics of prostate cancer discovered at autopsy in 207 African-American and 293 European-American males in New Orleans, Louisiana. The study included a few young individuals (a total of 12 subjects under the age of 45). The authors found a similar cancer frequency in the two populations in all age groups studied (20–70 yr of age). When they divided the tumors into “latent noninﬁltrative” and “latent inﬁltrative,” they found that African-American patients harbored a higher percentage of latent inﬁltrative cancers. However, the difference was not statistically signiﬁcant. Additionally, the authors indicated that larger, less differentiated tumors tended to be more common in younger African-American but not in European-American men. However, the available numbers of cases were insufﬁcient to draw deﬁnitive conclusions (32). The Wayne State University autopsy study also indicated a lack of signiﬁcant difference in the frequency of small cancer foci between the two races. They found an astonishingly high prevalence of “autopsy” prostate cancers in a predominantly younger cohort of men. They reported that 8, 31, 43, 46, 70, and 81% of African-American men in their third, fourth, ﬁfth, sixth, seventh, and eighth decades harbored foci of prostate cancer. The corresponding ﬁgures for European Americans were 8, 31, 37, 44, 65, and 83%, respectively (33). There were no signiﬁcant differences between the two races in terms of the number of foci of cancers discovered, their anatomic zonal distribution, Gleason score, or volume. However, an extension of this study found that high-grade prostatic intraepithelial neoplasia (PIN) was more prevalent and more extensive at an earlier age among African-American men than European-American men. In a microscopic evaluation of 525 step-section prostate glands of 314 African-American and 211 European-American men, they reported a higher prevalence of high-grade PIN in African-American men across a wide age range spectrum (ages 20–80 yr). The lesion was identiﬁed in 7, 26, 46, 72, 75, and 91% of African-American men in their third, fourth, ﬁfth, sixth, seventh, and eighth decades, respectively. The corresponding ﬁgures in European-American men were 8, 23, 29, 49, 53, and 67%, respectively. Similar data were reported from Brazil by Billis et al. (34), indicating a higher prevalence of high-grade PIN in men of Sub-Saharan African descent compared with European Brazilians and also that the former group suffered from higher prostate cancer-related morbidity and mortality. Another study from Stanford University demonstrated a higher volume of prostate cancer among African Americans compared with

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European Americans aged 40–49 yr who died from other causes. These investigators hypothesized that this fact may responsible for early malignant transformation to clinically signiﬁcant prostate cancer among African-American men vs European-American men (35). These autopsy studies may indicate that the disease process of clinically signiﬁcant prostate cancer is more aggressive, with greater volume, in young AfricanAmerican men compared with European-American men of similar age.

MOLECULAR EPIDEMIOLOGY The previously mentioned autopsy studies and clinical ﬁndings may be explained by the biologic/genetic mechanisms of this disease. Prostate cell division is controlled by testosterone after intracellular conversion to its reduced form, dihydrotestosterone (DHT), by 5-α-reductase. Ross et al. (36) demonstrate evidence suggesting that racial/ethnic variation in prostate cancer is partly caused by underlying differences in androgen secretion and metabolism. Young adult African-American men have at least 10% higher circulating testosterone levels than young adult White men, a difference that, if sustained over an extended period, is probably sufﬁcient to explain the 60–70% higher prostate cancer rates in older adult African-American men compared with EuropeanAmerican men (36). The question of whether these levels are sustained is controversial. Henderson et al. (37) report that African-American women have much higher ﬁrsttrimester testosterone levels than do White women. They speculate that these high testosterones levels contribute to the high rate of prostate cancer in their male offspring, possibly by an impact on the hypothalamic–pituitary–testicular feedback system, the gonodostat, such that higher circulating levels of testosterone occur in African Americans compared with Whites (37). High-grade PIN depends on androgen circulation. We mentioned earlier that signiﬁcant difference in high-grade PIN between African-American men and European Americans begins between 40 and 49 yr. It has also been reported that high-grade PIN is associated with the progressive prostate cancer (38). It is therefore probable that these events may contribute to the difference in the clinical incidence and outcome of prostate cancer between African Americans and European Americans. In the cell, >90% of free testosterone is irreversibly converted into the main prostatic androgen, DHT, through the enzymatic action of 5-α-reductase (39). DHT binds to the androgen receptor and forms a complex that, in conjunction with cofactor proteins and other transcription factors, facilitates androgen-induced regulation of genes involved in cellular proliferation and differentiation (40). Suppression of DHT may reduce the carcinogenic transformation of prostate cells. Elevated levels or increased activity of testosterone and intraprostatic DHT may partly account for racial differences in prostate cancer risk (41). Genes involved in the androgen metabolism cascade have been identiﬁed as possible candidates for genetic inﬂuences in prostate cancer. When these genes are found to be polymorphic and the variants are distributed differently across population groups, interest in them increases, as variation in DNA sequence could alter protein function and result in variation in disease risk. CYP3A4 is a gene involved in the oxidation of testosterone. Rebbeck et al. (42) identiﬁed a genetic variant of CYP3A4 that was associated with a higher clinical grade and stage in White men with prostate cancer. The allele frequency of the variant, G, is differentially distributed across racial and ethnic groups (43). In healthy volunteers

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(117 European Americans, 121 Hispanic Americans, 116 African-Americans, and 80 Asian Americans), Paris et al. (44) found that the frequency of the variant G allele was much more common among African-American men (81%) than among EuropeanAmerican (7%), Hispanic-American (20%), or Asian-American (0%) men. Among 174 African-American prostate cancer cases, 83% carried at least one variant allele; 28% of 116 African-American controls were homozygous for the G allele. This frequency increased to 46% among African-American prostate cancer cases, and homozygosity for the G allele was correlated with clinical characteristics (Gleason score >7, PSA >10, and higher grade/stage) (44). Powell et al. (45) conducted a genetic variant CYP3A4 and survival analysis among a diverse population of men undergoing radical prostatectomy. There were 778 men (448 European-American and 330 African-American men) who underwent radical prostatectomy as monotherapy and for which CYP3A4 analysis was available, from 1990 to 1996. Biochemical recurrence after prostatectomy was deﬁned as PSA > 0.4. Examination of disease progression and survival of men from the Karmanos Cancer Institute database was conducted. Kaplan-Meier curves were generated and correlated with CYP3A4, normal allele AA, heterozygous variant AG, and homozygous variant GG. DNA was isolated from tissue by a modiﬁed procedure using Qiagen tissue kits. Nonparametric Kaplan-Meier survival function estimates for progression-free survival time distribution following prostatectomy were obtained. The results demonstrated that the distribution of AA, AG, and GG alleles were racially/ethnically disproportional. European Americans presented with 92% wild-type allele, and African Americans were observed to have 38 and 43% heterozygous and homozygous variants, respectively. The AG and GG variants were associated with greater disease progression among men with pathologically locally advanced prostate cancer than among men diagnosed with the normal AA allele. A multivariate analysis of these data revealed that CYP3A4 was an independent predictor of prostate cancer progression (45). These data suggest that CYP3A4 may be partly responsible for the disparity of outcome among African Americans compared with European Americans with pathologically locally advanced prostate cancer, since there is a greater prevalence of the G allele among African-American men. Makridakis et al. (46) reported a variant of the SRD5A2 gene in which an alanine residue at codon 49 is replaced with threonine (A49T). A nested case-controlled design was used to access the risk of developing prostate cancer among 388 cases (216 African-Americans, 172 Hispanics) and 461 controls (261 African-Americans, 200 Hispanics) selected from a population-based cohort study in Los Angeles and Hawaii. The variant allele was rare among controls, but it conferred a relevant risk for both advanced and localized prostate cancer of 3.3 among African-American men and 2.5 among Hispanic men. Risk of advanced prostate cancer was increased among AfricanAmerican men (RR = 7.2) and Hispanic men (RR = 3.6) (46). In a separate study that did not include a control group, the A49T variant was observed among European Americans and was found to be associated with the pathologic characteristics of high frequency of extracapsular disease and greater lymph node metastasis reference (47). A shorter androgen receptor cytosine adenine guanine CAG repeat length may be associated with increased risk for the development of prostate cancer (48). It has been demonstrated that the shorter CAG repeats are associated with increased androgen stimulation and the diagnosis of prostate cancer at a younger age (49). It has also been reported that African-American men have a greater percentage of short CAG repeats on

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the androgen receptor gene than do European-American men (50). Several hormonal factors as well as other genetic factors may help to explain the increased incidence of clinically signiﬁcant prostate cancer among African-American men compared with European-American men. Further research in these areas is needed.

ENVIRONMENTAL FACTORS I believe that environmental factors (diet or other epigenetic factors) may play a signiﬁcant role in explaining the racial/ethnic differences of prostate cancer. Accumulating evidence indicates that a diet high in fat content is closely associated with prostate cancer progression (4). Observations and some preliminary evidence suggest that African Americans consume a diet high in fat content (51). It has been postulated that diet can alter steroid hormone proﬁles and therefore modify prostate cancer risk throughout life (52). If this is true, as Ross and Henderson (52) suggest, diet-regulated hormonal inﬂuences ﬁrst occur in utero. This may explain why African-American women have much higher ﬁrst-trimester testosterone levels than do White women, leading to the higher risk of prostate cancer among African-American men. Whittemore et al. (51) also studied prostate cancer in relation to diet among Blacks, Whites, and Asians in the United States and Canada. She noted a positive statistically signiﬁcant association of prostate cancer risk and total fat intake among all ethnic groups combined. This association was attributable to energy from saturated fats; after adjusting for saturated fat, risk was associated only weakly with monounsaturated fat and was unrelated to protein, carbohydrate, polyunsaturated fat, and total food energy. Fat intake and the percentage of energy from fat also differed appreciably among different ethnicities; they were highest in Blacks followed by Whites, Japanese Americans and Chinese Americans. Similar ethnic differences were seen in the consumption of red meats. However, crude estimates suggest that the differences in saturated fat intake account for about 10% of Black/White differences in prostate cancer incidence. These investigators suggest that their data support a causal role in prostate cancer for saturated fat intake but suggest that other factors are largely responsible for interethnic differences in risk (51). Giovannucci et al. (53) recently reported on the dietary intake between 1986 and 1992 of 47,894 health professionals who were free of cancer. In this cohort, intake of lycopene or other compounds in tomato-based foods appeared to reduce prostate cancer risk, but other carotenoids measured were unrelated to prostate cancer risk. These researchers further demonstrated that African-American men consumed tomato-based products infrequently, and their serum lycopene intake level was the lowest of all the ethnic groups studied. African-American men also had the highest incidence of prostate cancer in this study population (53).

SUMMARY The special problem of prostate cancer among African-American men is that the age-speciﬁc mortality rate between ages 45 and 69 yr is currently three times greater than in other ethnic groups. This striking disparity can be explained by multiple factors. This chapter has focused on clinical and molecular factors to explain these Surveillance, Epidemiology, and End Results registry ﬁndings. In summary, the more advanced the stage of prostate cancer (stage for stage), the greater the ethnic disparity. The younger the age at diagnosis, the greater the disparity

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between African and European Americans. Conversely, the earlier the stage and the older the population, (>70 yr), the less the difference in outcomes. We have demonstrated that biologic/genetic differences between racial/ethnic groups impact on characteristics of cancer and survival. There is growing genetic evidence that polymorphic gene variants associated with poor outcome are proportionately greater among African-American men than other ethnic groups. However, if prostate cancer is diagnosed early enough (pathologically organ-conﬁned) we can eliminate the disparity among African-American men vs other ethnic groups even though the biologic/genetic factors responsible for aggressive disease are more prevalent among these men.

REFERENCES 1. Ghafoor A, Jemal A, Cokkinides V, et al. Cancer statistics for African Americans. CA Cancer J Clin 2002;52:326–341. 2. American Cancer Society: Cancer Facts and Figures, 2003. American Cancer Society, 2003. National Home Ofﬁce, Atlanta, GA, 30,329–34,251. 3. Glover FE, Coffey DS, Douglas L, et al. The epidemiology of prostate cancer in Jamaica. J Urol 1998;159:1984–1986. 4. Wang Y, Corr JG, Thaler HT, Tao Y, Fair WR, Heston WD. Decreased growth of established human prostate LNCaP tumors in nude mice fed a low-fat diet. J Natl Cancer Inst 1995;87:1456–1462. 5. Osegbe DN. Prostate cancer in Nigeria: facts and non-facts. J Urol 1997;157:1340–1343. 6. Ogunbiyi JO, Shittu OB. Increased incidence of prostate cancer in Nigerians. J Natl Med Assoc 1999;91:159–164. 7. Athanase BA. Age and race distribution of high grade prostatic intraepithelial neoplasia (HGPIN): an autopsy study in Brazil (South America). In: Modern Pathology, 85th Annual Meeting 1996;9:71A. 8. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Mortality—All COD, Public-Use with State, Total U.S. (1969–2000), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2003. Underlying mortality data provided by NCHS (www.cdc.gov/nchs). 9. Powell IJ, Banerjee M, Sakr W, et al. Should African American men be tested for prostate carcinoma at an earlier age than white men? Cancer 1999;85:472–477. 10. Austin J, Oziz H, Potter L, et al. Diminished survival of young Blacks with adenocarcinoma of the prostate. Am J Clin Oncol 1990;13:465–469. 11. Stamey TA, Raimondo M, Yemoto CE, McNeal JE, Johnstone IM. Effect of aging on morphologic and clinical predictors of prostate cancer progression. J Urol 2000;163:54 (abstract 253). 12. Powell IJ, Schwartz K, Hussain M. Removal of the ﬁnancial barrier to health care: does it impact on prostate cancer at presentation and survival? A comparative study between Black and White men in a Veterans Affairs system. Urology 1995;46:825–830. 13. Powell IJ, Banerjee M, Novallo M, et al. Prostate cancer biochemical recurrence stage for stage is more frequent among African American than white men with locally advanced but not organ-conﬁned disease. Urology 2000;55:246–251. 14. Pettaway CA, Troncoso P, Ramirez EI. Prostate specific antigen and pathological features of prostate cancer in Black and White patients: a comparative study based on radical prostatectomy specimens. J Urol 1998;160:437–442. 15. Moul JW, Douglas TH, McCarthy WF, et al. Black race is an adverse prognostic factor for prostate cancer recurrence following radical prostatectomy in an equal access health care setting. J Urol 1996;155:1667–1673. 16. Freedland SJ, Jolkut M, Dorey F, et al. Race is not an independent predictor of biochemical recurrence after radical prostatectomy in an equal access medical center. Urology 2000;56:87–91. 17. Thompson I, Tangen C, Tolcher A, et al. Association of African American ethnic background with survival in men with metastatic prostate cancer. J Natl Cancer Inst 2001;93:219–275. 18. Powell IJ, Dey J, Dudley A, et al. Disease-free survival difference between African Americans and Whites after radical prostatectomy for local prostate cancer: a multivariable analysis. Urology 2002;59:907–912.

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19. Bianco FJ, Wood DP, Grignon DJ, Sakr WA, Pontes JE, Powell IJ. Prostate cancer stage shift has eliminated the gap in disease free survival in Black and White American men after radical prostatectomy. J Urol 2002;168:479–482. 20. Paquette EL, Connelly RR, Sesterhenn IA, et al. Improvements in pathologic staging for AfricanAmerican men undergoing radical retropubic prostatectomy during the prostate speciﬁc antigen era: implications for screening a high-risk group for prostate carcinoma. Cancer 2001;92:2673. 21. Powell IJ, Heilberun LK, Sakr W, et al. The predictive value of race as a clinical prognostic factor among patients with clinically localized prostate cancer: a multivariate analysis of positive margins. Urology 1997;49:726–731. 22. Sakr WA, Grignon DJ, Powell IJ, et al. Gleason score VII prostate cancer, a heterogeneous entity? Correlation with pathologic parameters and disease-free survival. Urology 2000;56:730–734. 23. Freeman VL, Leszczak J, Cooper RS. Race and the histologic grade of prostate cancer. Prostate 1997;30:79–84. 24. Land SA, Fowler JE, Bigler SA, et al. Cause speciﬁc survival or Black and White American veterans with prostate cancer. J Urol 1998;159:295 (abstract 1137). 25. Moul JW, Sesterhenn IA, Connelly RR, et al. Prostate speciﬁc antigen values at the time of prostate cancer diagnosis in African American men. JAMA 1995;274:1277–1281. 26. Moul JW, Connelly RR, Mooneyhan RM, et al. Racial differences in tumor volume and prostate speciﬁc antigen among radical prostatectomy patients. J Urol 1999;162:394–397. 27. Fowler JE Jr, Bigler SA, Kilambi NK, Land SA. Relationships between prostate speciﬁc antigen and prostate volume in black and white men with benign prostate biopsies. Urology 1999;53:1175–1178. 28. Brawer MK, Chetner MP, Beatie J, et al. Screening for prostate carcinoma with prostate speciﬁc antigen. J Urol 1992;147:841–845. 29. Smith DS, Bullock AD, Catalona WJ. Racial differences in operating characteristics of prostate cancer screening test. J Urol 1997;158:1861–1865. 30. Powell IJ, Heilbrun L, Littrup P, et al. Outcome of African American men screened for prostate cancer, the DEED (Detroit Education and Early Detection) study. J Urol 1997;158:146–149. 31. Sakr WA, Haas GP, Cassin BF, Pontes JE, Crissman JD. The frequency of carcinoma and intraepithelial neoplasm of the prostate in young male patients. J Urol 1993;150:379–385. 32. Guileyardo JM, Johnson WD, Welsh RA, et al. Prevalence of latent prostate carcinoma in two U.S. populations. J Natl Cancer Inst 1980;65:311–316. 33. Sakr WA, Grignon DJ, Haas G, et al. Age and racial distribution of prostate intraepithelial neoplasia. Eur Urol 1996;30:138–144. 34. Billis A. Age and race distribution of high grade prostatic intraepithelial neoplasia. An autopsy study in Brazil (South America) J Urol Pathol 1996;5:175–181. 35. Whittemore AS, Keller JP, Betensky R. Low grade latent prostate cancer volume: predictor of clinical cancer incidence? J Natl Cancer Inst 1991;83:1231–1235. 36. Ross Rk, Bernstein L, Judd H, et al. Serum testosterone levels in young black and white men. J Natl Cancer Inst 1986;76:45–48. 37. Henderson BE, Bernstien L, Ross RK, et al. The early in utero estrogen and testosterone environment of blacks and whites: potential effects on male offspring. Br J Cancer 1988;57:216–218. 38. Sakr WA. High-grade prostatic intraepithelial neoplasia: additional links to a potentially more aggressive prostate cancer? J Natl Cancer Inst 1998;90:486–487. 39. Ross RK, Pike MC, Coetzee GA, et al. Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility. Cancer Res 1998;58:4497–4504. 40. Ruijter E, van de Kaa C, Miller G, Ruiter D, Debruyne F, Schalken J. Molecular genetics and epidemiology of prostate carcinoma. Endocr Rev 1999;20:22–45. 41. Reichardt JKV, Makridakis N, Henderson BE, Yu MC, Pike MC, Ross RK. Genetic variability of the human SRD5A2 gene: implication for prostate cancer risk. Cancer Res 1995;55:3973–3975. 42. Rebbeck TR, Jaffe JM, Walker AH, Wein AJ, Malkowicz SB. Modiﬁcation of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 1998;90:1225–1229. 43. Walker AH, Jaffe JM, Gunasegaram S, et al. Characterization of an allelic variant in the nifedipinespeciﬁc element of CYP3A4: ethnic distribution and implications for prostate cancer risk. Hum Mutat, Mutation in Brief #191, URL: http://journals.wiley.com/1059-7794/pdf/mutations/191.pdf/1998. 44. Paris PL, Kupelian PA, Hall JM, et al. Assoication between a CYP3A4 genetic variant and clinical presentation in African American prostate cancer patients. Cancer Epidemiol Biomarkers Prev 1998;8:901–905. 45. Powell IJ, Land SJ, Dey J, et al. CYP3A4 Genetic variant and survival analysis among a diverse population of men undergoing radical prostatectomy. J Urol 2003;169 (abstract 291):75.

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46. Makridakis NM, Ross RK, Pike MC, et al. Association of mis-sense substitution in SRD5A2 gene with prostate cancer in African American and Hispanic men in Los Angeles. USA Lancet 1999;354:975–978. 47. Jaffe JM, Malkowicz SB, Walker AH, et al. Association of SRD5A2 genotype and pathological characteristics of prostate tumors. Cancer Res 2000;60:1626–1630. 48. Hardy DO, Scher HI, Bogenreider T, et al. Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onset. J Clin Endocrinol Metab 1996;81:4400–4405. 49. Coetzee GA, Ross RK. Prostate cancer and the androgen receptor. J Natl Cancer Inst 1994;86:872–873. 50. Ross RK, Henderson BE. Do diet and androgen alter prostate cancer risk via a common etiologic pathway? J Natl Cancer Inst 1994;86:252–254. 51. Whittemore AS, Kolonel LN, Wu AH, et al. Prostate cancer in relation to diet, physical activity and body size in Blacks, Whites, and Asians in the United States and Canada. J Natl Cancer Inst 1995;87:652–661. 52. Ross RK, Henderson BE. Do diet and androgen alter prostate cancer risk via a common etiologic pathway? J Natl Cancer Inst 1994;86:252–254. 53. Giovannucci E, Rimm EB, Colditz GA, et al. A prospective study of dietary fat and risk of prostate cancer. J Natl Cancer Inst 1993;85:1571–1579.

7

Current Issues in Pathologic Evaluation Howard S. Levin

INTRODUCTION In the past two decades there has been considerable progress in understanding the genetics and biology of prostate cancer. The pathologic diagnosis of prostatic adenocarcinoma (PCA), however, is the keystone on which its further management is presently based. Although serum prostate-speciﬁc antigen (PSA) elevation often initiates the search for PCA, PSA, the ratio of free to total serum PSA, PSA density, and PSA velocity help to deﬁne the risk of PCA but are not diagnostic at any level. The diagnosis of PCA demands pathologic conﬁrmation. In cases of PCA subjected to radical prostatectomy (RP), the pathologic evaluation of specimens determines prognosis and further therapy to a substantial degree. A number of issues demand consideration in optimizing diagnosis, prognosis, and future therapy.

PREPARATION AND PROCESSING OF DIAGNOSTIC MATERIAL In the 1980s in the United States, ﬁne-needle aspiration (FNA) was brieﬂy widely performed for the diagnosis of PCA, but because of the lack of experience with prostate FNA by most American pathologists, and with the availability of inexpensive, relatively atraumatic needle biopsies via spring-loaded biopsy guns, ultrasound-guided prostatic needle biopsy (PNBX) continues to be the principal mode of diagnosis of PCA. The PNBX presently popular is 18-gage, a narrower diameter than the manual perineal and transrectal biopsies performed for over half a century. Transrectal PNBX can be performed in examining rooms, usually with topical anesthesia. Pathologists have gotten used to the small size of the biopsy. Urologists have compensated for the small size of the biopsy by obtaining multiple cores, usually in a systematized way, often allowing the pathologist to diagnose PCA in bilateral, apical, midprostatic, basilar, or transition zone locations. Currently received PNBXs generally do not have crush artifact, which was more frequently found in manual biopsies. Some urologists still do From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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not label biopsies as to right and left side or the biopsy site, but most identify the site of the biopsy. Saturation biopsies with multiple cores per site are more common, particularly from patients with persistent PSA elevation or previous high-grade prostatic intraepithelial neoplasia (PIN). The author ﬁnds identiﬁcation of the biopsy site helpful because certain locations are predisposed to cancer lookalikes (e.g., the apex may contain Cowper’s glands, the base may contain vas deferens, seminal vesicles, or paraganglia, and transition zone biopsies may contain verumontanum mucosal gland hyperplasia). These are all benign ﬁndings that may confound the diagnosis of PCA. Indicating the location of a focus of PCA may be helpful to the clinician in distinguishing carcinoma localized to one or both sides of the prostate and may be extremely helpful if a focus of atypical small acinar proliferation (ASAP) is suspicious for carcinoma. Identiﬁcation of the site offers the urologist a better target for future rebiopsies. The laboratory has the choice of the ﬁxative into which the biopsy is to be placed. Most laboratories use 10% formalin as an all-purpose ﬁxative. Although formalin is easy to prepare, the resultant ﬁxation is not always optimal. Nuclear detail may be obscured in suboptimally ﬁxed tissue, and nucleoli may be difﬁcult or impossible to identify (1). Our laboratory has used Hollande’s solution, a modiﬁed Bouin’s ﬁxative, for biopsies of most organs for more than a decade and has found the resultant ﬁxation and nuclear appearance superior to that of formalin-ﬁxed tissue. Nuclear detail is extremely helpful in the diagnosis of PCA, particularly low-volume PCA (Fig. 1). Formalin, however, is probably the best ﬁxative for molecular studies. The urologist makes the choice as to how many core PNBXs are submitted and whether the site of the biopsy is indicated. If multiple cores are submitted in one bottle, they may be individually identiﬁed by different colored inks. In this case, biopsies from two or more sites can be placed in a single block. We utilized this method for several years to reduce the number of slides and the cost to the patient. We found that when multiple cores are in one block, the technologist tended to trim one core signiﬁcantly more than the others. Kao et al. (2) developed a computer simulation of core biopsies and found that when multiple cores are embedded together it is difﬁcult to position all cores in the same plane. Thus, the cut surface of the biopsies decreases and that for optimal surface representation and cancer detection, embedding of individual cores, is appropriate (2). We no longer use color coding and put one, two, or at most three biopsies from one site in a block. In our laboratory, most biopsies are designated as to laterality and to site. Usually there are one or two cores from each of six or more sites. Laboratories have different protocols regarding the making of PNBX slides. They range from single slides with one or two sections to serial sections exhausting the tissue on multiple slides. We make a ribbon of the block with usually three or four cuts on a slide. Three consecutive slides are made; consequently, 9 or 12 sections are customarily made of each core. We do not discard tissue between sections. We stain the first and third slides with hematoxylin and eosin (H&E), leaving the second slide unstained (Fig. 2). All our slides are electrostatically charged (so-called + slides) so that the tissue adheres to the slide if we perform an immunoperoxidase stain for highmolecular-weight keratin (keratin 903, 34 BE12). Immunohistochemical stain for high-molecular-weight keratin (HMWK) demonstrates basal cells in prostate glands. Malignant glands do not contain basal cells. All benign glands, however, do not demonstrate basal cell staining. The stain must be performed with positive and negative controls to ascertain accurate staining, and all benign glands that stain may not do

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Fig. 1. Sections were obtained from a radical prostatectomy specimen shortly after it arrived in the surgical pathology laboratory. Needle biopsies were obtained via an 18-gage spring-loaded biopsy gun. Cores were immediately ﬁxed in Hollande’s solution or 10% formalin. (A) Adenocarcinoma, Gleason pattern 3, ﬁxed in Hollande’s solution. Nuclear borders are distinct, and nucleoli are prominent. H&E ×40. (B) Adenocarcinoma ﬁxed in formalin, Gleason pattern 3. Many nuclei are smudgy and opaque. Nucleoli are only focally identiﬁable. H&E ×40. (ﬁgure continues)

so in a continuous manner. HMWK staining, although not perfect, is very useful. Recently, immunohistochemical stain for p63 has demonstrated nuclear staining for basal cells (3). A cocktail composed of HMWK and p63 has proved even more efﬁcacious (4). Utilization of α-methylacl-CoA-racemase (AMACR) may prove extremely

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Fig. 1. (continued) (C) Benign prostatic glands ﬁxed in Hollande’s solution. H&E ×40. (D) Benign prostatic glands ﬁxed in 10% formalin. Nuclear structure is less well deﬁned than in the Hollande’s solution. Many nuclei in the formalin-ﬁxed specimen are completely opaque. H&E ×40.

useful for the diagnosis of PCA (5,6). It is highly sensitive, but not completely speciﬁc for this diagnosis. The laboratory procedure has to be very well thought out in every step of the preparation of microscopic sections if pathologists are to identify all PCAs and atypical foci correctly. At every step, technical problems may inhibit optimal diagnosis. If tissue is initially trimmed away, small foci of carcinoma or atypical glands may never be seen.

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Fig. 2. Prostate biopsies from individual sites demonstrate that the ﬁrst and third slides are stained with H&E and the second slide is unstained. The unstained slides are available for immunohistochemical staining. All sections are on electrostatically charged slides.

If tissue between sections is not utilized and is thrown away, atypical foci in initial sections may not be further evaluated. If no intermediate section is left unstained on charged slides, the atypical focus may not be able to be studied further. If tissue is completely exhausted on H&E uncharged slides, there will be no further tissue to evaluate. Most of the time, the middle unstained slide is not used, but when it is needed, it is invaluable. The unstained slide can also be used for H&E or other histochemical or immunohistochemical stain. If a focus that needs study occurs on the third slide, next face deeper sections can be made on charged slides. We encourage the histotechnologists in our laboratory to cut 4-µm-thick sections and to avoid overstaining.

INTERPRETATION AND REPORTING OF THE BIOPSY In cases of PCA, pathologists should use the Gleason system for diagnosis. The system encompasses five patterns, and since the Gleason score sums the primary and secondary pattern, the scores can range from 2 to 10. In general, Gleason scores range from 6 to 10 in PNBX since Gleason patterns 1 and 2 are usually found only in transurethral resection (TUR) and prostatectomy specimens. Reports of Gleason total score 2, 3, or 4 in a PNBX should be suspect, since patterns 1 and 2 do not usually occur in biopsies. I report a total Gleason score that includes the primary and secondary pattern and indicate the components of the score in a comment. Some pathologists report a Gleason total score or, for example, Gleason 4 + 3 = Gleason total

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score 7. The reason for this is because not all pathologists report Gleason score correctly, and some urologists do not understand the scoring system. If the report leaves open the question of the total score, the urologist and the pathologist should clarify it. Some pathologists will not report a score if the focus is very small. Almost invariably, however, the pattern can be discerned and should be diagnosed. If only one pattern is present, this pattern represents both primary and secondary patterns, and thus, the pattern score is doubled. Biopsies with a Gleason 4 + 3 score have a higher risk of extracapsular extension than a Gleason 3 + 3 score, and therefore, the score may influence the therapeutic decision of knowledgeable urologists and radiation oncologists. I consider 4 + 3 biopsies that are predominantly 4 as poorly differentiated and those 3 + 4 biopsies that are predominantly 3 as moderately differentiated. Urologic pathologists do not always agree on Gleason scores. General pathologists have even a lower concordance among themselves. All pathologists may be developing greater concordance, perhaps as a result of experience and training. Renshaw et al. (7) indicate improvement in Gleason grading of biopsies by a group of pathologists in cases diagnosed from 1996 to 2000 compared with 1987 to 1996. The main source of disagreement with a referee urologic pathologist was undergrading of Gleason 7 biopsies as Gleason 6. DNA ploidy studies can be performed on the PNBX. It is not clear that the ploidy result offers more information than the Gleason total score (8). Ploidy in a PCA may vary from area to area in the carcinoma, as demonstrated in RP specimens. There are a variety of methods of reporting the amount of PCA in PNBXs. The pathologist should report the amount of PCA from each designated location. This can be done by measuring and reporting the largest dimension of PCA in each piece or reporting the total percentage of PCA in the cores from a given area. In every case, the number of cores involved by PCA should be reported. Carter et al. (9) used the following criteria for prediction of signiﬁcant stage T1c PCA (>0.2 cc): 1. 2. 3. 4.

PSA density 0.15 ng/mL/g or more. Gleason score 7 or greater in the PNBX. Three or more cores involved with PCA. Fifty percent or more involvement of any core with PCA.

When pretreatment criteria suggested significant tumor in the prostatectomy specimen, insignificant tumor was present in 10 of 64 cases (16%). When pretreatment criteria suggested insignificant tumor, significant tumor was present in two of eight cases (25%) (9). Wills et al. (10), in a study of 113 patients with sextant biopsies and RP, found that the most important predictors of pathologic stage by sextant biopsy were the number of cores involved and Gleason score > 6. When biopsies had Gleason score ≤ 6, two or fewer cores involved by PCA, and PSA < 4 ng/mL, 89% were organ-confined (10). In some PNBXs, periprostatic fat is present. PCA in fat indicates the presence of extracapsular extension. Occasionally, seminal vesicle is present in a biopsy specimen, and very rarely PCA involves the biopsied seminal vesicle. This too should be reported and may inﬂuence therapy. Perineural invasion (PNI) is useful in the identiﬁcation of PCA. Occasionally, PCA is very bland looking, and the ﬁnding of PNI conﬁrms the presence of PCA. It is important that the cancer surrounds or invades the nerve and is not just in proximity to

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Fig. 3. High-grade PIN in association with Gleason pattern 3 adenocarcinoma. Carcinomatous glands are present at the left of the photomicrograph. A large gland at the right demonstrates prominent basal cells with a keratin 903 stain. Some cells within the gland demonstrate prominent nucleoli indicative of high-grade PIN. Keratin 903 ×20.

or indented by it. If larger nerves show PNI in the biopsy, it has been reported that there is a greater risk of extracapsular extension in the RP specimen (11). Neuroendocrine differentiation (NED) may be recognized, usually by the presence of cells with cytoplasmic eosinophilic granules. NED should be conﬁrmed with chromogranin or synaptophysin immunohistochemical stains and reported. Although NED was believed to have a dire prognosis at one time, this is probably not the case. Small cell carcinoma, which usually represents dedifferentiation of PCA, does have a poorer prognosis and should be reported (12,13). There are a variety of entities that histologically mimic PCA. It is important that the pathologist recognize these and not misinterpret them as PCA. The principal PCA lookalikes are as follows: PIN, adenosis, clear cell cribriform hyperplasia, complete or partial lobular atrophy, basal cell hyperplasia, sclerosing adenosis, benign seminal vesicle or vas deferens, hyperplastic mesonephric remnants, paraganglia, verumontanum mucosal gland hyperplasia, nephrogenic adenoma in the periurethral area, and ASAP. The latter are atypical glands suspicious for but not diagnostic of PCA. About 50% of patients with ASAP will subsequently be diagnosed with PCA. An important concept to have arisen in the last 30 yr is that of prostatic intraepithelial neoplasia (PIN). Previously called dysplasia and large gland atypical hyperplasia, highgrade PIN is the only precursor of PCA of which pathologists are certain. High-grade PIN (grades 2 and 3), not low-grade PIN (grade 1), is often topographically associated with the major foci of PCA (Fig. 3). The ﬁnding of high-grade PIN should stimulate further biopsies if clinically indicated. Some pathologists will serially section the block if high-grade PIN is found. Reyes and Humphrey (14) completely sectioned 60 PNBXs

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with pure high-grade PIN identiﬁed in the ﬁrst three slides and found no PCA on complete sectioning of the blocks. It is important to indicate to the urologist that high-grade PIN does not mean that the patient necessarily has PCA. Conversely, repeat biopsies will identify PCA in approx 50% of cases. Klein et al. (15). found PCA in 50% of patients with high-grade PIN at the Cleveland Clinic Foundation (CCF) within 24 mo of the original diagnosis. Weinstein and Epstein (16) found 73% of patients with high-grade PIN to have PCA concurrently or on subsequent biopsy. Wills et al. (17) found the incidence of high-grade PIN in 439 consecutive sextant biopsies to be 5.5%. Qian et al. (18) found high-grade PIN in 86% of whole-mounted radical prostatectomy cases of PCA. There was a signiﬁcant correlation of PCA volume and high-grade PIN volume within 2 mm of PCA. PIN was multifocal and located in the nontransition zones in 63% of cases or in all zones of the prostate in 36% (18). Quinn et al. (19) found high-grade PIN in all 40 cases of whole-mounted stage B PCA in RP specimens. High-grade PIN was predominantly in peripheral and posterior regions, and those cases with extensive high-grade PIN had more multifocal carcinomas (14.6/case) than those with less high-grade PIN. Most dominant nodules of PCA had intermingled high-grade PIN. High-grade PIN was next to the dominant nodule of PCA in all cases (19).

PROCESSING OF RADICAL PROSTATECTOMY SPECIMENS We began whole-mount processing of RP specimens at the CCF in 1985 and replaced this with systematic sectioning of RP specimens in 1995. Our original purpose was the diagnosis and staging of PCA. Our original whole-mount specimens were sectioned from apex to base at 5-mm levels. The apex was shaved, and the block was cut three times at different levels to evaluate marginal involvement. Originally, the bladder neck was not systematically evaluated. Sections of the base of the seminal vesicles were taken. In 1995, we began sectioning the entire prostate transversely at 3-mm intervals (Fig. 4). The apex and the bladder neck are completely sectioned perpendicular to the inked surface like a cervical cone. The 3-mm section and the section immediately craniad to the apical section are always taken, as is the most basal section of the prostate and the base of the seminal vesicles. Any gross lesion suspected of being PCA is sectioned in its entirety; if no gross suspicious lesion is present, at least alternate transverse sections of the prostate are taken for microscopic section. Instead of whole-mount sections, hemisections or quarter sections of prostate are obtained and oriented with black ink. We and others compared results of whole-mount and selective sectioning as described above, and believe they are statistically equivalent in regard to identiﬁcation of extracapsular extension (ECE) and marginal involvement. Because most ECE is posterior, posterolateral, or lateral, some pathologists prefer to submit the entire posterior portion of the RP specimen (22). Our current methodology of complete perpendicular sectioning of the apex and bladder neck are more informative compared with what we did in the past. All fresh, grossly submitted prostates are inked blue on the right and, yellow on the left and ﬁxed in formalin for at least 24 h. They are sectioned and reviewed by anatomic pathology staff members. Sections are submitted, and slides are usually back in 24 h. A template is used to ensure that all important diagnostic and prognostic features are recorded in the surgical pathology report. Tissue from RP specimens represents an important resource for molecular, genetic, and pathologic study. Care and thought should be given as to how to obtain tissue for research purposes, carefully preserving important perimeters for diagnosis and prognosis. Tissue

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Fig. 4. Complete sections of formalin-ﬁxed prostate gland cut at 3-mm intervals. Top row: bladder neck (arrow), apex (curved arrow). Bottom row: base (arrow), base of seminal vesicles and vas deferens (curved arrow).

should only be obtained for research purposes from patients who have given permission. Care must be taken to observe current HIPPA guidelines. We initially had technicians present in the operating room at the completion of an RP. The technicians made a midline anterior transverse section through the mid-prostate and obtained six or eight blind core biopsies in a cranial or caudal direction. These were immediately snap frozen. They then approximated the prostatic capsule and ﬁxed the prostate in formalin for 24 h. The prostate was then sectioned in the usual manner. Only a small percentage of core biopsies were positive for carcinoma using this protocol. Since the beginning of 2003, the prostate has been quickly retrieved from the operating room. After inking, complete transverse section of the prostate is made through the mid-prostate. Often, a ﬁrm and/or yellowtinged focus of PCA is identiﬁed. Taking care not to damage the capsule or remove the entire suspicious area, a biopsy is obtained with a dermatologic, 5-mm-diameter core biopsy apparatus. Prostatic tissue is immediately divided and snap frozen at 70–80°C; then a frozen section is performed on half of each core. This has been much more satisfactory, yielding PCA tissue in about 50% of cases. The outer surface of the prostate is then inked, pinned with the cut surface against the parafﬁn block, and ﬁxed in formalin overnight (Fig. 5). Prostates are then cut and processed in the usual manner.

REPORTING OF THE RADICAL PROSTATECTOMY SPECIMEN The most important prognostic findings in the RP specimen are the Gleason score, ECE including seminal vesicle invasion, marginal involvement, and the identification of PCA with poor prognosis (Tables 1,2 and 3) (23,24). The volume of PCA has been considered by some to be an independent prognostic indicator (25). A Gleason score of the entire tumor is given indicating component parts in the template. Instead of

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Fig. 5. (A) The tissue segment on the left is the cranial half of the prostate. Four holes indicate the sites of core biopsies, two of which contained PCA. (B) Dermatologic biopsy apparatus and four core biopsies from specimen A. (ﬁgure continues)

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Fig. 5. (continued) (C) Inked RP specimen pinned to paraffin, cut surface down, and bathed in formalin.

Table 1 Essential Elements in the Report of a Prostatic Needle Biopsy The presence and location of prostatic adenocarcinoma (PCA) Gleason score of PCA An estimate of the volume of PCA The presence of prostatic intraepithelial neoplasia in the absence of PCA The presence of atypical/suspicious glands in the absence of PCA The presence of extracapsular extension by PCA The presence of perineural invasion The identiﬁcation of PCA with poor prognosis

Table 2 Essential Elements in the Report of a Radical Prostatectomy Specimen Gleason score of PCA Marginal involvement location Extracapsular extension, including seminal vesicle location, and extent The identiﬁcation of PCA with poor prognosis

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mandating that a secondary component must be 5% or more of the tumor, we record any percentage of Gleason pattern 4 or 5 PCA and report its percentage. In cases with androgen deprivation effect and/or radiation therapy, a Gleason score is not given. The distal 3 mm of the prostate is considered the apex, and we indicate whether PCA is present in the segments. We indicate if PCA is at the apical inked margin. Particularly in radical retropubic prostatectomies (RRPs), the apex may be difﬁcult to remove with a margin. We do not routinely take a prostatic urethral margin, in contrast to patients with transitional cell carcinoma (TCC) of the bladder, in which the urethral margin is important and is sectioned. PCA does not preferably extend to the urethral margin. The bladder neck margin is separately indicated. If a so-called median lobe is present, this is removed prior to obtaining a bladder neck section. Separate sections of the “median lobe” are submitted. The “median lobe” is a hyperplastic transition zone growing in a polypoid conﬁguration. It is very unlikely to contain PCA. When the gross fresh prostate is painted, ink is applied to the bladder neck margin. If PCA is at the ink, the margin is considered positive. When the margin is negative for PCA but the bladder neck contains glandular or stromal benign prostatic hypertrophy (BPH), this is reported, because it may indicate incomplete removal of benign prostatic tissue, the presence of which may cause postprostatectomy persistence of serum PSA. Pathologists in general are not convinced that a real prostatic capsule exists. There is ﬁbromuscular tissue that extends around the prostate over about 85% of its surface in the lateral and posterior regions. The width of the capsule is not certain, and it is not present anteriorly, where ordinarily the anterior ﬁbromuscular bundle and skeletal muscle ﬁbers intersect benign prostatic glands. Fat adherent to the lateral, posterolateral, and posterior prostate helps to deﬁne the peripheral surface of the capsule. Although capsular invasion has no prognostic signiﬁcance, we determine where the PCA involves the capsule. Often ECE, also known as capsular penetration, occurs in proximity to capsular invasion. The presence and degree of capsular invasion may determine if we need additional sections to evaluate ECE. ECE is the invasion of extraprostatic tissue. This includes periprostatic ﬁbroadipose tissue, neurovascular bundles, vas deferens, and seminal vesicles. We indicate the location of ECE, and measure the extent and location of maximal ECE. Established ECE has greater prognostic signiﬁcance than focal extension (Fig. 6). Established ECE is deeper and exists over a broader surface. In the region of the base of the prostate, it is often difﬁcult to interpret the presence and extent of ECE. Each section of the prostate has inked margins. Therefore, we can identify marginal involvement of apical, anterior, lateral, posterior, posterolateral, bladder neck, and

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Fig. 6. (A) Focal capsular penetration. A single neoplastic gland (arrow) is present adjacent to a neuroganglionic segment beyond the prostatic capsule. H&E ×10. (B) Established capsular penetration. Numerous glands of prostatic adenocarcinoma surround nerve segments well beyond prostate capsule. H&E ×5.

basilar margins (Fig. 7). We record the location of inked marginal involvement and the craniad distance from the apex in mm. Marginal involvement may or may not be significant. It may represent extension of the tumor to the specimen edge over a substantial area, or it can be microfocal at one point. It may represent the urologist’s incision of the capsule, which may be deﬁned as an iatrogenic positive margin. The location and

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Fig. 7. (A) Negative margin. The inked margin is at the top of the photograph. Neoplastic glands are separated from the ink by a thin band of collagen. H&E ×10. (B) Positive margin. Numerous glands of adenocarcinoma extend to inked margin (arrow). H&E ×10.

extent of tumor at the margin play a role in determining its signiﬁcance to the urologist. Blute et al. (26) evaluated the signiﬁcance of a positive surgical margin in speciﬁc and multiple foci. Twenty-six percent of their RRP patients had positive margins. Multivariate analysis revealed that positive surgical margins were a signiﬁcant predictor of clinical and PSA failure. Five-year clinical or biochemical failure-free survival was 85% for those without a positive margin and 56% for those with a positive margin. In their study, the prostate base positive margin was the only anatomic site signiﬁcant for

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subsequent biochemical or clinical failure. Fesseha et al. (27) found that a positive apical surgical margin in the absence of other positive margins or extracapsular extension elsewhere does not confer a worse prognosis for PSA failure than in an otherwise conﬁned tumor at a mean of 39 mo after RRP. In the CCF experience of 337 patients with T1–T2 PCA operated on from 1987 to 1993, surgical margin involvement by PCA was the most important independent factor predicting relapse, followed by Gleason score and capsular penetration (28). In the CCF experience of 337 patients with T1–T2 PCA, PNI in an RP specimen by itself had no prognostic signiﬁcance. The perineural space, which is not a lymphatic, however, is a main portal of egress of PCA into periprostatic tissue (Fig. 6B). Therefore, we look for PNI histologically and for ECE in areas of PNI, and we indicate PNI in the report. The basilar surface of the prostate is the most difﬁcult to assess, because it does not have a deﬁned capsule and because the transverse sections we use for most sections are not optimal for evaluation of the superior basal surface. However, we can make good evaluations of the lateral, anterior, and posterior surfaces of the base of the prostate. In the more cranial sections of the prostate, we can view the ejaculatory duct complex well and can see if PCA involves the ducts, utricle, ﬁbrovascular tissue, or muscle of the complex. Very rarely, PCA extends to the vas and seminal vesicle via the ejaculatory duct complex. This can occur in conjunction with or in the absence of ECE. Seminal vesicle (SV) invasion is one of the unfavorable prognostic features of PCA. We examine at least one complete cross-section of SV at its base in search of SV invasion, which is deﬁned as involvement of SV smooth muscle. In general, SV invasion is secondary to PCA ECE, but it can be secondary to extension along the ejaculatory duct apparatus. Very rarely, PCA metastasizes to SV via endothelium-lined spaces. High-grade PIN is very frequently in the prostate harboring PCA. Although it has no added prognostic signiﬁcance in an RP specimen, we record its presence to stress the association of high-grade PIN and PCA and to demonstrate its various appearances to pathology residents. Neuroendocrine cells are common in benign prostatic glandular tissue. PCA may contain focal NED, which can be conﬁrmed with immunoperoxidase stain for chromogranin or synaptophysin. Although NED tends to occur in Gleason score 6 and above tumors, its effect on prognosis is not known. Small cell carcinoma, which probably represents dedifferentiation of PCA, has a prognosis that is known to be poorer than the usual PCA (12,13). We report any NED in tumor cell prostatectomy specimens. Acute and chronic inﬂammation is often present in the RP specimen. It may be associated with lobular atrophy. Pathologists and molecular biologists are beginning to study the relationship of inﬂammation, atrophy, and carcinoma (29). I believe that inﬂammation should be reported in both biopsy and RP specimens.

TRANSURETHRAL RESECTION SPECIMENS TUR specimens are much less frequent because of alternative methods for ablating prostatic tissue. However, they do occur, and pathologists should process them recognizing that the biologic behavior of PCA is related to the volume and Gleason score of the neoplasm. The UICC stages of TUR-resected PCA are T1a (5% PCA with a Gleason score of <7) and T1b (>5% PCA and/or Gleason score >7). Egevad et al. (30) found that the percentage of Gleason pattern 4 and 5 in a TUR is predictive of diseasespeciﬁc survival in patients with PCA on deferred treatment. It is therefore important

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that the percentage and Gleason score of TUR obtained PCA be reported. Murphy et al. (31) found that processing 12 g of TUR-obtained prostate identiﬁes 90% of T1a and all high-grade PCAs. We process all tissue up to 12 g in a TUR specimen. If high-grade PIN or atypical glands suspicious for carcinoma are present in the specimen, we process the entire specimen.

LYMPH NODE INVOLVEMENT When RP became a frequent operation in the mid-1980s, bilateral pelvic lymphadenectomy usually preceded it. Frozen sections were performed on the lymph nodes. In some institutions, selected lymph nodes were frozen; at the CCF, all lymph nodes were dissected and frozen. The RPs of the mid-1980s were usually performed for digitally identiﬁed PCA, and it is not surprising that with larger tumors there were more frequent lymph node metastases. With the increasing use of serum PSA as a diagnostic tool, more recently diagnosed PCAs are usually not palpable and are discovered with blind or ultrasound-guided biopsies. As tumor volume decreased, there has been a lessened incidence of lymph node metastasis. At the CCF from 1989 to 1994, in 245 patients with clinically localized PCA who underwent RP preceded by pelvic lymphadenectomy, 16 patients (6.5%) had lymph node metastases. In 179 patients with at least one of the following favorable characteristics, only 4 (2.2%) had lymph node metastases (32): 1. Nonpalpable tumor (stage T1c PCA). 2. PSA values <10 ng/mL. 3. Gleason score of 6.

With a current low incidence of lymph node metastasis compared with an approx 10% incidence a decade earlier, at present fewer pelvic lymphadenectomies are being performed, particularly in stage T1c patients with 6 or lower Gleason scores, low serum PSA, and only unilateral PCA on biopsy (32,33). At the time of RP, if a frozen section is requested on a lymphadenectomy specimen, the pathologist should inquire whether the ﬁnding of PCA will alter the surgical procedure. If so, all lymph nodes should be frozen, since small as well as large lymph nodes may contain PCA. Lymphadenectomy can be performed as a separate procedure laparoscopically, and the urologist can await the result before performing the RP. It is important to realize that pelvic lymph nodes may contain abundant adipose tissue, and it is not always easy to determine if PCA is extranodal. I recommend dissecting and processing all lymph nodes, as well as processing the remaining fat in the specimens. There are almost always additional microscopic lymph nodes in the adipose tissue specimen. It should be recognized that meticulous lymph node dissections obtain approx 20 lymph nodes per case if external and internal iliac areas are completely dissected (34). This is a considerably larger number than we presently receive from nodal dissections and samplings. Changes owing to androgen deprivation therapy may or may not be present in lymph node metastases in patients treated with neoadjuvant androgen deprivation therapy (Fig. 8). Changes owing to androgen deprivation in lymph node metastases may make the metastases more difﬁcult to recognize.

EVALUATION OF TREATED PROSTATES The more traditional nonsurgical therapies for PCA are androgen deprivation therapy (ADT) and radiation therapy (RT). More recently, cryotherapy (CT) and laser therapy

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Fig. 8. Lymph node completely replaced by metastatic adenocarcinoma. The patient received androgen deprivation therapy, but the lymph node did not show androgen deprivation effect. H&E ×10.

have been increasingly used. I have no experience with laser therapy, which ablates or vaporizes tissue, but I have seen several examples of cryotherapy, which destroys prostatic parenchyma and alters residual glands. After CT, benign glands are still recognizable as such. The presence of prostatic glands after CT indicates incomplete destruction of the gland. Malignant glands can be recognized if they are present after CT. Irradiation has been used therapeutically for PCA for many decades. Postoperative biopsies 18–24 mo after completion of RT for serum PSA elevation and/or the presence of a nodule may demonstrate persistence of PCA. PNBX will demonstrate changes to benign and/or malignant prostate glands. The benign glands may demonstrate squamous metaplasia, atrophy, or elongation and will demonstrate atypical cytologic changes. They will, however, have demonstrable basal cells on H&E and/or HMWK stains (Fig. 9). Benign glands maintain a benign lobular architecture, although there is a reduction in the number of glands. To identify malignant glands, there must be architectural changes similar to those found in unirradiated glands. Irradiated PCA glands lack basal cells and may show prominent nucleoli, cytomegaly, and nucleomegaly (Fig. 10). When ADT is added to irradiation, changes characteristic of ADT, including cytoplasmic vacuolation and reduction in nuclear size or loss of nucleoli, may be present. It must be recognized that irradiated benign glands have variable cytologic changes but lack the architectural changes of PCA and contain basal cells. In addition to nuclear atypia, radiation induces stromal ﬁbrosis and vascular hyalinization (35). It is not possible to grade irradiated PCA accurately. ADT is often given prior to RP. This makes evaluation of ECE, marginal involvement, and lymph nodes more difﬁcult. Tumor cells may show nuclear pyknosis, loss of nucleoli, cytoplasmic vacuolation, and subsequent loss of cytoplasm (36,37) (Fig. 11).

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Fig. 9. (A) Irradiated prostate gland. Although benign glands appear to have a somewhat haphazard pattern, most benign glands demonstrate recognizable basal cells. H&E ×0. (B) Keratin 903 stain demonstrating basal cells in irradiated benign prostatic tissue. Basal cells appear black. Keratin 903 stain ×20.

Malignant cells may be individual, in clusters, or in linear groups. Naked nuclei from malignant cells may be surrounded by lymphocytes. The reduction in the number of glands and nuclear changes probably account for part of the downstaging of ADTtreated patients. This, however, has not translated into improved survival. Occasionally, keratin stains help to identify individual cells as epithelial and, depending on their location, as malignant. Benign prostatic tissue also demonstrates ADT effect, with squa-

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Fig. 10. Irradiated prostate. Diffuse inﬁltration of prostatic parenchyma by adenocarcinoma. H&E ×20.

Fig. 11. Prostatic adenocarcinoma with neoadjuvant androgen deprivation therapy. Numerous carcinomatous glands are present in the photomicrograph. Other neoplastic cells exist in clusters and linear arrangements. Cytoplasmic clearing is present in some cells. H&E ×20.

mous metaplasia, lobular and acinar atrophy, prominent basal cells, basal cell hyperplasia, and edematous changes of prostatic stroma. In my opinion, it is not possible to grade ADT-treated PCA accurately, and most pathologists do not grade PCA with androgen deprivation effect. Although ADT effect reduces the incidence of high-grade

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Fig. 12. High grade PIN and adenocarcinoma. Patient treated with neoadjuvant androgen deprivation therapy. High-molecular-weight keratin stain demonstrates prominent basal cells in glands with high grade PIN. Occasional carcinomatous glands (arrows) lack basal cells. High-molecular-weight keratin stain ×20.

PIN in prostatectomy specimens, the enhancement of basal cells may dramatically identify foci of high-grade PIN (Fig. 12).

EXTRAPROSTATIC METASTASES The diagnosis of PCA in extranodal locations, particularly lymph nodes, may be suspected if the metastasis has a cribriform architecture with the characteristic nucleolation of tumor cells. Immunoperoxidase stains for PSA and/or prostatic acid phosphatase can strongly suggest the presence of PCA. It should be pointed out, however, that some nonprostatic cancers can produce PSA, but these are exceedingly rare. Clinical conﬁrmation with serum PSA studies and prostatic biopsies can conﬁrm the diagnosis of PCA. Although PCA in an extraprostatic location is not curable, the correct diagnosis eliminates therapy for other tumors and makes palliative PCA therapy available for the patient.

REFERENCES 1. Murphy WM. A better nuclear ﬁxative for diagnostic bladder and prostate biopsies. J Urol Pathol 1993;1:79–87. 2. Kao J, Upton M, Zhand P, Rosen S. Individual prostate biopsy core embedding facilitates maximal tissue representation. J Urol 2002;168:496–499. 3. Signoretti S, Waltregny D, Dilks J, et al. p63 is a prostate basal cell marker and is required for prostate development. Am J Pathol 2000;157:1769–1775. 4. Zhou M, Shah R, Shen R, Rubin MA. Basal cell cocktail (34βE12 + p63) improves the detection of prostate basal cells. Am J Surg Pathol 2003;27:365–371. 5. Beach R, Gown AM, dePeralta-Venturina MN, et al. P504S immunohistochemical detection in 405 prostate specimens including 376 18-gauge needle biopsies. Am J Surg Pathol 2002;26:1588–1596.

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6. Zhou M, Chinnaiyan AM, Kleer CG, Lucas PC, Rubin MA. Alpha-methylacyl-CoA racemase. A novel tumor marker over-expressed in several human cancers and their precursor lesions. Am J Surg Pathol 2002;26(7):926–931. 7. Renshaw AA, Schultz D, Cote K, et al. Accurate grading of prostatic adenocarcinoma in prostate needle biopsies by general pathologists. Arch Pathol Lab Med 2003;127:1007–1008. 8. Humphrey PA, Walther PJ, Currin SM, Vollmer RT. Histologic grade, DNA ploidy and intraglandular tumor extent as indicators of tumor progression of clinical stage B prostatic carcinoma. A direct comparison. Am J Surg Pathol 1991;15:1165–1170. 9. Carter HB, Sauvageot J, Walsh PC, Epstein JI. Prospective evaluation of men with T1c adenocarcinoma of the prostate. J Urol 1997;157:2206–2209. 10. Wills ML, Sauvageot J, Partin AW, Gurganus R, Epstein JI. Ability of sextant biopsies to predict prostatectomy stage. Urology 1998;51:759–764. 11. Bastacky SI, Walsh PC, Epstein JI. Relationship between perineural tumor invasion on needle biopsy and radical prostatectomy capsular penetration in clinical stage B adenocarcinoma of the prostate. Am J Surg Pathol 1993;17:336–341. 12. Ro JY, Tetu B, Ayala AG, Ordonez NG. Small-cell carcinoma of the prostate: immunohistochemical and electron microscopic studies of 18 cases. Cancer 1987;59:977–982. 13. Tetu B, Ro JY, Ayala AG, et al. Small-cell carcinoma of the prostate. Part 1: A clinicopathologic study of 20 cases. Cancer 1987;59:1803–1809. 14. Reyes AO, Humphrey PA. Diagnostic effect of complete histologic sampling of prostate needle biopsy specimens. Am J Clin Pathol 1998;109:416–422. 15. Klein EA, Levin HS, Zippe CD, Krishnamurthy V. Prostatic intraepithelial neoplasia. In: Rous SN, ed. Urology Annual 1997. Blackwell Scientiﬁc, Oxford, UK, 1997, pp. 81–93. 16. Weinstein MH, Epstein JI. Signiﬁcance of high-grade prostatic intraepithelial neoplasia on needle biopsies. Hum Pathol 1993;24:624–629. 17. Wills ML, Hamper UM, Partin AW, Epstein JI. Incidence of high-grade prostatic intraepithelial neoplasia in sextant needle biopsy specimens. Urology 1997;49:367–373. 18. Qian J, Wollan P, Bostwick DG. The extent and multicentricity of high-grade prostatic intraepithelial neoplasia in clincally localized prostatic adenocarcinoma. Hum Pathol 1997;28:143–148. 19. Quinn BD, Cho KR, Epstein JI. Relationship of severe dysplasia to stage B adenocarcinoma of the prostate. Cancer 1990;65:2328–2337. 20. Hall GS, Kramer CE, Walsh PC, Epstein JI. Evaluation of radical prostatectomy specimens: a comparative analysis of various sampling methods. Am J Surg Pathol 1992;16:315–324. 21. Klein EA, Kupelian PA, Tuason L, Levin HS. Initial dissection of the lateral fascia reduces the positive margin rate in radical prostatectomy. Urology 1998;51:766–773. 22. Sohayda C, Kupelian PA, Levin HS, Klein EA. Extent of extracapsular extension in localized prostate cancer. Urology 2000;55:382–386. 23. Epstein JI, Partin AW, Sauvageot J, Walsh PC. Prediction of progression following radical prostatectomy. A multivariate analysis of 721 men with long-term follow-up. Am J Surg Pathol 1996;20:286–292. 24. Humphrey PA, Walther PJ. Adenocarcinoma of the prostate. Part II: Tissue prognosticators. Am J Clin Pathol 1993;100:256–269. 25. Humphrey PA, Vollmer RT. Intraglandular tumor extent and prognosis in prostatic carcinoma: application of a grid method to prostatectomy specimens. Hum Pathol 1990;21:799–804. 26. Blute ML, Bostwick DG, Bergstralh EJ, et al. Anatomic site-speciﬁc positive margins in organ-conﬁned prostate cancer and its impact on outcome after radical prostatectomy. Urology 1997;50:733–739. 27. Fesseha T, Sakr W, Grignon D, Banerjee M, Wood DP Jr, Pontes JE. Prognostic implications of a positive apical margin in radical prostatectomy specimens. J Urol 1997;158:2176–2179. 28. Kupelian P, Katcher J, Levin H, Zippe C, Klein E. Correlation of clinical and pathologic factors with rising prostate-speciﬁc antigen proﬁles after radical prostatectomy alone for clinically localized prostate cancer. Urology 1996;48:249–260. 29. De Marzo AM, Marchi VL, Epstein JI, Nelson WG. Proliferative inﬂammatory atrophy of the prostate. Implications for prostatic carcinogenesis. Am J Pathol 1999;155:1985–1992. 30. Egevad L, Granfors T, Karlberg L, Bergh A, Stattin P. Percent gleason grade 4/5 as prognostic factor in prostate cancer diagnosed at transurethral resection. J Urol 2002;168:509–513. 31. Murphy WM, Dean PJ, Brasﬁeld JA, Tatum L. Incidental carcinoma of the prostate: how much sampling is adequate? Am J Surg Pathol 1986;10:130–174. 32. Campbell SC, Klein EA, Levin HS, Piedmonte MR. Open pelvic lymph node dissection for prostate cancer: a reassessment. Urology 1995;46:352–355.

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33. Bluestein DL, Bostwick DG, Bergstralh EJ, Oesterling JE. Eliminating the need for bilateral lymphadenectomy in selected patients with prostate cancer. J Urol 1994;151:1315–1320. 34. Bader P, Burkhard FC, Markwalder R, Studer UE. Is a limited lymph node dissection an adequate staging procedure for prostate cancer. J Urol 2002;168:514–518. 35. Magi-Galluzzi C, Sanderson H, Epstein JI. Atypia in nonneoplastic prostate glands after radiotherapy for prostate cancer. Duration of atypia and relation to type of radiotherapy. Am J Surg Pathol 2003;27:206–212. 36. Murphy WM, Soloway MS, Barrow S. Pathologic changes associated with androgen deprivation therapy for prostate cancer. Cancer 1991;68:821–828. 37. Smith DM, Murphy WM. Histologic changes in prostate carcinomas treated with Leuprolide (luteinizing hormone-releasing hormone effect). Distinction from poor tumor differentiation. Cancer 1994;73:1472–1477.

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Current Trends in Biopsy Techniques Joseph C. Presti, Jr.

INTRODUCTION Optimization of prostate cancer detection techniques is crucial for both medical and economic reasons. Early detection is more likely to result in curable disease. Opponents to prostate cancer screening often cite, as one of their arguments, the inefﬁciency of current detection strategies. Over the past several years, reﬁnements in prostate cancer detection have focused on modifications in prostate-specific antigen (PSA; free:total ratios, complexed levels) as well as biopsy techniques. Transperineal biopsies performed under digital guidance were the predominant method of prostate cancer detection utilized until the 1980s. When introduced in 1989, systematic sextant biopsies under transrectal ultrasound guidance revolutionized our ability to detect prostate cancer (1). The pivotal work of Hodge et al. (1) resulted in a safe and rapid means to sample the prostate better. As originally described, systematic sextant biopsies are usually performed in the parasagittal plane halfway between the lateral border and midline of the prostate on both right and left sides from the base, mid-gland, and apex (Fig. 1). Derivation of the sextant template was random yet did provide a symmetric approach to sampling the prostate. Surprisingly, little was done regarding the reﬁnement of this technique until in an editorial in 1995, Stamey suggested moving the biopsies more laterally to sample the anterior horns of peripheral zone better (Fig. 2) (2). This recommendation was supported by careful analyses of radical prostatectomy specimens, which helped to characterize better the zonal anatomy of the prostate as well as the origin of prostate cancers (3). It was clear that most prostate cancers (approx 80%) originated in the peripheral zone, and thus some investigators began exploring alternative systematic biopsy schemes to sample the peripheral zone more extensively and thus improve cancer detection rates. As with any situation that involves sampling, the possibility of sampling error exists. This notion was supported in prostate biopsy series by a study demonstrating an inverse relationship between prostate gland size and cancer detection rates as determined by sextant biopsies (Fig. 3) (4). It is now recognized that sextant biopsies could miss up to From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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Fig. 1. (A) Standard sextant biopsy in the coronal plane showing apex, mid and base biopsies. (B) Standard sextant biopsy in cross-sectional plane at level of mid-gland showing needle placement halfway between the midline and the lateral edge of the prostate.

30% of cancers (5,6). The notion of sampling error has been further supported by the novel study of Levine et al. (7). In this study two consecutive sets of sextant biopsies of the prostate in a single ofﬁce visit in 137 consecutive patients were performed. A total of 43 cancers were detected in the entire study population (31% cancer detection rate). Using the ﬁrst sextant biopsy set as the reference set, 30 cancers were detected (70% of all cancers), so the second biopsy set increased the detection rate by 30%. However, if the second biopsy set was used as the reference, 40 cancers were detected (93% of all

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Fig. 2. Needle cores are directed more laterally to sample better the anterior horn of the peripheral zone (solid arrows) compared with standard sextant needle cores (dashed arrows).

Fig. 3. Cancer detection rates as determined by sextant biopsies in a referral-based population are inversely related to prostate size.

cancers), whereas the ﬁrst biopsy set would have only increased the detection rate by 7%. Owing to the recognition that sextant biopsies have a high false-negative rate and that more extended biopsy schemes result in higher cancer detection rates, most urologists now obtain more than six cores when performing prostate biopsies. A recent survey demonstrated that only 17% of urologists perform a sextant biopsy scheme (8). The rationale for this approach will now be brieﬂy reviewed.

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Fig. 4. Five-region biopsy scheme, including a total of 13 cores from the standard sextant (regions 2 and 4), the lateral aspect of the gland (regions 1 and 5), and the midline (region 3).

EVOLUTION OF THE EXTENDED BIOPSY SCHEMES FOR INITIAL BIOPSY PATIENTS One of the ﬁrst studies to assess the utility of extended peripheral zone biopsy schemes, came from Eskew et al. (9), who reported on their ﬁve-region biopsy scheme (Fig. 4). The ﬁve regions included the standard sextant biopsy regimen obtained halfway between the lateral border and midline of the prostate on both right and left sides (regions 2 and 4); an additional two biopsies were obtained from each lateral aspect of the prostate (regions 1 and 5) and three biopsies from the midline at the apex, mid-gland, and base (region 3). Of the 119 patients, 48 (40%) had cancer on the biopsy, of which 17 (35% of cancers detected) were only detected in regions 1, 3, and 5. Of note, only two cancers were detected solely by the three centrally placed biopsies of region 3. With respect to complications, these investigators reported an 80% incidence of gross hematuria, which they attributed to the region 3 biopsies that probably penetrated the urethra. The above work prompted us to investigate the utility of adding four lateral biopsies of the peripheral zone to the routine sextant biopsy regimen (10-core biopsy scheme) (10). Since the midline biopsies, as described above, had a very low unique cancer detection rate and resulted in a high complication rate, they were deleted from our biopsy template (Fig. 5). We completed a prospective evaluation of 483 consecutive patients who had not been previously biopsied and were referred for an abnormal

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Fig. 5. Ten-core biopsy scheme consisting of standard sextant and laterally directed cores at mid and base.

digital rectal exam or an elevated PSA. All identified hypoechoic lesions were first biopsied prior to obtaining systematic biopsies. Sextant biopsies were obtained in the midlobar parasagittal plane, halfway between the lateral edge and midline of the prostate gland, at the base, midgland, and apex. The lateral biopsies were performed by positioning the probe just medial to the lateral edge of the prostate at the mid and base portions of the gland. Patients with prostate sizes exceeding 50 cc also underwent systematic sextant anteriorly directed biopsies in the midlobar parasagittal plane at the apex, mid, and base. The needle was advanced to within 1.5 cm of the anterior prostate capsule prior to ﬁring the biopsy gun. Forty-two percent of the patients had cancer on biopsy (202/483). Routine sextant biopsies detected 161 cancers (80% of all cancers detected) whereas the combination of sextant and lateral biopsies, for a total of 10 peripheral zone biopsies, detected 194 cancers (96% of all cancers detected). The eight missed cancers were detected by the lesion-directed (n = 5) or the anteriorly directed biopsies in glands >50 cc (n = 3). We noted several important results from this study: 1. Traditional sextant biopsies may miss over 20% of cancers. 2. A lateral sextant regimen (apex, lateral mid, lateral base) outperforms the traditional midlobar sextant regimen (89% vs 80%, respectively; p = 0.027). 3. Regardless of the number of systematic biopsies performed (6 vs 8 vs 10), variations in cancer detection rates were most pronounced in patients with PSA levels <10 ng/mL or

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Fig. 6. Eleven-core biopsy scheme. Two lighter sites are transition zone biopsies.

in patients with prostate sizes ≥ 50 cc, reﬂecting the importance of sampling as patients with lower PSA levels or larger prostates more commonly may have smaller cancer volumes per unit of prostate tissue. 4. Anteriorly directed biopsies rarely uniquely identify cancers in men undergoing initial biopsies with an extended peripheral zone scheme. 5. When performed in conjunction with extended peripheral zone biopsy schemes, lesiondirected biopsies provide little unique cancer identiﬁcation. 6. When comparing the detection rates of the ﬁve systematic peripheral zone regions in the 10-biopsy scheme, the midlobar base region demonstrated the lowest detection rate as well as the lowest unique cancer detection rate. From the latter observation we felt that the midlobar base biopsy could be omitted from the systematic biopsy scheme. The low yield from this site might be because this biopsy site may, in part, be sampling the central zone, where the incidence of cancer is low.

Babaian et al. (11) evaluated an 11-core biopsy strategy in 362 patients. Of note, only 85 of these patients (23%) were ﬁrst-time biopsy patients. The biopsy scheme included the standard sextant along with bilateral anterior horn biopsies, bilateral transition zone biopsies, and a midline biopsy (Fig. 6). The detection rate for patients undergoing initial biopsy was 34% (29 of 85), and nine cancers were uniquely identiﬁed by nonsextant sites (31% increase in cancer detection rate). Of the nonsextant, uniquely identiﬁed cancers, seven were identiﬁed by the anterior horn biopsies and two by the transition zone biopsy.

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Fig. 7. Twelve-core biopsy scheme.

Gore et al. (12) evaluated a 12-core biopsy scheme in 396 patients. A standard sextant scheme was combined with a laterally directed sextant scheme at the apex, mid, and base bilaterally (Fig. 7). This series included 264 (67%) ﬁrst-time biopsy patients, and the cancer detection rate in this subgroup was 42%. Standard sextant biopsies would have detected only 71% of the cancers in this group. The lateral sextant biopsy scheme along with the apical and base biopsies from the standard sextant scheme detected all the cancers in this subgroup. All of the above studies were single-site, academic center experiences. Recently we reported on a retrospective series of 2299 patients who had undergone a 12-core systematic biopsy scheme (similar to what is depicted in Fig. 7) by 167 community-based urologists (13). All patients were ﬁrst-time biopsy patients, and the overall cancer detection rate was 44%. This large series demonstrated the reproducibility of extended biopsy schemes in the hands of practicing urologists, and it is interesting to note that the overall detection rates were essentially identical to those demonstrated by several of the aforementioned studies. It is obvious that detection rates in referral-based populations (patients referred for an abnormal digital rectal examination or an elevated PSA level) will vary as a function of the patient population and this large series enabled analyses that could be stratiﬁed for age and PSA. Table 1 demonstrates the detection rates as a function of age. Note that the detection rate increases with increasing age; however, also note that the percentage of patients with high-grade cancer on the biopsy (presence of grade 4 or 5) also increases with increasing age. Similar observations are

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Presti Jr. Table 1 Age-Stratiﬁed Detection Rates

Age

No. of patients

No. of cancers

Detection rate (%)

% with Grade 4 or 5

516 338 465 441 332 207

171 133 211 214 177 114

33 39 45 49 53 55

46 56 62 63 68 81

≤59 60–64 65–69 70–74 75–79 ≥80

Table 2 PSA-Stratiﬁed Detection Rates PSA (ng/mL) <2 2–4 4.1–7 7.1–10 10.1–20 >20

No. of patients

No. of cancers

Detection rate (%)

% with Grade 4 or 5

86 145 800 313 227 112

16 50 350 157 110 76

19 35 44 50 49 68

36 36 59 64 72 80

Table 3 Site-Speciﬁc Overall and Unique Cancer Detection Rates in Multipractice Initial Biopsy Study (N = 2299) Site Apex Mid Base Lateral apex Lateral mid Lateral base

Overall detection rate (%)

Unique detection rate (%)

50 48 42 52 54 49

5.8 3.1 4.2 7.0 5.6 3.7

seen when the data are stratiﬁed for PSA (Table 2). Increasing PSA levels are associated with higher detection rates as well as a higher percentage of patients harboring high-grade cancer. Table 3 shows the overall and unique cancer detection rates for each of the speciﬁc biopsy sites in the 12-core biopsy scheme. In general, the lowest yield comes from the midlobar mid and midlobar base biopsy from the standard sextant scheme. When various biopsy schemes were retrospectively simulated and then compared with the gold-standard 12-biopsy scheme (assuming it detects 100% of the cancers in the population), the following rates were observed: standard sextant had 78%; lateral apex, lateral mid, and lateral base (lateral sextant) had 83%; apex, lateral apex, lateral mid, and lateral base

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Fig. 8. Optimal 10-core scheme. Similar to 12-core scheme, deleting the biopsies at the base from the standard sextant scheme.

(optimal 8-core scheme) had 92%; and apex, mid, lateral apex, lateral mid, and lateral base (optimal 10-core scheme) had 96%. We thus feel that the optimal biopsy scheme for initial biopsy patients is at least a 10-core scheme, as shown in Fig. 8.

REPEAT BIOPSY STRATEGIES Patients who have undergone a negative prostate biopsy often return to the ofﬁce for further evaluation because of a persistently elevated or rising PSA or change in the digital rectal examination. We will next focus our discussion on identifying appropriate strategies for patients undergoing repeat biopsy. In the previously mentioned study of Babaian et al. (11), 81 of 277 patients (29%) with a prior negative biopsy were found to have cancer. It should be noted that sextant sites identiﬁed 54 (67%) cancers in this series and uniquely identiﬁed cancers in 20 (25%). Nonsextant sites uniquely identiﬁed 27 cancers (33%). The anterior horn sites uniquely identiﬁed 15, the transition zone sites uniquely identiﬁed 9, and the midline sites uniquely identiﬁed 2. One patient had multiple alternate sites positive. Some investigators have advocated more aggressive biopsy schemes in patients undergoing repeat biopsy. The largest of such series analyzed 224 men who underwent “saturation” prostate biopsies (14). It must be noted that these biopsies are performed under anesthesia as an outpatient procedure. The mean number of cores obtained was 23 (range, 14–45). Indications for repeat biopsy included elevated PSA in 108, abnormal

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digitial rectal exam and elevated PSA in 27, abnormal digital rectal examination alone in 4, high-grade prostatic intraepithelial neoplasia in 64, and atypia in 21. Cancer was detected in 77 of 224 patients (34%). Complications occurred in 27 patients (12%) and included sepsis in 1, hematuria requiring hospitalization in 12, and urinary retention in 10. This study did not provide information regarding positive biopsy site identiﬁcation; thus statements regarding the utility of such approaches seem premature. A smaller series advocating “saturation” biopsies assessed 57 patients undergoing repeat biopsy (15). An average of 22.5 cores (range, 15–31) taken from six sagittal regions were obtained under intravenous sedation. High-grade prostatic intraepithelial neoplasia or atypia was the indication for repeat biopsy in 18 (32%). Cancer was found in 17 patients (30%), and complications occurred in 7 (12%, urinary retention in 6, rectal bleeding in 1). Individual core biopsy results were not reported; however, only one cancer was uniquely identiﬁed by a transition zone biopsy. Another approach similar to saturation biopsy techniques has used a transperineal template to sample the prostate better. In this series, 88 men had a mean of 15.1 cores taken, and cancer was identiﬁed in 38 (43%) (16). High-grade prostatic intraepithelial neoplasia or atypia was the indication for repeat biopsy in 12 (14%). All procedures were performed on an outpatient basis using general or regional anesthesia. Although this study suggested the zone of origin for the cancers (peripheral or transition) based on the speciﬁc sector of the core on the grid, such assumptions might be ﬂawed owing to variation in prostate sizes and shapes as well as the anatomic boundaries of the peripheral and transition zones. (The anterior horn of the peripheral zone extends anteriorly in the lateral aspect of the mid and base of the gland, whereas essentially the entire apex is comprised of the peripheral zone.) The above studies, while reporting on patients undergoing repeat biopsy, did not in our minds clarify the optimal biopsy scheme for patients undergoing repeat biopsy. Such a scheme should be an ofﬁce-based approach, not utilizing intravenous sedation or general anesthesia. In order to deﬁne such a scheme, site-speciﬁc cores needed to be individually labeled, so as to identify both overall and unique cancer detection rates for a speciﬁc site. In addition, since the presence of high-grade prostatic intraepithelial neoplasia or atypia might inﬂuence cancer detection rates, it seemed necessary to exclude such “high-risk” patients from a repeat biopsy cohort. We recently reported on our experience at Stanford with 185 patients who had previously undergone a negative biopsy (17). All patients underwent a 10-core systematic biopsy scheme (Fig. 5). A subset of 111 patients underwent six additional biopsies directed anteriorly at the apex, mid, and base of the gland. None of these patients had high-grade prostatic intraepithelial neoplasia or atypia on the previous biopsy, and all procedures were performed in the ofﬁce with intrarectal lidocaine gel alone. Cancer was detected in 67 patients (36%). Site-speciﬁc detection rates are shown in Table 4. The important point about this study was that the highest overall and unique cancer detection rates were seen in the apical and laterally directed biopsies. In addition, the anteriorly directed biopsies had a very low unique cancer detection rate. This suggests that most patients who undergo repeat biopsy do not need anteriorly directed biopsies to sample the transition zone as long as extended peripheral zone sampling is utilized. An important caveat to this conclusion is that the anteriorly directed biopsies tend to be the most painful to the patient and thus, since their unique yield is low, their utility is limited. More recently we updated our repeat biopsy study population and have reported on 218 patients undergoing our 10-core systematic biopsy scheme (18). A subset of 139

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Table 4 Site-Speciﬁc Overall and Unique Cancer Detection Rates in Stanford Repeat Biopsy Study (N = 185) Site

Overall detection rate (%)

Unique detection rate (%)

46 36 27 37 43 31 18 15

13.4 4.5 1.5 7.4 13.4 2.6 0 2.6

Apex Mid Base Lateral mid Lateral base Anterior apex Anterior mid Anterior base

Table 5 Overall and Unique Site-Speciﬁc Cancer Detection Rates by Type of Prior Negative Biopsy (N = 218)a Overall detection rate (%) Site Apex Mid Base Lateral mid Lateral base Six anterior biopsies a

Unique detection rate (%)

Prior sextant

Prior extended

Prior sextant

Prior extended

49 41 32 51 56 32

56 17 22 0 28 33

6.8 0 1.7 6.8 13.6 3.4

27.8 5.6 5.6 0 11.1 5.6

Anterior biopsies include anterior apex, anterior mid, and anterior base sites.

underwent six additional anteriorly directed biopsies. None of these patients had highgrade prostatic intraepithelial neoplasia or atypia on the previous biopsy, and all procedures were performed in the ofﬁce with intrarectal lidocaine jelly alone. Clinicopathologic features of patients with cancer on the biopsy were compared as a function of type of prior negative biopsy. A total of 77 of 218 (35%) patients had cancer on repeat biopsy. Cancer detection rates were higher and trended toward signiﬁcance in patients who had undergone a prior sextant biopsy compared with a prior extended biopsy scheme. Of the 153 patients who had undergone a prior sextant biopsy, 59 patients (39%) had cancer on repeat biopsy. Of the 65 patients who had undergone a prior extended biopsy, 18 patients (28%) had cancer on repeat biopsy. Site-speciﬁc detection rates are shown in Table 5 stratiﬁed by the type of prior negative biopsy. In general, apical and laterally directed biopsies resulted in the highest overall and unique cancer detection rates. The yield from laterally directed biopsies decreased in patients who had undergone prior extended biopsy schemes, as these regions had been previously sampled by this negative biopsy. Also, note that unique cancer yields in the anterior biopsies (cumulative for a total of six biopsies per patient) were low regardless of type of prior biopsy scheme (3.4% for prior sextant biopsy and 5.6% for prior extended biopsy).

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LOCAL ANESTHESIA DURING PROSTATE BIOPSY As the number of biopsy cores in a systematic biopsy scheme has increased, the question of patient tolerance in the clinic setting has needed to be addressed. Two major types of local anesthesia have been described: a periprostatic block using a lidocaine injection, or intrarectal lidocaine gel. In the former, a spinal needle is placed under transrectal ultrasound guidance adjacent to the vascular pedicles at the base of the prostate, and a 1% lidocaine solution is injected. In the latter, a 2% lidocaine gel is instilled into the rectum prior to the ultrasound probe. Several investigators have reported on these methods in randomized, placebo-controlled trials. With respect to intrarectal lidocaine gel, no statistical difference was observed in pain relief between the placebo groups and the lidocaine gel groups in two studies (19,20). In one of these, 108 men were randomized in a double-blinded fashion to receive intrarectal lidocaine gel or KY jelly prior to prostate biopsy. A visual analog pain scale demonstrated no difference in pain perception between the two groups. Surprisingly, neither the number of biopsies obtained nor prostate size correlated with pain levels, however; an inverse relationship was noted between age and pain levels. A randomized, placebo-controlled study using a lidocaine block demonstrated a signiﬁcant reduction in pain in the patients receiving lidocaine (21). A randomized trial between intrarectal lidocaine gel and a lidocaine block has been completed, and superior pain relief was reported in the patients receiving the lidocaine block compared with the group receiving intrarectal lidocaine gel (22). In this study, 150 men were randomized, and a visual analog pain scale was utilized. Pain was signiﬁcantly lower in the group receiving the lidocaine block compared with the intrarectal lidocaine gel group.

CONCLUSIONS Our work, along with the work of other investigators, suggests that a 10–12-core scheme is optimal in most initial and repeat biopsy patients. These biopsy schemes should be heavily weighted toward the lateral aspect and the apex of the prostate to maximize peripheral zone sampling. Such schemes can be performed in the ofﬁce, are well tolerated without intravenous sedation, and result in high yields for cancer detection. Lidocaine blocks of the prostate signiﬁcantly increase the tolerance of the biopsy procedure.

REFERENCES 1. Hodge KK, McNeal JE, Terris MK, Stamey TA. Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol 1989;142:71–75. 2. Stamey TA. Making the most out of six systematic sextant biopsies. Urology 1995;45:2–12. 3. McNeal JE, Redwine EA, Freiha FS, Stamey TA. Zonal distribution of prostatic adenocarcinoma: correlation with histologic pattern and direction of spread. Am J Surg Pathol 1988;12:897–906. 4. Karakiewicz PI, Bazinet M, Aprikian AG, et al. Outcome of sextant biopsy according to gland volume. Urology 1997;49:55–59. 5. Rabbani F, Stroumbakis N, Kava BR, Cookson MS, Fair WR. Incidence and clinical signiﬁcance of false-negative sextant prostate biopsies. J Urol 1998;159:1247–1250. 6. Norberg M, Egevad L, Holmberg L, Sparén P, Norlén BJ, Busch C. The sextant protocol for ultrasound-guided core biopsies of the prostate underestimates the presence of cancer. Urology 1997;50:562–566. 7. Levine MA, Ittman M, Melamed J, Lepor H. Two consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate for the detection of prostate cancer. J Urol 1998;159:471–476. 8. Davis M, Sofer M, Kim SS, Soloway MS. The procedure of transrectal ultrasound guided biopsy of the prostate: a survey of patient preparation and biopsy technique. J Urol 2002;167:566–570.

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9. Eskew LA, Bare RL, McCullough DL. Systematic 5 region prostate biopsy is superior to sextant method for diagnosing carcinoma of the prostate. J Urol 1997;157:199–203. 10. Presti JC Jr, Chang JJ, Bhargava V, Shinohara K. The optimal systematic prostate biopsy scheme should include 8 rather than 6 biopsies: results of a prospective clinical trial. J Urol 2000;163:163–166. 11. Babaian RJ, Toi A, Kamoi K, et al. A comparative analysis of sextant and an extended 11-core multisite directed biopsy strategy. J Urol 2000;163:152–157. 12. Gore JL, Shariat SF, Miles BJ, et al. Optimal combinations of systematic sextant and laterally directed biopsies for the detection of prostate cancer. J Urol 2001;165:1554–1559. 13. Presti JC Jr, O’Dowd G, Miller MC, Mattu R, Veltri RW. Extended peripheral zone biopsy schemes increase cancer detection rates and minimize variance in prostate speciﬁc antigen and age related cancer rates: results of a community multi-practice study. J Urol 2003;169:125–129. 14. Stewart CS, Leibovich BC, Weaver AL, Lieber MM. Prostate cancer diagnosis using a saturation needle biopsy technique after previous negative sextant biosies. J Urol 2001;166:86–92. 15. Borboroglu PG, Comer SW, Riffenburgh RH, Amling CL. Extensive repeat transrectal ultrasound guided prostate biopsy in patients with previous benign sextant biopsies. J Urol 2000;163:158–162. 16. Igel TC, Knight MK, Young PR, et al. Systematic transperineal ultrasound guided template biopsy of the prostate in patients at high risk. J Urol 2001;165:1575–1579. 17. Chon CH, Lai FC, McNeal JE and Presti JC Jr. Use of extended systematic sampling in patients with a prior negative prostate needle biopsy. J Urol 2002;167:2457–2460. 18. Hong YM, Lai FC, Chon CH, McNeal JE, Presti JC Jr. Impact of prior biopsy scheme on pathologic features of cancers detected on repeat biopsies. Urol Oncol, in press. 19. Chang SS, Alberts G, Wells N, Smith JA Jr, Cookson MS. Intrarectal lidocaine during transrectal prostate biopsy: results of a prospective double-blind randomized trial. J Urol 2001;166:2178–2180. 20. Desgrandchamps F, Meria P, Irani J, Desgrippes A, Teillac P, Le Duc A. The rectal administration of lidocaine gel and tolerance of transrectal ultrasonography-guided biopsy of the prostate: a prospective randomized placebo-controlled study. BJU Int 1999;83:1007–1009. 21. Leibovici D, Zisman A, Siegel YI, Sella A, Kleinmann J, Lindner A. Local anesthesia for prostate biopsy by periprostatic lidocaine injection: a double-blind placebo controlled study. J Urol 2002;167:563–565. 22. Alavi AS, Soloway MS, Vaidya A, Lynne CM, Gheiler EL. Local anesthesia for ultrasound guided prostate biopsy: a prospective randomized trial comparing 2 methods. J Urol 2001;166:1343–1345.

II

LOCALIZED DISEASE: TREATMENT AND OUTCOMES

9

Predicting Outcomes Artiﬁcial Neural Networks and Nomograms

Audrey C. Rhee, Christopher J. Di Blasio, Daniel Cho, and Michael W. Kattan

INTRODUCTION In 2002, an estimated 189,000 new cases of prostate cancer were diagnosed, with approx 30,200 deaths related to diseases (1). Thus prostate cancer is the most common cancer and the second most common cause of cancer death in American men. The advent of prostate-speciﬁc antigen (PSA) screening has led to a stage migration, whereby most prostate cancers are discovered while the tumor is still conﬁned to the gland proper (2). Treatments for clinically localized tumors include radical prostatectomy (RP) (3–6), external-beam radiotherapy (XRT) (7,8) brachytherapy (9), and conservative management, with or without androgen-deprivation therapy (ADT) (10,11). Although randomized clinical trials are under way to compare treatment options (12), it is uncertain which treatment provides the best outcomes with respect to cancer control, as well as quality of life. The natural history of prostate cancer is generally indolent, requiring many years to elapse between its diagnosis and the development of disease-related symptoms. Therefore, a patient with prostate cancer is more likely to be affected by competing risk factors (i.e., comorbid illness) during his lifetime, and thus there is an obvious need for instruments to aid the patient and his physician in decision making when selecting a therapy for prostate cancer. Counseling patients requires making predictions. For the patient with newly diagnosed prostate cancer, the physician must consider the patient’s life expectancy, the tumor characteristics (e.g., Gleason grade, clinical stage), and the efﬁcacy of (and potential complications or side effects associated with) available treatments, as well as the probability of developing metastases or dying if treated conservatively or not at all. A clinician must be able to predict the likelihood that a particular treatment will eradicate a patient’s cancer, while at the same time considering the potential short- and longterm impacts that a treatment may have on quality of life.

From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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Fig. 1. Artiﬁcial neural network (ANN) architecture. It has p input units, r hidden units, and y output unit. W is a weight factor. The arrows indicate the direction the ﬂow of information travels. (Adapted from ref. 92.)

There are several methods for predicting outcomes. One approach, clinical judgment, requires the clinician to draw on previous experience with similar patients to predict a particular patient’s outcome following primary therapy. Although a clinician’s assessment might incorporate more factors than statistical models (13) and have the ability to recall rare and isolated events (14), mental prediction incorporates a number of biases (15,16). Clinical experts do not recall all cases equally. Thus, exceptional cases may tend to stand out and, consequently, have an inappropriately large inﬂuence on the evaluation of new cases. Additionally, clinicians tend to predict the desired outcome rather than that which might be more likely to occur (16). To obviate these limitations in human prediction, statistical models have been designed to aid both the physician and patient in the decision-making process. Artificial neural networks (ANNs) and nomograms are two examples (Figs. 1 and 2). Both of these instruments use algorithms that incorporate multiple clinical parameters (e.g., serum PSA level, clinical stage, Gleason grade[s]) to calculate the probability that a certain endpoint (e.g., serum PSA recurrence after treatment) will occur. Although these instruments are based on different statistical models, their ultimate goal is to aid the patient or physician in the decision-making process. Tables 1 through 9 outline contemporary models used for predicting various clinical outcomes related to prostate cancer. We discuss ANNs and nomograms and the manner in which both models can be applied to patients with prostate cancer.

PREDICTIVE MODEL CONSTRUCTION CONSIDERATIONS Several factors must be considered when designing predictive models. The instrument should be able to predict accurately which patients will or will not reach the clin-

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Fig. 2. Preoperative nomogram based on 983 patients treated at The Methodist Hospital, Houston, TX, for predicting prostate cancer recurrence after radical prostatectomy. (Adapted from ref. 29.)

ical endpoint (discrimination). In addition, it must incorporate parameters that are reliable and commonly used, demonstrate maximal correlation between actual and predicted values (calibration), produce consistent results when applied to different patient populations (validation), and easy to use. Additionally, prediction models must be constructed using a sufﬁcient number of patients (to avoid overﬁtting), as well as a sufﬁcient number of patients who reach the endpoint being analyzed (e.g., death from disease). Ideally, a predictive model should demonstrate generalizability. That is, when applied to heterogeneous novel populations, it should repeatedly perform with the same accuracy. Models that use small datasets, improper imputation methods (i.e., estimating missing values for a given variable), discard important predictive factors, incorporate too many (or too few) variables, and have a high frequency of missing data are generally less accurate and not generalizable (17). There are several options for dealing with missing data. First, records with missing data can simply be deleted. Although this is obviously the easier approach, it results in a suboptimal model by potentially creating bias and increasing variance, making predictions less reliable (17). It is suggested that, rather than deleting these records, data be estimated based on the descriptive statistics (mean, median, or mode) of the study group’s results. Regression models that generate the missing value by analyzing other

Table 1 Initial Prostate Evaluation, Predicting Positive Biopsy Ref.

Method

Prediction form

162

Stamey et al. (98)

Trad Stat

Risk group

Carlson et al. (100) Snow et al. (34)

Trad Stat Neural network

Probability table Not provided

Djavan et al. (91)

Neural network

Probability graphs

Eastham et al. (101)

Trad Stat

Nomogram

Variables

Accuracy

Validated

Pt age, creatinine phosphokinase, isoenzyme activity, prostatic acid phosphatase, PSA Pt age, % free PSA, PSA Pt age, change in PSA between, visits, DRE, PSA, ultrasound

AUC 0.96 SD 0.018 Not available Class. Acc 0.87 Sensitivity 0.84 Speciﬁcity 0.88 PPV 0.73 NPV 0.94 AUC 0.913

Yes (99)

4–10 ng/mL PSA, % free PSA, ratio of PSA density of transition zone, PSA velocity, free PSA, transition zone volume, total PSA, PSA density 2.5–4.0 ng/mL PSA, ratio of PSA density of transition zone, % free PSA, PSA density, prostate volume Pt age, race, serum PSA (with suspicious DRE)

Yes (100) Yes (34)

Yes (91)

AUC 0.876

AUC 0.75

Yes (101)

Abbreviations: Trad Stat, traditional statistical methods; Pt, patient; PSA, prostatic speciﬁc antigen; DRE, digital rectal exam; AUC, area under the receiver operator characteristic curve; PPV, positive predictive value; NPV, negative predictive value; Class. Acc., classiﬁcation accuracy.

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Table 2 Predicting Pathologic Stage for Clinically Localized Cancer Method

Prediction form

Narayan et al. Trad Stat (102)

Probability graph

Partin et al. (47,48)

Probability table

Ref.

Neural network

Variables

Accuracy

Validated

Biopsy-based stage, biopsy Gleason score, PSA Biopsy Gleason score, clinical stage, PSA

Not available

No

Not provided

Yes (47,48,50)

Abbreviations: Trad Stat, traditional statistical method; PSA, prostatic speciﬁc antigen.

Table 3 Predicting Speciﬁc Pathologic Features for Clinically Localized Cancer Prediction form

Ref.

Method

Epstein et al. (103)

Trad Stat Risk group

Gilliland et al. Trad Stat Risk group (104) Pisansky et al. Trad Stat Probability (105) graph Bluestein et al. Trad Stat Probability (106) graph

Variables Biopsy Gleason score, tumor length in biopsy cores, adverse pathology on biopsy, PSA density Pt age, biopsy Gleason score, PSA Biopsy Gleason score (primary grade), clinical stage, PSA Biopsy Gleason score, clinical stage, PSA

Accuracy PPV 0.95 NPV 0.65

Validated Yes, failed

AUC 0.63 No Sensitivity 0.18 Speciﬁcity 0.95 AUC 0.80 Yes (105)

AUC 0.82

Yes (106)

Abbreviations: Trad Stat, traditional statistical methods; PSA, prostatic speciﬁc antigen; AUC, area under the receiver operator characteristic curve; PPV, positive predictive value; NPV, negative predictive value.

predictors from a patient’s record can also be used; the missing value is then constructed from results of similar cases (i.e., imputation). In general, the regression model approach is more accurate than the use of descriptive statistics for imputation of missing values, as the latter method is biased when predictive factors are associated with each other (17). Multivariable models must incorporate an “appropriate” number of variables. Removing predictive factors that are not routinely measured, or that can demonstrate high variance between measurements (e.g., testosterone), will result in an instrument with greater generalizability (i.e., it can be applied to a more heterogeneous population) (17). However, removing variables that are statistically insigniﬁcant can actually harm the predictive accuracy of the model. Similar to forward selection and backward elimination (18–20), the removal of these variables can act to enhance the inﬂuence of the remaining variables artiﬁcially in the model (21). Additionally, by selecting only statistically signiﬁcant variables, conﬁdence intervals are falsely narrowed (22), pro-

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Rhee et al. Table 4 Using Pretreatment Variables to Predict PSA Recurrence After Radical Prostatectomy for Clinically Localized Cancer

Ref.

Method

Prediction form

Variables

D’Amico et al. Trad Stat Probability Biopsy Gleason score, (107) table clinical stage, PSA D’Amico et al. Trad Stat Risk group Biopsy Gleason score, (108) clinical stage, % positive biopsy cores, PSA Kattan et al. Trad Stat Nomogram Biopsy Gleason score (29) (primary and secondary grade), clinical stage, PSA Han et al. Trad Stat Probability Biopsy Gleason score, (109) table preoperative PSA, clinical stage, RP specimen Gleason score, organ conﬁnement status

Accuracy

Validated

Not available

Yes (62,107)

Class. Acc. 0.80

Yes (108)

Concordance index 0.74

Yes (29,62,64)

Not available

No

Abbreviations: Trad Stat, traditional statistical methods; PSA, prostatic speciﬁc antigen; Class. Acc., classiﬁcation accuracy; RP, radical prostatectomy.

Table 5 Using Pretreatment Variables to Predict PSA Recurrence After External Beam Radiotherapy for Clinically Localized Cancer Prediction form

Ref.

Method

D’Amico et al. (107) D’Amico et al. (28)

Trad Stat

Pisansky et al. (110) Shipley et al. (76) Kattan et al. (26)

Trad Stat

Risk group

Trad Stat

Probability table Nomogram

Trad Stat

Trad Stat

Probability table Probability graph

Variables Biopsy Gleason score, clinical stage, PSA Biopsy Gleason score, clinical stage, % positive biopsy cores, PSA Biopsy Gleason score, clinical stage, PSA Biopsy Gleason score, clinical stage, PSA Biopsy Gleason score, clinical stage, PSA, hormone therapy, radiation dose delivered

Accuracy

Validated

Not available Yes (62,107) Class. Acc. 0.80

Yes (28)

Not available Yes 110 Not available No AUC 0.76 (17)

Yes (26)

Abbreviations: Trad Stat, traditional statistical methods; PSA, prostatic speciﬁc antigen; AUC, area under the receiver operator characteristic curve; Class. Acc., classiﬁcation accuracy.

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Table 6 Using Pretreatment Variables to Predict PSA Recurrence After Brachytherapy for Clinically Localized Cancer Method

Prediction form

D’Amico et al. Trad Stat (28)

Probability graph

Ref.

Ragde et al. (77)

Neural Risk group network

Kattan et al. (58)

Trad Stat

Variables

Accuracy

Validated

Biopsy Gleason score, clinical stage, % positive biopsy cores, PSA Pt age, biopsy Gleason score, clinical stage, 45-Gy external beam radiation, PSA

Class. Acc. 0.80

Yes (28)

Nomogram Biopsy Gleason score, clinical stage, external beam radiation, PSA

Class. Acc. 0.76 Yes (77) Sensitivity 0.55 Speciﬁcity 0.90 PPV 0.76 NPV 0.82 Concordance Yes (58) index 0.61–0.64

Abbreviations: Trad Stat, traditional statistical methods; Pt, patient, PSA, prostatic speciﬁc antigen; PPV, positive predictive value; NPV, negative predictive value; Class. Acc., classiﬁcation accuracy.

Table 7 Postoperative Variables to Predict PSA Recurrence After Radical Prostatectomy Method

Prediction form

D’Amico et al. Trad Stat (111)

Probability graph

Bauer et al. (19)

Trad Stat

Risk group

Kattan et al. (30)

Trad Stat

Nomogram

Ref.

Variables

Accuracy

Pathologic stage, PSA, Not available RP specimen Gleason sum, surgical margins Organ-conﬁned, PSA, Not available race, RP specimen Gleason sum LN-positive, prostate Concordance capsule involvement, index 0.88 PSA, RP specimen Gleason sum, surgical margins, seminal vesicle invasion

Validated No

Yes, failed (19) Yes (30,63)

Abbreviations: Trad Stat, traditional statistical methods; PSA, prostatic speciﬁc antigen; RP, radical prostatectomy; LN, lymph node.

ducing an instrument that appears more accurate than it is. Conversely, considering too many variables (or too few study cases) can result in overﬁtting, whereby the model becomes too focused on the training dataset and loses its generalizability. It is suggested that no more than 1 variable for every 10 events (e.g., death from prostate cancer) be used when designing a model (23).

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Rhee et al. Table 8 Increasing PSA Predicting for Recurrence

Ref.

Method

Prediction form

Partin et al. (112)

Trad Stat

Probability graph

Pound et al. (113)

Trad Stat

Probability table

Variables

Accuracy

PSA velocity, Not available RP specimen Gleason sum, pathologic stage PSA doubling time, Not available RP specimen Gleason sum, time to biochemical recurrence

Validated No

No

Abbreviations: Trad Stat, tradition statistical methods; PSA, prostatic speciﬁc antigen; RP, radical prostatectomy.

Table 9 Predicting Survival in Men With Metastatic Prostate Cancer Ref.

Method

Prediction form

Smaletz et al. (57)

Trad Stat

Nomogram

Halabi et al. (56)

Trad Stat

Nomogram

Variables

Accuracy

Pt age, KPS, Hgb, Concordance PSA, LDH, ALK, index 0.67 albumin Visceral disease, AUC 0.68 Gleason score, performance status, baseline PSA, LDH, alkaline phosphatase, Hgb

Validated Yes (57)

Yes (56)

Abbreviations: Pt, patient; KPS, Karnofsky performance status; Hgb, hemoglobin; LDH, lactate dehydrogenase; ALK, alkaline phosphatase; AUC, area under the receiver operator characteristic curve; PSA, prostate-speciﬁc antigen; Trad Stat, traditional statistical methods.

When considering continuous variables (e.g., serum PSA), linear relationships should not be forced. If this is done, the model assumes that, for any given value on the x-axis, the effect of change in the x-axis is constant across the spectrum of x. For example, when interpreting rises in serum PSA level in a linear fashion, the model assumes that a given rise in the value represents the same impact along the spectrum of PSA values. Thus, a rise in serum PSA from 3 to 4 ng/mL would represent the same relationship as a rise from 100 to 101 ng/mL when, in fact, these incremental rises may not be of equal signiﬁcance. Predictive models can be designed to allow ﬂexibility in linear relationships by using restricted cubic splines (17). Although this is beyond the scope of this discussion, it is useful to know that the application of restricted cubic splines affords a regression model the ability to utilize nonlinear relationships. The method of counting risk factors should be avoided in a predictive model (24). By counting risk factors, it is assumed that each variable in the model carries an equal weight for determining prognosis (e.g., clinical stage and serum PSA are equally prog-

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nostic). Furthermore, this method requires that continuous variables be converted into categorical variables (e.g., a serum PSA of 4 ng/mL is placed into the <10-ng/mL category), which removes information regarding the actual value. Thus, the model essentially incorporates a risk grouping schema upon which to base predictions. Risk grouping places similar, although not identical, patients into the same category and attempts to predict an individual’s prognosis based on the behavior of the group. Although this approach attempts to identify patients with similar prognoses, risk groups are generally comprised of a heterogeneous population of patients (21). Thus, grouping patients tends to reduce the predictive accuracy of a prognostic model and provides suboptimal information when predicting outcomes for an individual (21,25–27). For example, D’Amico et al. (28) developed a risk grouping scheme to compare cancer control rates between patients with localized prostate cancer treated with RP, XRT, and brachytherapy. This approach classiﬁes patients into low-, intermediate-, and high-risk groups for disease progression based on clinical stage, biopsy Gleason sum, and serum PSA level. Low-risk patients were deﬁned as stage T1c or T2a, Gleason score 2–6 and serum PSA < 10 ng/mL. Intermediate-risk patients were deﬁned as T2b or Gleason score 7 or serum PSA 10–20 ng/mL. High-risk patients included those with T2c or Gleason score 8–10 or PSA > 20 ng/mL. Using this scheme, consider two different patients. Patient A is clinically staged as T2c with a serum PSA of 2 ng/mL and a biopsy Gleason score of 3 + 3 = 6. Patient B is also clinically staged as T2c but has a serum PSA of 28 ng/mL and a Gleason score of 4 + 4 = 8. Applying the above scheme, both patients would be classiﬁed as “high risk” (patient A because he is clinical stage T2c; patient B because of clinical stage T2c or PSA above 20 ng/mL or Gleason score of 8); however, the prognosis of each might be quite different (see section on nomograms 1 below). This demonstrates the heterogeneity produced by risk-grouping methods ultimately results in suboptimal predictions for an individual patient. When possible, data should be maintained in their most elementary form. This enables the maximal extraction of useful information without any loss of data that may be of prognostic importance. For example, using the primary and secondary Gleason grades separately is more advantageous than using the Gleason sum alone (29,30). A model for predicting outcomes should demonstrate sufﬁcient accuracy. Predictive accuracy can be measured using several methods. Discrimination refers to the ability of an instrument to separate patients with different responses (17). In other words, this term applies to the ability of a predictive model to rank correctly which patients are more likely to encounter a particular clinical outcome (e.g., PSA recurrence after RP). Discrimination can be measured in several ways, including area under the receiver operating characteristic (ROC) curve and concordance index methods. The area under the ROC curve (AUC) method requires binary outcomes for measuring discrimination. Thus patients must be delegated to one outcome group or the other (e.g., cured versus failed). This presents difﬁculty when the ROC method is applied to time-to-event data (e.g., time to disease progression), because patients with short follow-up times must be excluded from the analysis (31,32). Conversely, the concordance index (33) measures the probability that given two randomly selected patients, the patient who relapses ﬁrst had a higher probability of recurrence. This method can be applied to continuous, binary, ordinal, or time-to-event outcomes (17). The concordance index ranges from 0.5 (equivalent to a coin toss, i.e., the instrument affords no predictive value) to 1.0

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(perfect ability to predict). Unlike the ROC method, the concordance index is capable of functioning independently of the level of patient censoring and thus is ideal for analyzing time-to-event data (31). It should be noted that the concordance index and the AUC are sometimes used interchangeably, as medical professionals tend to be more familiar with the latter term. Additionally, both are measured using the same 0.5–1.0 scale and are equivalent when there is no case censoring. Just because a model is discriminating does not mean that it is entirely accurate. For example, an instrument may be perfectly able to separate patients into those likely to recur after treatment vs those unlikely to recur, but its predicted probabilities might be inaccurate (e.g., always too high). Thus, in addition to discrimination, a model’s accuracy should also be assessed. This can be performed using classiﬁcation accuracy or the means squared error techniques, as well as calibration (discussed below). The classiﬁcation accuracy method measures the proportion (%) of patients in a study group who were correctly predicted by the instrument being tested. This method requires binary outcomes (like ROC analysis). Additionally, it requires that patients with short follow-up times be censored based on the fact that they cannot be considered truly cured (34) and, at the same time, cannot be eliminated without creating bias (35). The means squared error is used for measuring the accuracy of a model that predicts continuous outcomes. For example, if an instrument were designed using pretreatment clinical parameters to predict the tumor volume of the pathologic specimen after radical prostatectomy, the model would utilize the means squared error method. However, this technique is not appropriate when predicting outcomes that are ordinal (i.e., categorical) or censored. Calibration refers to the extent of bias incorporated into a predictive model (17). That is, it assesses the difference between predicted and actual outcomes. For example, if the instrument predicts that 10% of a patient group will fail after primary therapy, and 10% of those patients do indeed fail, the instrument is perfectly calibrated for the endpoint that it is predicting in that particular subgroup of patients. Calibration is usually illustrated using graphs. For example, Fig. 3 shows the calibration plot for a pretreatment nomogram that predicts the 5-yr probability that a patient will experience PSA recurrence after primary definitive treatment of clinically localized prostate cancer with RP (29). The x-axis represents the nomogram-predicted values, and the y-axis represents the actual recurrence probabilities. The dashed line represents a reference line where an ideal nomogram would lie, and the solid line depicts the nomogram’s actual performance. Dots represent subcohorts of the dataset, with X representing the bootstrap-corrected estimate (see second paragraph below) of the nomogram’s performance and vertical bars representing 95% confidence intervals. In this example, the nomogram provides better predictions for patients at higher risk for progression as evidenced by the close approximation of the dotted and solid lines, as well as narrower confidence intervals as the progression-free probability increases along the x-axis. The ultimate test of a model’s utility is its ability to perform similarly when applied to different patient populations, or when reapplied to the same population, which is termed validation. Validation can be performed internally and externally. Internal validation refers to the testing of a model by applying it to data that are not mutually exclusive from the training dataset. Internal validation techniques include data splitting (36), cross-validation (37), bootstrapping (38,39), and jackknife (39) techniques. Data splitting involves the sequestration of a random portion of the original cohort. The

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Fig. 3. Calibration of the preoperative nomogram. Dashed line is reference line where an ideal nomogram would lie. Solid line is performance of current nomogram. Dots are subcohorts of the data set. X is bootstrap-corrected estimate of nomogram performance. Vertical bars are 95% conﬁdence intervals. Note the wider conﬁdence intervals at lower predicted probabilities of recurrence. (Adapted from ref. 29.)

sequestered group is used for validation purposes, and the remainder is used as the training dataset (i.e., used to build or to train the model). Cross-validation, on the other hand, involves repeatedly data splitting the cohort and reapplying the instrument. Sufﬁcient cross-validation techniques may require over 200 data-splitting cycles to obtain accurate performance estimates (37). Although both techniques result in a high variance in the model’s prediction accuracy, the data-splitting technique has less variance because only a single “split” is considered, and measurements of accuracy can vary widely among splits (17). Conversely, cross-validation considers a multitude of splits and tends to produce more reliable estimates. Bootstrapping (37–39) involves removing a small random sample of patients from the cohort while the remaining patients are analyzed as the actual results. The sample of patients removed is then applied to the model to generate the predicted results. Predicted and actual results are compared, and the process is repeated several hundred times to generate a coefﬁcient that represents a measure of predictive accuracy. The jackknife method (39) is similar to the bootstrap method but, instead, sequentially removes one patient (rather than a sample) at a time. This patient’s predicted outcome is then compared with his actual outcome to assess model accuracy. This process is repeated for each patient, eventually resulting in an overall measure of the instrument’s predictive accuracy. Ideally, the ability of a model to predict outcomes accurately should also be assessed using external validation. This process applies the instrument to independent datasets that were uninvolved in the training of the model. The result is an unbiased assessment of the tool’s predictive accuracy (17). Perhaps most importantly, a predictive instrument should be comprehensible, userfriendly (especially for nonstatisticians), and applicable in different settings. As some models (especially nomograms) can be tedious to use in paper format, several software

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packages have been developed for web-based or ofﬂine use with personal digital assistants (PDAs) or personal computers (PCs). This format is more easily implemented in the home or ofﬁce setting, allowing patients and/or physicians to generate predicted probabilities using speciﬁc clinical parameters. For instance, Brainmaker (California Scientiﬁc Software, Nevada City, CA) and Matlab (ScienceOps, Lynnwood, WA) offer commercial ANN software packages. Similarly, several nomograms are available for free access and download at www.nomograms.org.

ARTIFICIAL NEURAL NETWORKS ANNs are nonlinear mathematical models used to predict outcomes based on multiple predictor variables (40,41). In essence, the structure and function of ANNs is derived from the neuronal organization of the human brain. ANNs consist of nodes that act like neurons, with each input node representing a particular clinical parameter or variable (e.g., serum PSA). Nodes are connected to each other through signal pathways, with each pathway assigning a certain “weight” (i.e., coefﬁcient) to the node value that represents its prognostic signiﬁcance (42). Typically, an ANN consists of three layers of nodes: input, hidden, and output. To illustrate the ANN structure, the multilayer perceptron (MLP) model will be discussed (Fig. 1) (43). Information proceeds unidirectionally from the input layer, through the hidden layer(s), and to the output layer. There are no lateral connections between nodes within the same layer. Ultimately, a predicted outcome is generated from the output layer, known as the ANN output. This information ﬂow is referred to as a feedforward ANN. The input layer represents the ﬁrst layer of the ANN. An input node represents a single variable being included in the model (e.g., serum PSA). Thus, the input layer consists of multiple nodes, each representing a separate clinical variable. Based on the assumption that most clinical parameters do not function in a linear fashion, the interlayer pathways connecting nodes delegate a certain weight to each node based on the ANN’s assessment of the prognostic signiﬁcance of the variables. Thus nodes in the second, or hidden layer(s), receive weighted information from the input layer that can be excitatory or inhibitory in nature (like a positive or negative coefﬁcient in regression analysis), depending on the relationship between the variable and the outcome. The node processes all incoming signals using equations that calculate the total sum (excitatory plus inhibitory) of the weighted input. This sum is added to a bias term (see below), which acts to adjust for error within the equation. Similar to a neuron, the net sum of the input data is passed on to the next layer of nodes. Note that whereas more complex ANNs generally involve multiple layers of hidden nodes, in this simpliﬁed example, the third (or last) layer represents the output layer. Nodes in the output layer receive signals from the hidden layer nodes and repeat the summation process (as described above), eventually generating an ANN output, which represents the predicted probability of a particular outcome. Developing an ANN generally involves three stages: training, cross-validation, and external validation. ANNs are “trainable” models. In other words, their performance is trained by the dataset used to build them, and they continually “learn” associations between variables and outcomes until their accuracy meets sufﬁcient standards (as deﬁned by the ANN engineer or clinician). For example, in the ﬁrst phase of ANN learning, internodal pathways are assigned random arbitrary weights (43). A training

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dataset, which consists of a patient cohort with known outcomes, is then applied to the ANN and the predicted output is compared with the actual outcomes. The error, or difference between predicted and actual values, is used to generate a bias term, which is incorporated into a pathway’s weighting equation for a particular node. In this manner, referred to as back-propagation (44), different nodes (i.e., clinical parameters) are assigned different weights that more accurately represent the prognostic signiﬁcance of that particular variable. This process is repeated many times, each time molding the weights of the clinical parameters to produce a predicted output that more closely approximates the actual outcome. Throughout the training process, the ANN is subjected to intermittent testing with cross-validation. During the cross-validation phases, the “learning” ability of the ANN is arrested such that it will not back-propagate any new findings or adjust node weights during this process. If, upon successive cross-validations, the difference between predicted and actual outcomes (i.e., error) becomes smaller, the ANN is probably still capable of further training. Thus, its “learning” ability is reactivated, and the training process continues. If, however, the cross-validation reveals a sharp rise in the error, it is likely that the ANN has been overtrained, which is analogous to overfitting a statistical model (43). That is, it has become so familiar with the training dataset that it has begun to memorize intricacies of the data. In this way, the ANN is perfectly able to predict outcomes for the training dataset, but when it is applied to new data (e.g., during external validation), it does not produce accurate predictions. When the instrument is no longer applicable to heterogeneous populations with similar accuracy, it has lost its generalizability (43). Thus, cross-validation is used to gauge the progress of ANN training. When the error between predicted and actual outcomes is acceptable on repeated cross-validation, further analysis with independent datasets (i.e., external validation) can be performed to obtain an unbiased assessment of the ANN’s performance. With this, the accuracy (e.g., AUC) of the ANN can be measured (41).

Partin Tables Using multinomial log-linear regression analysis (45,46), Partin et al. designed (47) and updated (48) an ANN to predict the pathologic stage of the RP specimen before surgery, based on an earlier model that used logistic regression (Table 10) (49). Although the Partin tables are commonly referred to as nomograms, they are actually derived from ANNs. The 1997 version of the Partin tables (47) was based on 4133 men with clinically localized prostate cancer treated at three academic institutions. The instrument was used to predict simultaneously the likelihood of organ-conﬁned disease, isolated extracapsular extension, seminal vesicle involvement, or pelvic lymph node involvement. Predictor variables included the clinical stage, pretreatment serum PSA levels (0.0–4.0, 4.1–10.0, 10.1–20.0, or >20.0 ng/mL), and biopsy-derived Gleason sum. When the Partin ANN was subjected to bootstrap analysis for validation with 1000 samples, it demonstrated the predicted probability of a particular pathologic stage 72.4% of the time to within 10% of the observed probabilities (organ-conﬁned disease, 67.3%; extracapsular extension, 59.6%; seminal vesicle involvement, 79.6%; lymph node involvement, 82.9%). This instrument was externally validated with area under the ROC curve (AUC) analysis using an independent dataset of 2475 men treated at the Mayo Clinic (50). Blute et al. (50) validated the 1997 Partin tables demonstrating an AUC of 0.76 (vs

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approx 0.73 in the Partin series) for predicting the pathologic stage in patients with organ-conﬁned disease and 0.84 (vs approx 0.82 in the Partin series) in patients with node-positive disease (50). Calibration plots for the validation dataset demonstrated that the Partin tables were best calibrated for predicting the probability of seminal vesicle invasion but were less accurate for predicting nodal status and the probability of organ-conﬁned disease. Because of the stage migration of prostate cancer that has occurred since the advent of PSA screening, clinical parameters have undergone a shift, with more men presenting with clinical stage T1c, Gleason sums of 5–6, and serum PSA levels < 10 ng/mL (48). To incorporate this demographic change, an updated version of the Partin tables has been published that reapplies the instrument to a contemporary group of patients (48). This instrument, also based on multinomial log-linear regression, was applied to 5079 men treated with RP between 1994 and 2000 at the Johns Hopkins Hospital. This instrument also utilized the pretreatment serum PSA level (1.0–2.5, 2.6–4.0, 4.1–6.0, 6.1–10.0, or >10.0 ng/mL), clinical stage (51), and Gleason sum to predict simultaneously the probability of organ-conﬁned disease, extracapsular extension, seminal vesicle invasion, and lymph node involvement. After training, the model was subjected to bootstrap analysis. Medians of the predicted probabilities (with 95% conﬁdence intervals) from 1000 bootstrap samples are presented in the contemporary Partin tables (Tables 10–13). The Partin tables are used by ﬁrst locating the table corresponding to the patient’s clinical stage. Next, the patient’s Gleason score is located along the top axis, labeled “Gleason Score.” The user then scrolls down in the row corresponding to the Gleason score until intercepting with the pretreatment serum PSA level. At the point of interception, several numbers (within a cell) are provided that represent the probability of different pathologic outcomes. This cell provides predicted probabilities of organ-conﬁned disease, extracapsular extension, seminal vesicle involvement, or lymph node involvement (with 95% conﬁdence intervals). For example, a man presenting with a tumor clinically staged as T2a, a pretreatment serum PSA level of 4 ng/mL, and a Gleason score of 3 + 4 = 7 has a 50% (43–57) predicted probability of having organ-conﬁned disease, 41% (35–48) of having extracapsular extension, 7% (3–12) of having seminal vesicle invasion, and 2% (0–4) of having lymph node involvement.

NOMOGRAMS Similar to ANNs, nomograms are models used to predict outcomes. In particular, they are a type of calculating chart with scales that graphically depict how several predictor variables are related to the probability that a given outcome will occur (e.g., PSA recurrence). Speciﬁcally, they are visual interpretations of the regression analysis upon which they are based. Theoretically, nomograms can be developed from other predictive models such as ANNs; however, they usually are not. Nomograms based on Cox proportional hazards regression analysis typically involve linear relationships; however, the application of restricted cubic splines (17) affords a ﬂexibility to nomograms that parallels that of ANNs and allows them to analyze data in a nonlinear fashion. As mentioned above, risk-grouping stratiﬁcation techniques (e.g., clinical stage) have been used to obtain prognostic information upon which to base predictions. Although this approach is logical, it ultimately groups similar, but not identical, patients into heterogeneous groups of patients (21). This method tends to reduce the predictive accuracy of a model (21,25,26,40,52), and it has proved to be less reliable

Table 10 Clinical Stage T1c (Nonpalpable, PSA Elevated) Gleason scorea PSA range (ng/mL) 0–2.5

2.6–4.0

173

4.1–6.0

6.1–10.0

>10.0

a

Pathologic stage

2–4

5–6

3+4=7

4+3=7

8–10

Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+)

95 (89–99) 5 (1–11) — — 92 (82–98) 8 (2–18) — — 90 (78–98) 10 () — — 87 (73–97) 13 (3–27) — — 80 (61–95) 20 (5–39) — —

90 (88–93) 9 (7–12) 0 (0–1) — 84 (81–86) 15 (13–18) 1 (0–1) — 80 (78–83) 19 (16–21) 1 (0–1) 0 (0–1) 75 (72–77) 23 (21–25) 2 (2–3) 0 (0–1) 62 (58–64) 33 (30–36) 4 (3–5) 2 (1–3)

79 (74–85) 17 (13–23) 2 (1–5) 1 (0–2) 68 (62–74) 27 (22–33) 4 (2–7) 1 (0–2) 63 (58–68) 32 (27–36) 3 (2–5) 2 (1–3) 54 (49–59) 36 (32–40) 8 (6–11) 2 (1–3) 37 (32–42) 43 (38–48) 12 (9–17) 8 (5–11)

71 (62–79) 25 (18–34) 2 (1–5) 1 (0–4) 58 (48–67) 37 (29–46) 4 (1–7) 1 (0–3) 52 (43–60) 42 (35–50) 3 (1–6) 3 (1–5) 43 (35–51) 47 (40–54) 8 (4–12) 2 (1–4) 27 (21–34) 51 (44–59) 11 (6–17) 10 (5–17)

66 (54–76) 28 (20–38) 4 (1–10) 1 (0–4) 52 (41–63) 40 (31–50) 6 (3–12) 1 (0–4) 46 (36–56) 45 (36–54) 5 (3–9) 3 (1–6) 37 (28–46) 48 (39–57) 13 (8–19) 3 (1–5) 22 (16–30) 50 (42–59) 17 (10–25) 11 (5–18)

Data are medians of the predicted probabilities, with 95% conﬁdence intervals in parentheses. Reprinted with permission from Urology, Vol number 58, Partin AW, Mangold LA, Lamm DM, et al. Contemporary update of prostate cancer staging nomograms (Partin tables) for the new millenium. Elsevier, New York, 2001, pp. 843–848.

Table 11 Clinical Stage T2a (Palpable <1/2 of One Lobe) Gleason scorea PSA range (ng/mL) 0–2.5

2.6–4.0

174

4.1–6.0

6.1–10.0

>10.0

a

Pathologic stage

2–4

5–6

3+4=7

4+3=7

8–10

Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+)

91 (79–98) 9 (2–21) — — 85 (69–96) 15 (4–31) — — 81 (63–95) 19 (5–37) — — 76 (56–94) 24 (6–44) — — 65 (43–89) 35 (11–57) — —

81 (77–85) 17 (13–21) 1 (0–2) 0 (0–1) 71 (66–75) 27 (23–31) 2 (1–3) 0 (0–1) 66 (62–70) 32 (28–36) 1 (1–2) 1 (0–2) 58 (54–61) 37 (34–41) 4 (3–5) 1 (0–2) 42 (38–46) 47 (43–52) 6 (4–8) 4 (3–7)

64 (56–71) 29 (23–36) 5 (1–9) 2 (0–5) 50 (43–57) 41 (35–48) 7 (3–12) 2 (0–4) 44 (39–50) 46 (40–52) 5 (3–8) 4 (2–7) 35 (30–40) 49 (43–54) 13 (9–18) 3 (2–6) 20 (17–24) 49 (43–55) 16 (11–22) 14 (9–21)

53 (43–63) 40 (30–49) 4 (1–9) 3 (0–8) 39 (30–48) 52 (43–61) 6 (2–12) 2 (0–6) 33 (25–41) 56 (48–64) 5 (2–8) 6 (3–11) 25 (19–32) 58 (51–66) 11 (6–17) 5 (2–8) 14 (10–18) 55 (46–64) 13 (7–20) 18 (10–27)

47 (35–59) 42 (32–53) 7 (2–16) 3 (0–9) 33 (24–44) 53 (44–63) 10 (4–18) 3 (0–8) 28 (20–37) 58 (49–66) 8 (4–13) 6 (2–12) 21 (15–28) 57 (48–65) 17 (11–26) 5 (2–10) 11 (7–15) 52 (41–62) 19 (12–29) 17 (9–29)

Data are medians of the predicted probabilities, with 95% conﬁdence intervals in parentheses. Reprinted with permission from Urology, Vol number 58, Partin AW, Mangold LA, Lamm DM, et al. Contemporary update of prostate cancer staging nomograms (Partin tables) for the new millenium. Elsevier, New York, 2001, pp. 843–848.

Table 12 Clinical Stage T2b (Palpable >1/2 of One Lobe, not on Both Lobes) Gleason scorea PSA range (ng/mL) 0–2.5

2.6–4.0

175

4.1–6.0

6.1–10.0

>10.0

a

Pathologic stage

2–4

5–6

3+4=7

4+3=7

8–10

Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+)

88 (73–97) 12 (3–27) — — 80 (61–95) 20 (5–39) — — 75 (55–93) 25 (7–45) — — 69 (47–91) 31 (9–53) — — 57 (35–86) 43 (14–65) — —

75 (69–81) 22 (17–28) 2 (0–3) 1 (0–2) 63 (57–69) 34 (28–40) 2 (1–4) 1 (0–2) 57 (52–63) 39 (33–44) 2 (1–3) 2 (1–3) 49 (43–54) 44 (39–49) 5 (3–8) 2 (1–3) 33 (28–38) 52 (46–56) 8 (5–11) 8 (5–12)

54 (46–63) 35 (28–43) 6 (2–12) 4 (0–10) 41 (33–48) 47 (40–55) 9 (4–15) 3 (0–8) 35 (29–40) 51 (44–57) 7 (4–11) 7 (4–13) 26 (22–31) 52 (46–58) 16 (10–22) 6 (4–10) 14 (11–17) 47 (40–53) 17 (12–24) 22 (15–30)

43 (33–54) 45 (35–56) 5 (1–11) 6 (0–14) 30 (22–39) 57 (47–67) 7 (3–14) 4 (0–12) 25 (18–32) 60 (50–68) 5 (3–9) 10 (5–18) 19 (14–25) 60 (52–68) 13 (7–20) 8 (5–14) 9 (6–13) 50 (40–60) 13 (8–21) 27 (16–39)

37 (26–49) 46 (35–58) 9 (2–20) 6 (0–16) 25 (17–34) 57 (46–68) 12 (5–22) 5 (0–14) 21 (14–29) 59 (49–69) 9 (4–16) 10 (4–20) 15 (10–21) 57 (48–67) 19 (11–29) 8 (4–16) 7 (4–10) 46 (36–59) 19 (12–29) 27 (14–40)

Data are medians of the predicted probabilities, with 95% conﬁdence intervals in parentheses. Reprinted with permission from Urology, Vol number 58, Partin AW, Mangold LA, Lamm DM, et al. Contemporary update of prostate cancer staging nomograms (Partin tables) for the new millenium. Elsevier, New York, 2001, pp. 843–848.

Table 13 Clinical Stage T2c (Palpable on Both Lobes) Gleason scorea PSA range (ng/mL) 0–2.5

2.6–4.0

176

4.1–6.0

6.1–10.0

>10.0

a

Pathologic stage

2–4

5–6

3+4=7

4+3=7

8–10

Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+) Organ-conﬁned Extraprostatic extension Seminal vesicle (+) Lymph node (+)

86 (71–97) 14 (3–29) — — 78 (58–94) 22 (6–42) — — 73 (52–93) 27 (7–48) — — 67 (45–91) 33 (9–55) — — 54 (32–85) 46 (15–68) — —

73 (63–81) 24 (17–33) 1 (0–4) 1 (0–4) 61 (50–70) 36 (27–45) 2 (1–5) 1 (0–4) 55 (44–64) 40 (32–50) 2 (1–4) 3 (1–7) 46 (36–56) 46 (37–55) 5 (2–9) 3 (1–6) 30 (21–38) 51 (42–60) 6 (2–12) 13 (6–22)

51 (38–63) 36 (26–48) 5 (1–13) 6 (0–18) 38 (27–50) 48 (37–59) 8 (2–17) 5 (0–15) 31 (23–41) 50 (40–60) 6 (2–11) 12 (5–23) 24 (17–32) 52 (42–61) 13 (6–23) 10 (5–18) 11 (7–17) 42 (30–55) 13 (6–24) 33 (18–49)

39 (26–54) 45 (32–59) 5 (1–12) 9 (0–26) 27 (18–40) 57 (44–70) 6 (2–16) 7 (0–21) 21 (14–31) 57 (43–68) 4 (1–10) 16 (6–32) 16 (10–24) 58 (46–69) 11 (4–21) 13 (6–25) 7 (4–12) 43 (29–59) 10 (3–20) 38 (20–58)

34 (21–48) 47 (33–61) 8 (2–19) 10 (0–27) 23 (14–34) 57 (4–70) 10 (3–22) 8 (0–22) 18 (11–28) 57 (43–70) 7 (2–15) 16 (6–33) 13 (8–20) 56 (43–69) 16 (6–29) 13 (5–26) 6 (3–10) 41 (27–57) 15 (5–28) 38 (20–59)

Data are medians of the predicted probabilities, with 95% conﬁdence intervals in parentheses. Reprinted with permission from Urology, Vol number 58, Partin AW, Mangold LA, Lamm DM, et al. Contemporary update of prostate cancer staging nomograms (Partin tables) for the new millenium. Elsevier, New York, 2001, pp. 843–848.

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Fig. 4. Prostate cancer disease states. The arrows represent transitions between states. The width of the arrow is proportional to the probability that a patient will, over time, move toward the next state (e.g., metastases) rather than toward death from another cause. (Reprinted with permission from Urology, Vol number 55, Scher HI, Heller G. Clinical states in prostate cancer: toward a dynamic model of disease progression. Elsevier, New York, 2000, p. 323.)

than nomograms (53). Patients A and B above can be used to illustrate this. Patient A (clinical stage T2c, serum PSA of 2 ng/mL, and Gleason score of 3 + 3 = 6) and patient B (clinical stage T2c, serum PSA of 28 ng/mL, and Gleason score of 4 + 4 = 8) are both classiﬁed as “high-risk” using the risk stratiﬁcation created by D’Amico et al. (28). Applying each patient’s clinical parameters to the preoperative RP nomogram (outlined below), we see that the nomogram predicts a continuous 5-yr freedom from progression of 86% (95% CI: 76–96) for patient A, and 25% (85% CI: 15–35) for patient B. Thus, it is obvious that these patients have quite different prognoses when the nomogram is used. However, risk grouping fails to identify this difference. An additional drawback to risk grouping is the psychological impact on a patient of relegation to a certain degree of risk. For example, intermediate risk is a particularly nebulous term. A patient placed in this group is either left to interpret what intermediate risk means or to accept the physician’s interpretation. Rather than relying on interpretations, nomograms provide a number (e.g., 35%) that represents the probability that the patient will progress within a certain amount of time. Rather than deﬁning the disease by risk grouping, viewing prostate cancer as a continuum of connected disease states, from diagnosis to death, might be more appropriate (Fig. 4) (54). Along each step of the disease pathway, nomograms can be useful for providing standardized estimates of prognosis (21) or the probability of progression to the next disease state, and they have generally been found to outperform clinical experts (14,16,55). For example, in a newly diagnosed patient, nomograms can aid in the decision about whether or not to treat, and if treatment is chosen, to identify which treatment option is best for an individual, as well as to assist in predicting outcomes for a particular treatment. For patients treated with deﬁnitive therapy, nomograms can help predict the probability that the patient will recur (biochemically, locally or with distant spread). They can assist the physician in identifying patients who may beneﬁt from adjuvant treatment, as well as allow tailoring of follow-up schedules based on the patient’s individual risk of progression (13). Furthermore, for patients demonstrating

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Fig. 5. Screenshot of personal digital assistant (PDA) application available for download at www.nomograms.org.

evidence of disease progression, nomograms can provide outcome predictions after different salvage therapies (56,57). Thus, for each clinical state of the disease pathway, the nomogram can be used to make a tailored prediction based on a patient’s speciﬁc clinical parameters. Using the design methodologies outlined here, several nomograms have been constructed that predict outcomes in patients with prostate cancer. Although many nomograms for prostate cancer exist (13), we will limit the discussion to four contemporary models that predict the continuous risk of disease progression following deﬁnitive therapy with RP (29,30), XRT (26), and brachytherapy (58). Similar models exist for metastatic hormone-refractory prostate cancer (56,57) as well as renal cell carcinoma (25) and sarcoma (52). All are available for free access and download at www.nomograms.org for PDAs (Fig. 5) (59) and PCs.

Radical Prostatectomy Since Walsh’s landmark description (60) of the local anatomy of the prostate gland in relation to its adjacent neurovascular structures, complication rates have markedly decreased, making RP the most common treatment for localized prostate cancer in men under the age of 70 (61). Owing to a lack of large randomized trials that quantify longterm survival beneﬁts of RP, Kattan et al. developed and validated (62–64) both pretreatment (29) and post-treatment (30) nomograms for predicting the continuous probability of disease progression following RP.

Pretreatment Clinical stage, biopsy Gleason score, and pretreatment serum PSA level have been shown to be prognostic factors for predicting disease progression after RP (6,29,47,49,65). These factors have been combined to predict the ﬁnal pathologic stage of the RP specimen (47–49). However, this endpoint is not necessarily associated with the risk of disease progression (66). For example, Hull et al. (65) demonstrated that 50% of patients found to have non-organ-conﬁned disease did not experience recurrence 10 yr after RP. Therefore, pathologic evidence of extraprostatic disease does not impart a deﬁnite progression of disease after deﬁnitive therapy with RP. Kattan et al. (29) devised a pretreatment nomogram that predicts the 5-yr probability of disease progression after RP. This nomogram was based on a Cox proportional haz-

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ards regression model with cubic splines that was applied to 983 patients with clinically localized prostate cancer (T1c–T3a N×M0) (51) treated with RP by a single surgeon. Predictor variables included clinical stage, biopsy-derived primary and secondary Gleason grades, and pretreatment serum PSA level. Disease progression was deﬁned as an initial PSA rise of ≥0.4 ng/mL followed by any further rise above this level, evidence of clinical recurrence (local, regional, or distant), administration of adjuvant therapy, or death from prostate cancer. In addition, patients in whom RP was aborted owing to the discovery of lymph node metastasis during pelvic lymph node dissection were considered to have failed treatment (i.e., they evidenced disease progression at the time of surgery). This nomogram is used by locating the patient’s value for each predictor variable on its respective scale, with each position on the scale corresponding to a point value found on the axis labeled “Points” (Fig. 2). Therefore, a PSA value of 10 ng/mL corresponds to approx 57 points, as determined by drawing a vertical line upward from a value of 10 on the “PSA” axis to the “Points” axis. The point values for clinical stage and Gleason grade are determined in a similar fashion. Point values for each variable are then summed to obtain a total point value. This value is plotted on the “Total Points” axis, and a vertical line is drawn downward to intersect with the axis labeled “60 month recurrence free probability,” which predicts the likelihood that a patient will remain free from disease recurrence for 5 yr after therapy. Overall progression free probability for this cohort was 73% (95% CI: 69–76%) at 5 yr and 68% (95% CI: 62–73%) at 10 yr. When validated for accuracy using a sequestered dataset, the nomogram demonstrated an AUC of 0.79 (29) and when applied to external data yielded AUCs between 0.75 (64) and 0.81 (62). Figure 3 displays the nomogram’s calibration plots, demonstrating that the nomogram is well calibrated overall, but is better for predicting outcomes for patients with a higher likelihood of disease progression (as evidenced by the overlap between dotted and solid lines).

Posttreatment In an effort to identify patients more likely to experience disease recurrence after deﬁnitive treatment with RP for localized prostate cancer, we constructed a postoperative RP nomogram (Fig. 6) (30). This instrument predicts the 7-yr probability of disease progression after RP based on 996 men with clinically localized prostate cancer (T1–T3c N×M0) (51) treated by a single surgeon. Predictor variables included pretreatment serum PSA level, primary and secondary Gleason grades of the surgical specimen, prostatic capsular invasion, surgical margin status, seminal vesical invasion, and lymph node status. Treatment failure was deﬁned as an initial PSA rise of ≥0.4 ng/mL followed by any further rise above this level, clinical evidence of disease progression (local or distant), initiation of adjuvant therapy, or death from prostate cancer. The 7-yr recurrence-free probability for the cohort was 73% (95% CI: 68–76%). Upon validation, an AUC of 0.89 (30) was demonstrated with an overall AUC of 0.80 when validated using external datasets from ﬁve separate institutions (63). Calibration plots are shown in Fig. 7.

External Beam Radiotherapy The past several decades have shown tremendous improvements in radiation techniques for treating localized prostate cancer. With the development of

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Fig. 6. Postoperative nomogram based on 996 patients treated at the Methodist Hospital, Houston, TX, for predicting prostate-specific antigen (PSA) recurrence after radical prostatectomy. For prostatic capsular invasion (Pros. Cap. Inv.), “None” refers to L0–L1, “Inv. Capsule” refers to L2, “Focal” refers to L3F, and “Established” refers to L3E. (From Kattan MW, Wheeler TM, Scardino PT. Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer. J Clin Oncol 1999;17:1499. Reprinted with permission from the American Society of Clinical Oncology.)

three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT), radiation oncologists are capable of delivering considerably higher radiation doses to the prostate gland with reduced damage to surrounding tissues (67,68). In patients seeking treatment for clinically localized prostate cancer, direct comparisons between surgical and radiation therapies are difﬁcult for several reasons. Unlike surgery, treatment with radiotherapy does not afford the removal of a specimen for analysis. Therefore, direct comparisons of pathologic stage-matched patients cannot be made between these treatment groups. Furthermore, the use of neoadjuvant hormonal deprivation therapy in combination with XRT has shown signiﬁcant survival beneﬁts for men with locally advanced prostate cancer (68). The use of neoadjuvant therapy confounds serum PSA relapse rates, rendering the accurate comparison of efﬁcacy impossible among treatment groups. Similarly, advances in the techniques used to administer XRT have improved cancer control to the point where clinical trials using traditional methods of radiotherapy may not be applicable to contemporary patients.

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Fig. 7. Calibration of the postoperative nomogram. Dashed line is reference line where an ideal nomogram would lie. Solid line is performance of current nomogram. Dots are subcohorts of the data set. X is bootstrap-corrected estimate of nomogram performance. Vertical bars are 95% conﬁdence intervals. Note the wider conﬁdence intervals at lower predicted probabilities of recurrence. (From Kattan MW, Wheeler TM, Scardino PT. Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer. J Clin Oncol 1999;17:1499. Reprinted with permission from the American Society of Clinical Oncology.)

Furthermore, a standard deﬁnition of biochemical recurrence that is applicable to both treatment arms has not yet been established. In an effort to provide a measure with which to compare treatment options and to aid in decision analysis, Kattan et al. (26) developed a pretreatment nomogram for predicting the probability of remaining free from PSA recurrence for 5 yr following deﬁnitive therapy with 3D-CRT (Fig. 8). The nomogram again utilized Cox proportional hazards regression with cubic splines and was applied to 1042 men treated with 3D-CRT at the Memorial Sloan-Kettering Cancer Center (MSKCC) between 1988 and 1998. Predictor variables included clinical stage (51), biopsy Gleason sum, pretreatment serum PSA level, receipt of neoadjuvant hormonal deprivation therapy prior to 3D-CRT, and the radiation dose delivered. Treatment failure was based on the consensus deﬁnition of the American Society for Therapeutic Radiation and Oncology (69). Here, PSA recurrence was deﬁned as three cumulative rises of serum PSA level, with the date of failure considered to be midway between the ﬁrst rise and the PSA level immediately before this rise. The Somer’s D rank correlation (17) was used to test the predictive accuracy of this nomogram, whereby a coefﬁcient of 0 represents no discriminatory ability and a value of 1 represents perfect discrimination between predicted and actual results. This coefﬁcient can be converted to a concordance index by dividing by 2 and adding to 0.5. Validation of this instrument was performed using bootstrap analysis on the MSKCC cohort, yielding a concordance index of 0.73 (Somer’s D correlation coefﬁcient of 0.46). When externally validated with a cohort of 912 men treated at the Cleveland Clinic, a concordance index of 0.76 (Somer’s D correlation coefﬁcient of 0.52) was demonstrated,

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Fig. 8. Three-dimensional conformal radiation therapy (3D-CRT) nomogram, based on 1042 patients treated at MSKCC for predicting prostate-speciﬁc antigen (PSA) recurrence after radiation therapy. (From Kattan MW, Zelefsky MJ, Kupelian PA, et al. Pretreatment nomogram for predicting the outcome of three-dimensional conformal radiotherapy in prostate cancer. J Clin Oncol 2000;18:3352. Reprinted with permission from the American Society of Clinical Oncology.)

which was signiﬁcantly superior to the best risk stratiﬁcation available (Somer’s D correlation coefﬁcient of 0.47; p = 0.0001). Nomogram calibration plots (Fig. 9) demonstrated close approximation between ideal and actual nomogram predictions, especially for patients with progression-free probabilities between 0.5 and 0.7.

Brachytherapy Traditionally, permanent implantation of 125I seeds was performed as an open surgical procedure following pelvic lymph node dissection, whereby seeds were placed into the prostate gland in a freehand fashion (70). This method demonstrated higher rates of local recurrence than expected (71), and brachytherapy fell out of favor as a treatment option for localized prostate cancer until the transperineal approach using ultrasound or ﬂuoroscopic guidance became available (72,73). This modality offers certain advantages to RP, including the use of local or regional anesthesia (as opposed to general anesthesia), as well as its performance as an outpatient procedure and shorter convalescence. Similarly, brachytherapy is administered as one procedure, compared with the

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Fig. 9. 3D-CRT nomogram calibration. Vertical axis is actual PSA recurrence-free survival at 60 mo. Dashed line represents an ideal nomogram. Solid line is current nomogram performance with 95% conﬁdence intervals. Open circle represents dataset subcohorts. X represents the bootstrap-corrected estimate of nomogram. (From Kattan MW, Zelefsky MJ, Kupelian PA, et al. Pretreatment nomogram for predicting the outcome of three-dimensional conformal radiotherapy in prostate cancer. J Clin Oncol 2000;18:3352. Reprinted with permission from the American Society of Clinical Oncology.)

multiple treatments over a number of weeks that are required for XRT. Although there have been claims that brachytherapy offers a favorable quality of life proﬁle compared with RP or XRT, these have been largely unsubstantiated (74). Because of the lack of data for identifying patients at risk for biochemical recurrence after brachytherapy, we developed a pretreatment nomogram that predicts the continuous 5-yr probability of freedom from PSA recurrence after permanent 125I seed implantation using a perineal template (Fig. 10) (58). This nomogram was developed using Cox proportional hazards regression with cubic splines to analyze a cohort of 920 men treated at MSKCC for T1–2 prostate cancer treated with primary brachytherapy without adjuvant hormonal therapy. Predictor variables included pretreatment serum PSA level, clinical stage (75), biopsy Gleason sum, and administration of XRT. Treatment failure was deﬁned as PSA recurrence in conjunction with a modiﬁed (76) version of the ASTRO criteria (69). Using this version, for patients whose PSA levels were rising at the time of last follow-up, but in whom “failure” had not yet been documented, the follow-up time was truncated just before the rise in PSA level but before the patient was rendered a failure (76). Additionally, administration of adjuvant hormonal deprivation therapy, clinical evidence of disease progression (local, regional, or distant), or death from prostate cancer, were considered treatment failures.

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Fig. 10. Nomogram for predicting 5-yr freedom from prostate-speciﬁc antigen (PSA) recurrence after permanent prostate brachytherapy without neoadjuvant androgen ablative therapy. (Reprinted with permission from Urology, Vol number 58, Kattan MW, Potters L, Blasko JC, et al. Pretreatment nomogram for predicting freedom from recurrence after permanent prostate brachytherapy in prostate cancer. Elsevier, New York, 2001, pp. 393–399.)

Using two independent datasets from separate institutions, this instrument was externally validated. Validation with 1827 men treated at the Seattle Prostate Institute demonstrated a concordance index of 0.61. Similarly, validation with 765 men treated at the Arizona Oncology Services yielded a concordance index of 0.64. These indicated that the nomogram offered discriminatory ability clearly superior to chance (p < 0.0001) but was not as predictive as the nomograms developed for RP (29,30) or XRT (26). Calibration plots are shown for each of the validation datasets (Fig. 11).

COMPARING ANNS AND NOMOGRAMS Both ANNs and nomograms are attractive prediction models to assist in clinical decision making. Through pattern recognition and back-propagation, ANNs are capable of prediction based on nonlinear relationships between predictor variables. Similarly, nomograms are capable of prediction by using nonlinear relationships via the application of regression models with splines. In addition, they have the ability to uti-

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Fig. 11. Brachytherapy nomogram calibration curves for validation cohorts. (A) Seattle Prostate Institute. (B) Arizona Oncology Services. The x-axis represents nomogram predictions. The y-axis represents the actual 5-yr freedom from recurrence using the Kaplan-Meier method. Each point represents a subcohort of approx 150 patients; the vertical bands are 95% confidence intervals. (Reprinted with permission from Urology, Vol number 58, Kattan MW, Potters L, Blasko JC, et al. Pretreatment nomogram for predicting freedom from recurrence after permanent prostate brachytherapy in prostate cancer. Elsevier, New York, 2001, pp. 393–399.)

lize actuarial survival analysis, which is appropriate for predicting time-to-event outcomes in the presence of case censoring. Several series have attempted to compare ANNs and nomograms on the basis of the more traditional statistical methods used by the latter (Table 14) (77–89).

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Wei et al. (90) assert that, because of their ability to detect complex nonlinear relationships and to identify all possible interactions between predictor variables and outcome, neural networks perform equally to or better than the traditional statistical methods utilized by nomograms. Ragde et al. (77) created an ANN to predict the 10-yr disease-free survival based on 152 patients treated with brachytherapy either alone or in combination with 45 Gy of XRT. When examining the probability of success or failure (as deﬁned by a serum PSA level ≥ 0.5) of brachytherapy alone, they found that the ANN performed with 10% more accuracy (in either case) when predicting the 10-yr disease-speciﬁc survival. The ANN was internally validated by randomly withholding 16% of the cohort. Similarly, Veltri et al. (78) compared a logistic regression model (UroScore™) with an ANN for predicting the probability of a patient’s having organconﬁned prostate cancer. Both methods were applied to 756 patients who had undergone RP (434 with organ-conﬁned, 173 with non-organ-conﬁned [i.e., extracapsular extension], and 149 with metastatic disease) to decipher which would more accurately identify patients with organ-confined disease. Although both methods accurately detected >95% patients with organ-conﬁned disease, they found that the ANN demonstrated a signiﬁcantly higher classiﬁcation accuracy (≥96% vs 40%) and validation result (75.8–78.2% vs 35.9%) when using a three-outcome model (i.e., organ-conﬁned vs non-organ-conﬁned vs metastatic disease). The logistic regression models, however, enabled improved classiﬁcation of non-organ-conﬁned patients (67.3% vs 14.7%). When these methods are applied to a two-outcome scheme (i.e., organ-conﬁned/nonorgan-conﬁned vs metastatic disease), the ANN only marginally outperformed the regression model during training approx 89% vs approx 87%) and validation (approx 83.3% vs approx 79.2%). Djavan et al. (91), on the other hand, prospectively compared ANNs with logistic regression models in men with total serum PSA levels from 2.5 to 4 ng/mL, and from 4 to 10 ng/mL. A separate ANN was developed for each group and compared with regression models. Although signiﬁcantly higher AUCs were demonstrated when the ANNs were compared with univariate models, when they were compared with multivariate regression models, the AUCs were not signiﬁcantly different, either for the 2.5–4 ng/mL group (87.6 vs 85, respectively) or for the 4–10 ng/mL groups (91.3 vs 90, respectively). Undoubtedly, it is difﬁcult to compare these prediction models (91–93). In two comprehensive literature reviews, Schwartzer et al. analyzed studies that compared ANNs with traditional statistical models between 1991 and 1995 (93) and between 1999 and 2001 (92). They demonstrated that most series failed to provide adequate descriptions of ANN architecture (i.e., the complexity of the ANN) and published “overoptimistic” results that had not been tested externally for validation with independent datasets. Furthermore, inconsistencies included “naive” censoring strategies, application to inappropriate endpoints, and unsuitable or undisclosed statistical methods used for comparisons between ANN and nomogram predictive accuracy. Thus, it is difﬁcult to draw reliable conclusions about which model represents the most accurate and reliable instrument.

CONCLUSIONS Both ANNs and nomograms have proved to be useful as clinical prediction models. However, both face several limitations in their applications and accuracy. Although these instruments are able to predict outcomes, they are not capable of recommending an ideal treatment (94). That is, they are able to provide information that is useful for decision

Table 14 Comparison of Artiﬁcial Neural Networks (ANNs) and Traditional Statistical (Trad St) Models in Prostate Cancer Study

Endpoint

Predictor variables

(Presumed) disease-free survival

Pt age, clinical stage, PSA, Gleason grade, external beam radiation therapy

Veltri et al. (78)

Organ-conﬁned disease

Horninger et al. (79)

Positive biopsy

Han et al. (80)

Organ-conﬁned disease

Clinical stage, sextant biopsy pathology variables Pt age, PSA, % free PSA, clinical stage, prostate volume, PSA density transition zone volume, PSA transition zone density Pt age, PSA, clinical stage, biopsy Gleason score

Ziada et al. (81)

Pathologic stage and biochemical recurrence

Clinical stage, prostate volume, PSA, biopsy Gleason score, % cancer in biopsy

Han et al. (82)

Biochemical recurrence (up to 3 yr)

RP specimen Gleason grades (primary and secondary), surgical margin status, pathologic stage extracapsular extension, biopsy Gleason score, PSA, Pt age, race

187

Ragde et al. (77)

ANN accuracy

Trad St accuracy

Validation performed

Class. acc. 76% Sensitivity 55% Speciﬁcity 90% PPV 76% NPV 82% Class. acc. ≥ 96%

Class. acc. 66% Sensitivity 15% Speciﬁcity 94% PPV 59% NPV 64% Class. acc. 40%

Yes

Yes

Not available

Not available

Yes

AUC 77% Sensitivity 30% Speciﬁcity 21% Pathologic stage: Class. acc. 80% Sensitivity 79% Speciﬁcity 81% AUC 81% Sensitivity 16% PPV 25% NPV 91%

AUC 72% Sensitivity 27% Speciﬁcity 16% Pathologic stage: Class. acc. 67% Sensitivity 67% Speciﬁcity 85% AUC 68% Sensitivity 11% PPV 20% NPV 91%

Yes

Yes

Yes

(Table continues)

Table 14 (Continued) Study

Endpoint

Predictor variables

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Finne et al. (83)

Positive biopsy

PSA, % free PSA, clinical stage, prostate volume

Potter et al. (84)

Biochemical recurrence

Murphy et al. (86)

Treatment response

Murphy et al. (85)

Disease-free survival (nodal disease)

Mattfeldt et al. (87)

Disease-free survival

Pt age, quantitative nuclear grade, DNA ploidy, RP specimen Gleason score, ECE, SMS Prostate markers and immune activity markers Remission/progression, clinical stage, bone scan, ProstaScint® complex PSA, free PSA, total PSA Gleason score, WHO grade, diameter of tumor, morphometric parameters

Ronco et al. (88)

Diagnosis

US variables, Pt age, PSA, clinical diagnosis, no. of biopsies

Virtanen et al. (89)

Diagnosis

Total PSA, free PSA, clinical stage, family history

ANN accuracy

Trad St accuracy

Validation performed

Class. acc. 47% Sensitivity 95% Speciﬁcity 33% PPV 29% NPV 95% Class. acc. 78.1% Sensitivity 84.3% Speciﬁcity 72.2% Not available

Class. acc. 40% Sensitivity 95% Spciﬁcity 24% PPV 27% NPV 94% Class acc. 53% Sensitivity 39% Speciﬁcity 67% Not available

Yes

No

Sensitivity 95% Speciﬁcity 15%

Not available

Yes

Class. acc. 83% Sensitivity 85% Speciﬁcity 80% PPV 81% NPV 84% Class. acc. 82.8% PPV 81.8% NPV 90.3% Efﬁciency 41% Sensitivity 85% Speciﬁcity 26% PPV 28% NPV 84%

Class. acc. 70% Sensitivity 55% Speciﬁcity 85% PPV 78% NPV 65% Class. acc. 83.9% PPV 67.2% NPV 91.0% Efﬁciency 52% Sensitivity 87% Speciﬁcity 41% PPV 33% NPV 92%

Yes

Yes

Yes

Yes

Pt, patient; PPV, positive predictive value; NPV, negative predictive value; AUC, area under receiver operator characteristic curve; PSA, prostate-speciﬁc antigen; PNI, perineural invasion; ECE, extracapsular extension; SMS, surgical margin status; RP, radical prostatectomy; WHO, World Health Organization; US, ultrasound.

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analysis. However, they do not act as a surrogate for the physician–patient relationship. Additionally, these tools are generally constructed (25,26,29,30,47–49,52,58) and validated (50,62–64,95) at academic institutions. Because of this, patients treated at these facilities may vary considerably from the general population. Indeed, both models present a proﬁle of limitations. Training for ANNs is slow, and a “credit assignment problem” (43) exists, which relates to the difﬁculty of quantifying the prognostic weight of a particular variable. In fact, it is unclear whether the predictor variable is even being used at all by the ANN (96). This is referred to as the “black box” effect (43). Furthermore, in the face of equal predictive accuracy between ANNs and logistic regression models, ANNs do not afford the same degree of reproducibility in duplicating models. In other words, if a highly accurate ANN were to be created, it is not guaranteed that a duplicate (i.e., with the same clinical parameters) could be produced, because the initial training of the ANN involves assigning random weights to each predictor variable. On the other hand, nomograms, although based on traditional statistical models that are more familiar to clinicians, generally require statisticians for their design, and they are based on a less ﬂexible architecture. However, nomograms are not as prone to overﬁtting as ANNs and, once modeled, are fully capable of identical reproduction. Undoubtedly, both models pose a potential for rejection by clinicians who may not understand the model’s underlying principles and applications. In addition, these models are imperfect, and it is not likely that researchers, clinicians, or statisticians will identify all prognostic factors related to prostate cancer. Even if this were possible, variability in measurements, standardized techniques, and definitions (e.g., which serum PSA level truly defines treatment failure) is required. Thus, there will always remain a certain amount of unpredictability in these models. Nonetheless, ANNs and nomograms both represent a promising set of tools to aid in clinical decision making and patient counseling, as well as in clinical trial design (21,94). Indeed, conclusive evidence of the utility of predictive models may be demonstrated by a randomized trial comparing predictive accuracy of the clinician alone vs the clinician with the aid of a nomogram. Ultimately, the goal of these models is to predict outcomes with 100% accuracy and discriminating ability when they are applied to a distinctly heterogeneous population. In addition, although cancer control remains the main thrust of prostate cancer treatment, the ultimate measure of treatment success is not survival at any cost to the patient, but quality-adjusted survival (97). With continued efforts to identify new prognostic factors and to design models capable of increasingly accurate predictions of a variety of clinical endpoints (including quality of life outcomes), it is likely that ANNs and nomograms will become commonplace in clinical practice.

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66. Wheeler TM, Dillioglugil O, Kattan MW, et al. Clinical and pathologic signiﬁcance of the level and extent of capsular invasion in clinical stage T1–2 prostate cancer. Hum Pathol 1998;29:856–862. 67. Perez CA, Michalski JM, Purdy JA, et al. Three-dimensional conformal radiation therapy (3-D CRT), brachytherapy, and new therapeutic modalities. Rays 2000;25:331–343. 68. Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997;337:295–300. 69. American Society for Therapeutic Radiology and Oncology Consensus Panel. Consensus statement. Guidelines for PSA following radiation therapy. American Society for Therapeutic Radiology and Oncology Consensus Panel. Int J Radiat Oncol Biol Phys 1997;37:1035. 70. Hilaris BS. Brachytherapy in cancer of the prostate: an historical perspective. Semin Surg Oncol 1997;13:399–405. 71. Zelefsky MJ, Whitmore WF Jr. Long-term results of retropubic permanent 125-iodine implantation of the prostate for clinically localized prostatic cancer. J Urol 1997;158:23–29. 72. Ragde H, Korb LJ, Elgamal A, et al. Modern prostate brachytherapy: prostate speciﬁc antigen results in 219 patients with up to 12 years of observed follow-up. Am Cancer Soc 2000;89:135–141. 73. Zelefsky MJ, Hollister T, Raben A, et al. Five-year biochemical outcome and toxicity with transperineal CT-planned permanent I-125 prostate implantation for patients with localized prostate cancer. Int J Radiat Oncol Biol Phys 2000;47:1261–1266. 74. D’Amico AV, Vogelzang NA. Prostate brachytherapy: increasing demand for the procedure despite the lack of standardized quality assurance and long-term outcome data. Cancer 1999;86:1632–1634. 75. Fleming ID, Cooper JS, Henson DE, et al. AJCC Cancer Staging Manual 5th ed. Lippincott-Raven, Philadelphia, 1997. 76. Shipley WU, Thames HD, Sandler HM, et al. Radiation therapy for clinically localized prostate cancer: a multi-institutional pooled analysis. JAMA 1999;281:1598–1604. 77. Ragde H, Elgamal AA, Snow PB, et al. Ten-year disease free survival after transperineal sonographyguided iodine-125 brachytherapy with or without 45-gray external beam irradiation in the treatment of patients with clinically localized low to high Gleason grade prostate carcinoma. Cancer 1998;83:989–1001. 78. Veltri RW, Chaudhari M, Miller MC, et al. Comparison of logistic regression and neural net modeling for prediction of prostate cancer pathologic. Clin Chem 2002;48:1828–1834. 79. Horninger W, Bartsch G, Snow PB, et al. The problem of cutoff levels in a screened population: appropriateness of informing screenees about their risk of having prostate carcinoma. Cancer 2001;91:1667–1672. 80. Han M, Snow PB, Brandt JM, et al. Evaluation of artiﬁcial neural networks for the prediction of pathologic stage in prostate carcinoma. Cancer 2001;91:1661–1666. 81. Ziada AM, Lisle TC, Snow PB, et al. Impact of different variables on the outcome of patients with clinically conﬁned prostate carcinoma: prediction of pathologic stage and biochemical failure using an artiﬁcial neural network. Cancer 2001;91:1653–1660. 82. Han M, Snow PB, Epstein JI, et al. A neural network predicts progression for men with Gleason score 3+4 versus 4+3 tumors after radical prostatectomy. Urology 2000;56:994–999. 83. Finne P, Finne R, Auvinen A, et al. Predicting the outcome of prostate biopsy in screen-positive men by a multilayer perceptron network. Urology 2000;56:418–422. 84. Potter SR, Miller MC, Mangold LA, et al. Genetically engineered neural networks for predicting prostate cancer progression after radical prostatectomy. Urology 1999;54:791–795. 85. Murphy GP, Snow PB, Brandt J, et al. Evaluation of prostate cancer patients receiving multiple staging tests including ProstaScint scintiscans. Prostate 2000;42:145–149. 86. Murphy GP, Snow P, Simmons SJ, et al. Use of artiﬁcial neural networks in evaluating prognostic factors determining the response to dendritic cells pulsed with PSMA peptides in prostate cancer patients. Prostate 2000;42:67–72. 87. Mattfeld T, Kestler HA, Hautmann R, et al. Prediction of prostatic cancer progression after radical prostatectomy using artiﬁcial neural networks: a feasibility study. BJU Int 1999;84:316–323. 88. Ronco AL, Fernandez R. Improving ultrasonographic diagnosis of prostate cancer with neural networks. Ultrasound Med Biol 1999;25:729–733. 89. Virtanen A, Gomari M, Kranse R, et al. Estimation of prostate cancer probability by logistic regression: free and total prostate-speciﬁc antigen, digital rectal examination and heredity are signiﬁcant variables. Clin Chem 1999;45:987–994. 90. Wei JT, Ashutosh T. Artiﬁcial neural networks in urology. Prog Urol 1999;54:945–948. 91. Djavan B, Remzi M, Zlotta A, et al. Novel artiﬁcial neural network for early detection of prostate cancer. J Clin Oncol 2002;20:921–929.

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92. Schwartzer G, Schumacher M. Artiﬁcial neural networks for diagnosis and prognosis in prostate cancer. Semin Urol Oncol 2002;20:89–95. 93. Schwartzer G, Werner V, Schumacher M. On the misuses of artiﬁcial neural networks for prognostic and diagnostic classiﬁcation in oncology. Stat Med 2000;19:541–561. 94. Kattan MW, Eastham JA. Algorithms for PSA recurrence after treatment of localized prostate cancer. Clin Prostate Cancer 2003;1(9):221–226. 95. Kattan MW, Stapleton AM, Wheeler TM, et al. Evaluation of a nomogram used to predict the pathologic stage of clinically localized prostate carcinoma. Cancer 1997;79:528–537. 96. Kattan MW, Beck JR. Artiﬁcial neural networks for medical classiﬁcation decisions. Arch Pathol Lab Med 1995;119:672–677. 97. Kattan MW, Cowen ME, Miles BJ. A decision analysis for treatment of clinically localized prostate cancer. J Gen Intern Med 1997;12:299–305. 98. Stamey T, Barnhill SD, Zhang Z, et al. A neural network (ProstAsure™) with high sensitivity and speciﬁcity for diagnosing prostate cancer in men with a PSA<4.0 ng/mL. J Urol 1997;157(Suppl):364. 99. Babaian RJ, Fritsche HA, Zhang Z, et al. Evaluation of prostAsure index in the detection of prostate cancer: a preliminary report. Urology 1998;51:132–136. 100. Carlson GD, Calvanese CB, Partin AW. An algorithm combining age, total prostate-specific antigen (PSA), and percent free PSA to predict prostate cancer: results on 4298 cases. Urology 1998;52:455–456. 101. Eastham JA, May R, Robertson JL, et al. Development of a nomogram that predicts the probability of a positive prostate biopsy in men with an abnormal digital rectal examination and a prostate-speciﬁc antigen between 0 and 4 ng/mL. Urology 1999;54:709–713. 102. Narayan P, Gajendran V, Taylor SP, et al. The role of transrectal ultrasound-guided biopsy-based staging, preoperative serum prostate-speciﬁc antigen, and biopsy Gleason score in prediction of ﬁnal pathologic diagnosis in prostate cancer. Urology 1995;46:205–212. 103. Epstein JI, Walsh PC, Carmichael M, et al. Pathologic and clinical ﬁndings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA 1994;271:368–374. 104. Gilliland FD, Hoffman RM, Hamilton A, et al. Predicting extracapsular extension of prostate cancer in men treated with radical prostatectomy: results from the population based prostate cancer outcomes study. J Urol 1999;162:1341–1345. 105. Pisansky TM, Blute ML, Suman VJ, et al. Correlation of pretherapy prostate cancer characteristics with seminal vesicle invasion in radical prostatectomy specimens. Int J Radiat Oncol Biol Phys 1996;36:585–591. 106. Bluestein DL, Bostwick DG, Bergstralh EJ, et al. Eliminating the need for bilateral pelvic lymphadenectomy in select patients with prostate cancer. J Urol 1994;151:1315–1320. 107. D’Amico AV, Whittington R, Malkowicz SB, et al. Pretreatment nomogram for prostate-speciﬁc antigen recurrence after radical prostatectomy or external-beam radiation therapy for clinically localized prostate cancer. J Clin Oncol 1999;17:168–172. 108. D’Amico AV, Whittington R, Malkowicz SB, et al. Clinical utility of percentage of positive prostate bopsies in deﬁning biochemical outcome after radical prostatectomy for patients with clinically localized prostate cancer. J Clin Oncol 2000;18:1164–1172. 109. Han M, Partin AW, Zahurak M, et al. Biochemical (prostate speciﬁc antigen) recurrence probability following radical prostatectomy for clinically localized prostate cancer. J Urol 2003;169:517–523. 110. Pisansky TM, Kahn MJ, Bostwick DG. An enhanced prognostic system for clinically localized carcinoma of the prostate. Cancer 1997;79:2154–2161. 111. D’Amico AV, Whittington R, Malkowicz SB, et al. The combination of preoperative prostate speciﬁc antigen and postoperative pathological ﬁndings to predict prostate speciﬁc antigen outcome in clinically localized prostate cancer. J Urol 1998;160:2096–2101. 112. Partin AW, Pearson JD, Landis PK, et al. Evaluation of serum prostate-speciﬁc antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases. Urology 1994;43:649–689. 113. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999;281:1591–1597.

10

When Is Observation Appropriate? Kisseng Hsieh and Peter C. Albertsen

INTRODUCTION The natural history of prostate cancer encompasses a wide spectrum of clinical outcomes. In the absence of treatment, some patients experience a rapid progression to metastases and death, whereas others live with their disease for many years, ultimately succumbing to competing medical hazards. Only about 30% of the patients in the Veterans Administration Cooperative Urological Research Group (VACURG) studies of prostate cancer actually died from prostate cancer (1). In 2003, an estimated 220,900 American men will be diagnosed with prostate cancer and 28,900 will die from this disease (2). These statistics suggest that variable outcomes are as prevalent today as they were approx half a century ago. The wide spectrum of clinical outcomes places a special burden on physicians treating patients with prostate cancer. Physicians cannot easily determine whether the interventions they propose are likely to alter the natural outcome of this disease. Unlike some cancers, in which death is a virtual certainty in the absence of treatment, the natural history of prostate cancer is much more varied. When counseling patients with this disease, clinicians often follow the safest approach and recommend aggressive therapy. If the disease progresses, the physician takes solace in thinking he/she has done everything possible. If the disease does not progress, the physician assumes that he/she has “cured” the patient. Many patients, however, do not require aggressive treatment. Identifying who they may be requires considerable clinical acumen. The efﬁcacy of different treatment strategies remains uncertain for many patients. This is especially true following the introduction of widespread testing for prostatespeciﬁc antigen (PSA). A recent randomized trial conducted in Sweden suggests a cause-speciﬁc survival beneﬁt for those patients undergoing surgery, but a signiﬁcant overall survival beneﬁt has yet to be demonstrated compared with patients undergoing conservative management (3). Less information is available concerning the impact of radiation therapy. The advent of testing for PSA has dramatically increased our ability to detect early-stage prostate cancer and monitor the progression of this disease, but it has also increased the uncertainty concerning the natural history of these cancers and From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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how best to manage men with less aggressive forms of this disease. To understand who may beneﬁt from treatment and who is an appropriate candidate for observation, clinicians must have a good understanding of the natural history of prostate cancer. The purpose of this chapter is to review the critical studies that have led to our current understanding of the natural history of prostate cancer to help the reader understand which patients may be appropriate candidates for observation. Both genetic and environmental factors combine to impact on the long-term outcome of this disease. Using standardized assessments of tumor histology and volume, clinicians can better estimate the relative risk posed by different prostate cancers and the relative value provided by different treatment strategies. By reﬁning our understanding of the risks and beneﬁts of different therapeutic approaches, patients can select a strategy appropriate to their personal situation that hopefully optimizes their life expectancy with a minimal compromise to their quality of life. For some patients observation may be the preferred alternative.

RISK FACTORS FOR PROSTATE CANCER Genetic Factors Researchers have recently identiﬁed family history as a risk factor for prostate cancer. In 1992, Carter et al. (4) reported that 9% of 691 cases of prostate cancer identiﬁed at the Johns Hopkins Hospital were genetically linked and that 43% of incident cases occurring in men younger than age 55 yr were hereditary. Hereditary prostate cancer is deﬁned as prostate cancer involving at least two brothers before the age of 55 yr or prostate cancer involving each of three generations in either the paternal or maternal lineage (5). The risk of being diagnosed with prostate cancer is greater for brothers than for sons of men with prostate cancer and appears to be highest for men with ﬁrstdegree relatives who were diagnosed with prostate cancer at an early age (6–12). A speciﬁc prostate cancer gene has yet to be identiﬁed. Both X-linked and autosomal recessive inheritance mechanisms have been proposed. Several prostate cancer susceptibility genes have been recognized and mapped. A genome-wide linkage analysis performed by Smith et al. (13) in 1996 identiﬁed the HPC1 (hereditary prostate cancer 1) gene on chromosome 1q24-25. Initially thought to be responsible for a large number of cancers, this gene is now suspected in only 6% of prostate cancers. Since then several other genes have been linked to prostate cancer. These include the PCAP (predisposing for cancer of the prostate) gene (14), the HPCX (human prostate cancer) gene (15), the CAPB (cancer of the prostate and brain) gene (16), the HPC2/ELAC2 gene (17), and the HPC20 gene (18). Epidemiologists estimate that the incidence of hereditary prostate cancer may be as high as 5–10% in the general population and almost 40% in men diagnosed before age 55 yr (4,5,19). No differences in histology have been noted among hereditary prostate cancers compared with sporadic cases (20–23). Both appear to present with multifocal distribution within the prostate, and both appear to have a similar prognosis (18,22,24–28). Therefore genetic factors alone cannot distinguish which men may be appropriate candidates for observation. Although some authors believe that a greater portion of men with hereditary prostate cancers are at risk of dying from their disease, this theory has not been proved (29). As with sporadic prostate cancer, the natural history of hereditary cancer is poorly understood. Since patients with hereditary prostate cancer tend to be relatively young, they

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are often treated aggressively. However, the lead time of 6–7 yr associated with the earlier screening of men with a history of familial prostate cancer makes survival comparisons between sporadic and familial prostate cancers difﬁcult (13,19,21,23,29).

Race For many years epidemiologists have recognized that race is a signiﬁcant factor associated with the incidence of prostate cancer. African-American men have one of the highest incidence rates of prostate cancer in the world, whereas Asians have one of the lowest. The relative risk of prostate cancer diagnosis is 60% higher among AfricanAmerican men compared with their White counterparts. The natural history of prostate cancer also appears to be more aggressive among African Americans compared with Whites, resulting in a relative risk of dying from prostate cancer that is 200% higher (30). When compared with Asians, African-American men have a 60-fold higher incidence of prostate cancer and a mortality rate that is 12 times higher compared with men residing in Hong Kong (31). Although race may contribute to varying incidences in prostate cancer, it is unclear whether it plays a role in prostate cancer progression following treatment. In a multivariate analysis of 1468 patients, Grossfield and associates (32) found that race was not a significant factor predicting disease recurrence after adjusting for patient education and income. Eastham et al. (32a) demonstrated similar recurrence rates following prostatectomy among African-American men and White men. Unfortunately, other studies have yielded conflicting findings (32–35). Race, therefore, does not appear to be an important factor in determining whether observation may be an appropriate strategy.

Environment The large number of genes linked to prostate cancer suggests that environmental factors must also play a signiﬁcant role in promoting carcinogenesis. The mortality rate from prostate cancer in the more westernized sections of Asia, for example, is rising faster than anywhere else in the world. The incidence of prostate cancer in JapaneseAmericans is 43 times greater than in native Japanese men (31,36). This increased risk appears to have occurred within one generation. Differences in nutritional intake between western and Asian societies have been implicated as a possible explanation for this phenomenon. The higher saturated fat content and the increased consumption of red meat in the American diet has been associated with increased relative risks of prostate cancer of 1.3–2.0 and 1.5–2.0, respectively, compared with those populations with low fat and red meat intake (36,37). Increased dietary fat leads to higher plasma concentrations of fatty acids, which may inhibit the ability of androgens to bind to sex hormone-binding globulin, resulting in elevated serum androgen levels (38). High-fat diets also tend to be low in fiber, thus decreasing the fecal excretion of androgens (39). Asian diets, in contrast, are high in legumes and phytoestrogens. These nutritional sources are low in fat and rich in fiber and protein and contain assorted micronutrients. Furthermore, soybeans contain an abundance of anticarcinogens such as protease inhibitors, phyate, phytosterols, saponins, ligins, and isoflavins (40). Isoflavones are weak plant estrogens that may weakly bind to androgen receptors, interfering with androgen activity (41). Additionally, genistein, the prominent isoflavone in soy, may influence signal transduction. Genistein has been shown to suppress the growth of androgen-dependent and

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-independent cells in vitro (42). Other proposed anticancer mechanisms of soy include inhibition of PSA secretion and production, modulation of growth factors, and inhibition of angiogenesis (43–46). How changes in environmental factors can alter the natural history of prostate cancer remains unknown. Many patients diagnosed with prostate cancer, including those on observation, have adopted low-fat, soy-based diets. Data, however, are insufficient to determine whether this type of diet provides a survival advantage.

FACTORS IMPACTING ON THE NATURAL PROGRESSION OF PROSTATE CANCER Patient Factors Including Age and Competing Medical Hazards Many men diagnosed with prostate cancer will die from competing medical hazards, not prostate cancer. This concept was recognized by Barnes in 1969 (47), well before the development of PSA levels as a marker. He analyzed the long-term survival of patients with clinically localized prostate cancer treated conservatively. Ten- and 15-yr overall survival rates were only 50 and 30%, respectively. Approximately two-thirds of these patients died from diseases other than prostate cancer. Barnes (47) concluded that competing medical hazards were as important as tumor stage and grade when selecting therapy and that observation was indicated in prostate cancer patients with an expected life expectancy <10 yr. More recently, Albertsen et al. (48) explored the impact of competing medical hazards and the risk of death from prostate cancer in a cohort of men with localized prostate cancer. These patients were managed with either observation or antiandrogen therapy alone. To determine the comorbidities of these patients, three validated instruments were utilized; the Index of Co-Existent Disease, the Charlson Index, and the Kaplan-Feinstein Index (49–51). Men with competing medical hazards in the highest two categories rarely died from prostate cancer. Among all men with prostate cancer, 40% died of competing medical hazards, and 34% died from prostate cancer. These findings suggest that older men in their mid-70s who have other significant comorbidities are less likely to die from prostate cancer and are good candidates for observation. Patient comorbidities are the second most powerful predictor of survival behind tumor grade. Therefore the combination of patient age and comorbidities should be one of the most important factors when considering observation as a treatment strategy.

Tumor Histology THE VETERAN’S ADMINISTRATION COOPERATIVE UROLOGY GROUP STUDIES AND THE GLEASON GRADING SYSTEM Many physicians have recognized the important relationship between histology and the clinical outcome of prostate cancer (52,53). This information, however, has only recently been incorporated into treatment decision analysis. Prior to the publication of the Gleason grading system, many pathologists found it difficult to classify prostate cancers consistently according to their malignant potential. Gleason’s accumulated experience with almost 3000 tumors from the VACURG studies confirmed that prostate cancer histology was strongly correlated with the clinical behavior of this cancer and that prostate cancer histology provided information concerning out-

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come that was independent of clinical stage. Because of its relative simplicity, pathologists have adopted Gleason’s scoring system as the standard for assessing prostate cancer histology. The VACURG studies were begun in 1960 as controlled, randomized, prospective comparisons of the different treatments available for prostate cancer (54). Three different protocols enrolled a total of 2911 men that were available for follow-up clinical correlation by 1974. Clinical outcomes were assessed by calculating the number of deaths per patient-year of follow-up. Mortality rates were strongly correlated with both the primary and secondary histology patterns, but the average histology pattern provided the strongest correlation. Accordingly, Gleason proposed summing the pattern scores to provide the best predictor of clinical outcome. This sum is now frequently called the Gleason score. A review of the clinical outcomes of the patients involved in this study demonstrates that grading prostate cancers by histology can separate patients into groups that experience markedly different mortality rates. Patients with Gleason score 2–5 tumors had a cancer death rate of only 0.012 or 1.2 deaths/100 patient-years. The remaining 2187 patients with Gleason scores from 6 to 10 had a cancer death rate of 0.124 deaths/patient-year, a rate that is 10 times higher than the rate for men with low-grade disease.

Tumor Volume The volume of prostate cancer at the time of diagnosis is the other key variable that consistently predicts long-term clinical outcome. Prior to the advent of PSA testing, clinicians relied on the digital rectal examination and imaging studies such as the bone scan and computerized tomography to assess the extent of disease. The introduction of PSA testing has enabled clinicians to identify disease much earlier than previously imagined. McNeal and colleagues (55) have demonstrated that tumors <0.5 cc frequently occur in older men but rarely extend beyond the conﬁnes of the prostate. Tumors >3.0 cc often demonstrate invasion into the seminal vesicle. Tumors that are ≥6.0 cc are rarely curable even with aggressive management. In a large autopsy series, McNeal and colleagues (55) showed that only tumors containing poorly differentiated histology features, speciﬁcally patterns 4 and/or 5, grow to sufﬁcient size to metastasize. Stamey et al. (56) have shown that many prostate cancers grow at a very slow rate. Half of all prostate cancers take more than 5 yr to double in size, compared with breast cancers, which can double in size every 3 mo. Most men over age 50 yr with prostate cancers < 0.5 cc at the time of diagnosis will not live long enough for their cancers to achieve sufﬁcient size to metastasize. Stamey et al. (57) have determined that patients with one or more cores containing >3 mm of tumor are likely to have a prostate volume > 0.5 cc. Although serum PSA levels are not sufﬁciently reliable to predict tumor burden for individual patients, serum PSA levels do correlate with tumor volume when evaluating large groups of men. In a classic analysis of over 10,000 men aged 50 yr and older participating in a screening program for prostate cancer, Catalona et al. (58) reported that only 45% of men with a PSA score greater than 10 ng/mL had disease localized to the prostate. Partin et al. (59) combined information provided by serum PSA level, Gleason score, and clinical stage to generate a series of tables to predict local tumor extension and capsule penetration.

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THE NATURAL HISTORY OF PROSTATE CANCER IN THE PRE-PSA ERA Several key studies have helped shape our understanding of the natural history of prostate cancer diagnosed in the era before the widespread use of PSA. They are reviewed below.

The Johansson Studies Between 1989 and 1997, Johansson and colleagues (60–62) published a series of three articles that documented the natural history of untreated prostate cancer in a population-based cohort of patients diagnosed with prostate cancer in Orebro Medical Center in Sweden, a hospital with a strictly deﬁned catchment area. No screening for prostate cancer took place during the period when this study population of 648 consecutive cases was assembled. The authors found relatively low 5- and 10-yr mortality rates among men with clinically localized disease and challenged the use of aggressive initial treatment for all patients with early stage prostate cancer. Their studies were criticized primarily because of issues surrounding selection of the study cohort. Johansson et al. utilized a prospective, population-based study design to assemble their study cohort. Between March 1977 and February 1984, all consecutive cases of clinically diagnosed prostate cancer were enrolled in the study. Diagnoses were conﬁrmed by ﬁne-needle aspiration biopsy of palpable prostate tumors in 542 (84%) of the 648 cases. In another 106 cases (16%), the diagnosis was made during surgery for benign prostate hyperplasia. Staging examinations included chest radiography, intravenous pyelography, bone scan, and skeletal radiography of suspicious lesions on bone scan. Digital rectal examination was also performed to determine the clinical stage of the disease. Medical information on six patients could not be located. Of the 642 patients evaluated, 300 had disease localized to the prostate (T0–T2), and 183 patients had locally advanced disease (T3–T4) without detectable metastases (M0). Metastatic disease was found in 159 patients (25%). Of the 300 patients with localized disease, 223 received no initial treatment. Of the remaining 77 patients, 2 underwent a radical prostatectomy, and 75 received some combination of external beam radiation, estrogen, estramustine, or an orchiectomy. Of the 342 patients with locally advanced disease or with metastatic disease, most were treated with hormonal therapy, predominantly with estrogen or estramustine. All patients were followed until death or until the end of the observation period on September 1, 1994. The observation period ranged from 126 to 210 mo, the average being 168 mo (14 yr). Patients were followed at least every year and some much more frequently. Prostate cancer was recorded as the underlying cause of death, a contributory cause of death, or unrelated to the cause of death for each patient who died during the follow-up period. An autopsy was performed if the cause of death was unclear. If the treatment of the prostate cancer was related to the patient’s death, for example, cardiovascular complications following estrogen therapy, prostate cancer was recorded as a contributory cause of death. Cause of death determinations were reviewed and compared with the classiﬁcation assigned by the county tumor registrar. There was agreement in 90% of cases, and no evidence of systematic over-ascertainment or under-ascertainment of prostate cancer cause of death. The authors performed several survival analyses including an analysis of all-cause survival and disease-speciﬁc survival. The effect of different variables on survival was determined using the Cox proportional hazards model.

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At the end of the observation period 541 (84%) of all 642 patients in the study cohort had died. Prostate cancer was considered the underlying cause of death in 201 patients (31%), whereas in 35 patients (5%), prostate cancer contributed to the cause of death. Prostate cancer accounted for more deaths among younger patients compared with older patients at the time of diagnosis. More patients with poorly differentiated tumors and/or advanced local tumors died of prostate cancer. For the 300 men with localized disease at the time of diagnosis, 37 (12%) developed metastases, and 33 (11%) died of their disease. Among the 223 patients with localized disease who received no initial therapy, 29 (13%) developed metastases, 25 (11%) died of prostate cancer, and 4 died of prostate cancer as a contributing cause of death. A careful review of the 223 patients receiving no initial therapy revealed that 148 had well-differentiated disease, and 66 had moderately differentiated disease. Presumably these cases would be classiﬁed as Gleason 2–6 tumors. Of the 148 patients with well-differentiated disease, only 9 (6%) died from prostate cancer and only 2 developed distant metastases. Results were not quite as good for men with moderately differentiated disease. Of these 66 men, 11 (17%) died from prostate cancer, and 2 (18%) developed metastatic disease. The nine men with poorly differentiated disease fared poorly. Three patients developed local progression, and six developed metastases. Five of these patients were dead from prostate cancer at the time of last follow-up. Based on their ﬁndings, Johannson et al. stated that men with well- or moderately differentiated disease have an excellent prognosis in the absence of any aggressive treatment. These ﬁndings are in agreement with those published by Gleason. Unfortunately, men with poorly differentiated prostate cancer had a high incidence of progression and death from their disease. This ﬁnding is also similar to that of Gleason. Of the 201 men who died from prostate cancer in the entire cohort of 642 men, 28 (13%) of these patients had well-differentiated prostate cancers, 101 (33%) had moderately differentiated cancers, and 72 (58%) had poorly differentiated cancers. When contributory causes are considered, a total of 68% of men presenting with poorly differentiated disease and 38% of men with moderately differentiated disease died from prostate cancer. Johannson et al. concluded their study by noting that because of the favorable survival rate among the untreated patients with early-stage disease, at least 80% of these patients would be treated without survival beneﬁt. Although this may be true for older men with well- and moderately differentiated disease, these results cannot be generalized to younger men and men with poorly differentiated cancers. The distribution of Gleason scores in contemporary series of incident cases is more heavily weighted toward moderate and poorly differentiated disease compared with the sample reported by Johannson et al.

The Chodak Study In 1994 Chodak et al. (63) published a report concerning the results of conservative management of clinically localized prostate cancer. Unlike the Johannson report, this study consisted of a pooled analysis of 828 case records from six nonrandomized studies published during the decade preceding the report. None of the patients included in the report underwent a radical prostatectomy or received radiation therapy. Patients who had symptomatic progression or who developed metastases received hormonal therapy. The ﬁnal report contained information derived from six previously reported studies (60,61,64–68). Two were conducted in the United States, two in Sweden, and one each in Scotland and Israel. The ﬁnal series consisted of 828 patients ranging in

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age from 37 to 93 yr at the time of diagnosis. Median follow-up of the study group was approx 6.5 yr. A Cox proportional hazards regression model was initially used to determine the combined effects of the patient’s age at diagnosis, tumor grade, disease stage, and the origin of the patient cohort on disease-speciﬁc survival. The risk ratio for disease progression was substantially higher for patients with poorly differentiated histology compared with all the other risk ratios. As a result, the authors stratiﬁed patients into three categories by biopsy tumor histology for subsequent analysis. The goal of the study was to calculate conservative estimates of the effect of nonaggressive treatment on disease-speciﬁc survival, overall survival, survival among patients who did not die of prostate cancer (noncancer survival), and metastasis-free survival among men with clinically localized prostate cancer. Disease-speciﬁc survival and metastasis-free survival for men with well, moderately, and poorly differentiated disease were reported. Patients with poorly differentiated (grade 3) cancers had a signiﬁcantly lower cancer-speciﬁc survival rate (34%) compared with men who had well (grade 1) or moderately (grade 2) differentiated cancers (87%). Men with moderately differentiated cancer (grade 2) had a lower diseasespeciﬁc survival rate compared with men who had well-differentiated disease (grade 1), but the difference was not statistically signiﬁcant. The rate of progression to metastasis differed signiﬁcantly among men with the three tumor grades. Men with poorly differentiated tumors were much more likely to progress to metastatic disease compared with men who were diagnosed with well-differentiated disease. These results are similar to those reported by Gleason and Johannson et al. The authors tested for several potential biases that could have compromised their ﬁndings. They concluded that the relatively favorable outcome associated with conservative management could not be explained by the inclusion of men with shorter than average life expectancies. They also investigated the potential impact of including patients with small, focal tumors because these patients are thought to have a more favorable outcome compared with patients with other stages of localized disease. They found that the inclusion of these cases did not affect the overall rates of disease-speciﬁc survival reported for the entire population of patients. Based on these ﬁndings, the authors concluded that prostate cancer is a progressive disease when managed conservatively. Furthermore, the prognosis of men with poorly differentiated disease is considerably worse compared with men with well- or moderately differentiated disease. The authors also commented that aggressive treatment of prostate cancer may result in a lower mortality from prostate cancer at 10 yr among men with well- and moderately differentiated disease, but the differences appear to be small. The relative beneﬁt of aggressive treatment for poorly differentiated disease is potentially much greater. Without treatment, these patients face a signiﬁcant risk of disease progression; therefore aggressive treatment is much more likely to provide a substantial survival beneﬁt.

The Lu-Yao Study In 1997, Lu-Yao and Yao (69) published an analysis of 59,876 prostate cancer registry patients aged 50–79 yr at diagnosis to ascertain overall and prostate cancer-speciﬁc survival rates among men treated with surgery, radiation, or a more conservative approach. Their study relied on the population-based records compiled by the Surveillance, Epidemiology, and End Results (SEER) study of the National Cancer Institute.

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Their study utilized the SEER histology classiﬁcation system: grade 1 (Gleason scores 2–4), grade 2 (scores 5–7), grade 3 (scores 8–10), and grade unknown. The patients included in the study were diagnosed between January 1, 1983 and December 31, 1992. Men with other cancers were excluded from the analysis. Using an intention to treat analysis, they found that cancer grade had a signiﬁcant effect on overall survival. All patients with well-differentiated disease had similar or even better overall survival compared with age-matched controls regardless of treatment. In contrast, patients with poorly differentiated disease had much lower overall survival rates compared with their age-matched controls. The risk of dying from prostate cancer within 10 yr of diagnosis was 10 times greater for men with poorly differentiated disease compared with men with well differentiated disease. Poorly differentiated cancers had a uniformly poor outcome for men with localized disease as well as regional disease. Furthermore, the authors found that the effect of poorly differentiated disease on survival was rapid. Five years after diagnosis, patients with poorly differentiated disease managed conservatively had a relative survival of only 0.61 compared with age-matched controls and a disease-speciﬁc survival of only 63–69%. Ten-year disease-speciﬁc survival rates for the entire cohort ranged from 45 to 94%. For men with well-differentiated disease, survival rates were 94, 90, and 93%, respectively, for men undergoing prostatectomy, radiation therapy, and conservative management. For men with moderately differentiated disease (Gleason score 5–7), 10-yr disease speciﬁc survival rates were 87, 76, and 77%, respectively. Men undergoing prostatectomy appeared to have a signiﬁcant survival advantage in this group compared with men treated with radiation or managed conservatively. Men with poorly differentiated disease had the worst 10-yr disease-speciﬁc survival rates. They were 67, 53, and 45%, respectively, for men undergoing prostatectomy, radiation therapy, and conservative management. Patients undergoing prostatectomy and radiotherapy had a higher relative and prostate cancer-speciﬁc survival with poorly differentiated disease compared with conservative management.

The Albertsen Study In 1998, we reported long-term outcomes of a competing risk analysis of 767 men diagnosed between 1971 and 1984 who were managed expectantly for clinically localized prostate cancer (70). Our study design consisted of a case series analysis of patients identiﬁed through the Connecticut tumor registry that satisﬁed several criteria. First, we searched for men with long-term follow-up extending 10–20 yr after diagnosis to capture the impact of prostate cancer and competing medical hazards. Second, we looked for men aged 55–74 yr at diagnosis to identify a group of men who had an average life expectancy of >10 yr. Third, we recovered the original histology slides of these patients to permit reanalysis using contemporary Gleason grading standards. Finally, we assembled a patient cohort sufﬁciently large to permit stratiﬁcation by the biopsy Gleason score and age at diagnosis, factors known to be important determinants of outcome. Long-term outcome information was obtained from the Connecticut tumor registry and the vital statistics bureau of the Department of Public Health. The mean follow-up of the patient cohort from diagnosis until death was 8.6 yr. Of the 157 patients lost to follow-up or known to be alive as of March 1, 1997, the mean follow-up was 15.4 yr. Only 2 of these men were lost to follow-up before 10 yr, 76 of these men were followed for 10–14 yr, and the remaining 79 were followed for ≥15 yr. Cause of death was determined by reviewing death certiﬁcates for each of the men who had died. Connecticut

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death certiﬁcates follow the format recommended by the World Health Assembly and contain two parts. Part I contains three lines for physicians to record the train of medical events leading directly to the patient’s death. Part II contains one line for physicians to record any “other signiﬁcant conditions: conditions contributing to death, but not related to cause.” For this study, men were classiﬁed as dying from prostate cancer if any of the lines on Part I of the death certiﬁcate mentioned prostate cancer. The results of our study are presented in Fig. 1. Few men (4–7%) with Gleason score 2–4 tumors identiﬁed by prostate biopsy had progression leading to death from prostate cancer within 15 yr of diagnosis. Most of the younger men are still alive, but they face the possibility of death from prostate cancer in the future. In contrast, most of the older men with Gleason score 2–4 tumors identiﬁed by biopsy at diagnosis have died from competing medical hazards rather than prostate cancer. Compared with men with well-differentiated tumors, men with Gleason score 5 and 6 tumors identiﬁed by prostate biopsy experienced a somewhat higher risk of death from prostate cancer when managed expectantly (6–11 and 18–30%, respectively). Of the younger men with Gleason score 5 and 6 tumors, more than half are still alive after 15 yr, whereas most of the older men have died from competing medical hazards. Men with Gleason scores 7 and 8–10 tumors identiﬁed by prostate biopsy experienced a very high rate of death from prostate cancer regardless of their age at diagnosis (42–70% and 60–87%, respectively). Very few of these men of any age are still alive. Most have died from prostate cancer, except for approx one-third of the oldest men, who died from competing medical hazards. Our data are remarkably consistent with those reported by Gleason, Johansson et al., Chodak et al., and Lu-Yao et al. After 15 yr, men diagnosed with low-grade disease (Gleason score 2–4) have a small risk of dying from prostate cancer. Men with moderate-grade disease (Gleason score 5–6) have a slightly higher risk of dying from prostate cancer, whereas men with high-grade disease (Gleason score 7–10) have a substantial risk of dying from their disease when managed expectantly.

THE NATURAL HISTORY OF PROSTATE CANCER IN THE PSA ERA The advent of testing for PSA has dramatically changed our understanding of the natural history of prostate cancer. PSA provides a tool for assessing the presence of prostate cancer and the progression of disease following treatment. Testing for serum PSA has also resulted in an earlier diagnosis for many men with prostate cancer, introducing a lead time compared with men diagnosed in the pre-PSA era. Traditionally, the impact of treatments designed to alter the natural history of this disease has been evaluated using 5and 10-yr survival rates. The widespread use of PSA-based screening has increased the number of patients who survive for more than 5 yr with their diagnosis. As a consequence, 5-yr survival rates cannot be relied on as an indicator of treatment efﬁcacy. Welch and Black (71) published an elegant manuscript exploring the impact of lead time on cancer mortality rates. They noted that the prevalence of any cancer and the consequences of any treatments depend on the level of screening. With the advent of PSA testing and the increased use of transrectal ultrasound-guided prostate biopsies, the recorded incidence of prostate cancer has increased. Furthermore, as prostate cancers are diagnosed earlier in the course of their disease, a stage migration toward lower stage disease has occurred. Until long-term outcome data become available, it is uncertain whether these changes have resulted in a survival beneﬁt.

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Fig. 1. Survival (white lower bands) and cumulative mortality from prostate cancer (dark gray upper bands) and other causes (light gray middle bands) up to 15 yr after diagnosis stratiﬁed by age at diagnosis and Gleason score. Percentage of men alive can be read from the left-hand scale, and percentage of men who have died from prostate cancer or from other causes during this interval can be read from the right-hand scale. (From Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998;280:975–980, with permission.

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The increased lead time in diagnosis that results from early detection distorts the perception of the natural history of prostate cancer and its response to intervention. Compared with historical series, modern studies examining the treatment and diagnosis of prostate cancer tend to suggest a more favorable outcome with intervention. Many of these studies, however, fail to adjust for the lead time associated with the earlier time of diagnosis. With respect to prostate cancer, PSA has introduced a lead time of several years into most clinical series examining survival rates following treatment intervention for prostate cancer. Since survival is usually measured from the time of diagnosis, studies in which prostate cancer was detected earlier because of an elevated serum PSA cannot be compared with reports from the pre-PSA era, when the diagnosis was commonly made at a much later stage. It is difﬁcult to adjust for lead time bias because simply adding or subtracting several years to survival estimates assumes that cases identiﬁed as a result of an elevated PSA progress at the same rate as those that eventually present clinically. This assumption may or may not be true and depends on the presence of length time bias. Length time bias affects comparisons that are unadjusted for the rate of disease progression. Usually the length of the detectable preclinical phase of prostate cancer is inversely related to the rate of disease progression. Disease detected by testing tends to progress more slowly than disease that would ultimately present clinically in the absence of testing. Length bias increases in magnitude as the detection threshold of the screening test is reduced. Additionally, the spectrum of detected disease is widened to include cases that progress very slowly. These cases may progress too slowly to become clinically relevant during a patient’s lifetime. PSA testing has clearly introduced a length time bias. This has been conﬁrmed by the recently published chemoprevention trial comparing ﬁnasteride vs placebo that identiﬁed prostate cancer in 18% of the men taking ﬁnasteride and 24% of the patients on placebo. This compares with the expected rate of 6% estimated at the start of the study (72). This study demonstrates that there is a large pool of subclinical disease present in the population. By lowering the PSA threshold for performing transrectal ultrasound and prostate biopsy, clinicians are identifying many of these cases that are unlikely to progress to clinically signiﬁcant disease. It is not known whether early-stage prostate cancer detected as a result of an elevated PSA progresses at the same rate as the clinical prostate cancers seen during the pre-PSA era. However, studies from the pre-PSA era have clearly demonstrated the minimal impact of well-differentiated and moderately differentiated disease on overall patient survival. Data from the PSA era amplify these ﬁndings. When lead time and length biases are considered, the probability that older men diagnosed in the PSA era will die of prostate cancer is further reduced. This is especially true for men with welland moderately differentiated disease and those men with signiﬁcant competing medical hazards. Lead time bias also applies to treatments that are implemented as a result of a lower threshold for diagnosis. When disease is diagnosed earlier in its course, treatments will appear to be more effective, whether or not this is true. As a result, new therapies often appear promising and may even replace older, safer, and more effective therapies. This cycle of increasing intervention as a result of misconceptions of disease prevalence and therapeutic effectiveness clearly pertains to prostate cancer. With the introduction of PSA testing, the number of radical prostatectomies performed has increased dramatically, peaking at 104,000 in 1992–1993 (73). Although this phenomenon has correlated

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with a reduction in the number of men dying of prostate cancer, it is difﬁcult to determine the exact relationship between these two observations. It is tempting to attribute improved survival rates seen with prostate cancer to the increased number of radical prostatectomies performed, but lead time and length time bias could just as easily account for these ﬁndings.

ESTIMATES OF LEAD TIME The Carter Study One of the early studies that contributed to our understanding of lead time and of the natural progression of prostate cancer as measured by a rising PSA is the report by Carter et al. (74) that evaluated longitudinal changes of PSA in men with and without prostate cancer. They performed a case-control study utilizing men participating in the Baltimore Longitudinal Study of Aging (BLSA). Although the sample size was small, consisting of only 18 men with prostate cancer, 20 men with benign prostate hyperplasia, and 16 controls, the authors suggested that the rate of change of PSA was an early clinical marker of the development of prostate cancer. Thirty-seven men with the diagnosis of prostate cancer were identified from 1459 male participants in the BLSA. Of these patients, 18 were older than age 60 yr and had participated in the study for at least 7 yr prior to the diagnosis of cancer. Patients were classified as having local, regional, or metastatic disease based on a clinical examination, a prostatic acid phosphatase determination, bone scan results, and a pathology report from the treating physician’s records. Sixteen subjects had no prior history of prostate disease and were selected as controls. Patients identified as controls were recruited between January 1990 and October 1990 when approx 200 men returned for their routine visits. Serum samples available in the BLSA serum bank were tested for serum PSA. Unfortunately, serum samples were not available for all subjects for each visit. A mixed effects regression model was used to test the hypothesis that, after controlling for the effect of age at diagnosis, PSA values increase faster in subjects with prostate cancer compared with controls. Observed PSA levels are shown for each patient as a function of years prior to diagnosis for subjects with prostate cancer. The patients with prostate cancer had signiﬁcantly greater rates of change in PSA levels compared with those patients without prostate cancer up to 10 yr before diagnosis. The graphs also demonstrate the variable progression of disease. Some patients with local or regional disease at diagnosis had an elevated serum PSA as much as 8 yr prior to diagnosis. Among patients presenting with metastatic disease, one patient had an elevated serum PSA level 16 yr prior to diagnosis. Unfortunately, no information was provided concerning the Gleason score of the patients with prostate cancer who were included in the study.

The Gann Study In 1995, Gann and colleagues (75) published a nested case-control study of men participating in the Physician’s Health Study (PHS), an ongoing randomized trial of βcarotene that enrolled 22,071 men aged 40–84 yr in 1982. Their purpose was to evaluate the validity of using PSA to screen for prostate cancer. A total of 366 men diagnosed with prostate cancer were matched to three controls by age. Controls were randomly selected from the entire cohort at risk at the time of case diagnosis. Gann et al. (75) reviewed the medical records of each case to determine the stage at diagnosis, tumor

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Fig. 2. Percent of tumors that theoretically could have been detected at earlier time than the actual diagnosis by prostate cancer screening using prostate-speciﬁc antigen. (Data derived from report by Gann PH, Hennekens CH, Sampfer MJ. A prospective evaluation of plasma prostate-speciﬁc antigen for detection of prostatic cancer. JAMA 1995;273:289–294.)

grade, Gleason score, type of presentation (screening vs symptoms), and PSA level just prior to treatment. If multiple tissue samples were available for evaluation, the highest Gleason score was recorded. Patients with regional or distant extension of their disease and all patients with Gleason scores of ≥7 were classiﬁed as having aggressive cancers. Patients with pathologically determined localized disease and Gleason score of ≤6 were classiﬁed as having nonaggressive cancers. The remaining patients who could not be staged pathologically and who had Gleason score ≤6 tumors were classiﬁed as having indeterminate aggressiveness. The mean age at baseline for both case patients and control patients was 62.9 yr, and the mean age at prostate cancer diagnosis was 68.7 yr. Figure 2 presents the distributions of lead times for fatal cancers and all cancers that were detectable by the baseline PSA level of 4 ng/mL or greater. On average, the diagnosis of prostate cancer was advanced 5.5 yr compared with the time of diagnosis in the pre-PSA era. This potential gain in lead time was based on a single screening PSA measurement and most likely underestimates the potential gain achieved by periodic screening. Lead time distributions for aggressive cancers (those with regional or distant extension of Gleason scores of 7–10) were similar to those of nonaggressive cancers (those with local extension only and a Gleason score of ≤6).

STUDIES REVIEWING THE NATURAL PROGRESSION OF DISEASE FOLLOWING TREATMENT Gerber et al. (76) published a multi-institutional pooled analysis of men with clinically localized prostate cancer treated by radical prostatectomy between 1970 and

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1993. They reported excellent 10-yr disease-speciﬁc survival estimates of 94, 80, and 77% for men with well (Gleason 2–4), moderate (Gleason 5–7), and poorly (Gleason 8–10) differentiated disease. Lu-Yao and Yao (68) estimated 10-yr disease-speciﬁc survival rates for men undergoing radical prostatectomy to be 94, 87, and 67% for men with well, moderate, and poorly differentiated disease, respectively (68). A review of these data initially suggests that radical prostatectomy is most efﬁcacious among men with well-differentiated disease and least efﬁcacious among men with poorly differentiated disease. Compared with the retrospective, population-based sample of 767 men diagnosed with localized disease in Connecticut during the same time period, we found that the 10-yr disease-speciﬁc survivals for men treated expectantly were 94, 71, and 30% for men with well, moderate, and poorly differentiated disease (70). Lu-Yao and Yao (69) estimated the 10-yr disease speciﬁc survival for expectant management to be 94, 77, and 45%, respectively. These results are identical to those reported by Gerber et al. (76) for men with well-differentiated disease, suggesting that expectant management achieves comparable results compared with radical prostatectomy for this subset of men. Conversely, results were much worse for men with poorly differentiated disease receiving expectant management, suggesting a potentially signiﬁcant advantage following surgery among men with poorly differentiated disease. These ﬁndings may be the result of selection biases, but the data suggest that expectant management is clearly not the optimal strategy for men with poorly differentiated cancers. For men with Gleason 5–7 tumors, the group of men most frequently targeted for aggressive intervention, disease-speciﬁc survival outcomes do not appear to be dramatically different. Gerber et al. (76) reported a 10-yr disease-speciﬁc survival of 80% (95% conﬁdence interval: 74–85) following radical prostatectomy. Data from Lu-Yao and Yao (68) estimated a 10-yr disease-speciﬁc survival of 77% (95% conﬁdence interval: 74–80), and our analysis suggests a 10-yr disease-speciﬁc survival of 72% (95% conﬁdence interval: 67–76) for men managed expectantly. Because of the signiﬁcant selection biases inherent in all three study groups, and the inadequate staging of many patients managed expectantly, it is difﬁcult to determine the relative efﬁcacy of surgery over expectant management for this group of patients. Lu-Yao and colleagues (77) also addressed this question from a different perspective. Using Medicare claims, they estimated the need for secondary cancer therapy among a group of Medicare patients diagnosed with prostate cancer during the period January 1, 1985 through December 31, 1991 and undergoing radical prostatectomy before December 31, 1992. Patients were considered to have had additional cancer therapy if they had radiation therapy, orchiectomy, and/or androgen-deprivation therapy by injection after radical prostatectomy. The interval between the initial treatment and any follow-up treatment was calculated from the date of radical prostatectomy to the ﬁrst day of the follow-up cancer therapy. The study population consisted of 3494 Medicare patients, 3173 of whom underwent radical prostatectomy within 3 mo of cancer diagnosis. A review of the surgical pathology reports suggested that <60% of patients whose records were included in the study had organ-conﬁned disease. Overall, the 5-yr cumulative incidence of having any additional cancer treatment after a radical prostatectomy was 35%. For patients with organ-conﬁned disease, the group most likely to beneﬁt from surgery, the 5-yr cumulative incidence of the need for additional cancer therapy was 24% and ranged from 16% for men with well-differentiated disease to 42% for

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men with poorly differentiated disease. Men with disease extending beyond the prostate capsule at the time of surgery had a much higher probability of needing additional treatment. Approximately 68% of men with poorly differentiated disease and extracapsular extension required additional cancer treatment within 5 yr of prostatectomy. For men at the greatest risk of disease progression, more than half required additional cancer therapy within 5 yr of undergoing a radical prostatectomy. These patients clearly need more effective therapies. The Mayo clinic recently published a competing risk analysis of men treated for presumed localized prostate cancer using radical prostatectomy (78). They reviewed the records of 751 men with clinically localized prostate cancer treated with radical prostatectomy between 1971 and 1984. They determined the incidence of death from prostate cancer and from other causes 20 yr following surgery. Patients’ competing medical hazards were quantiﬁed using the Charlson comorbidity score. In this report, Gleason score was the only signiﬁcant predictor of death from prostate cancer, whereas age and Charlson comorbidity score were signiﬁcant independent predictors of death from other causes. The 20-yr cumulative incidence of death from prostate cancer increased dramatically with higher Gleason scores. Younger patients had a slightly higher rate of death from prostate cancer, but for most age groups, outcomes were similar. For patients with Gleason scores 2–4, the cumulative incidence of death from prostate cancer was 6–7%. For patients with Gleason scores 8–10, the chance of dying from prostate cancer rose to 36–43%, with a slightly higher rate for younger patients. The chance of patients dying from other causes within 20 yr increased signiﬁcantly with age, regardless of Gleason score. The higher the Charlson score, the greater the chance of death from other causes for all age groups and Gleason scores. Conversely, the higher the Charlson score, the lower the chance of death from prostate cancer. These results are similar to those of studies focusing on conservative management. Radical prostatectomy appeared to have the greatest impact on survival among patients with poorly differentiated prostate cancer, including older patients. Approximately half of these men died from prostate cancer following surgery. However, their expected outcome with conservative management would probably have been much worse. Although most urologists currently tend to treat older patients with prostate cancer less aggressively than younger patients, this study suggests that healthy men in their seventies with poorly differentiated prostate cancer may beneﬁt from surgery. Because patients in this study were accrued prior to the widespread application of PSA, the impact of preoperative PSA on prostate speciﬁc and overall survival was not determined. Recently, Holmberg and associates (3) of the Scandinavian Prostatic Cancer Group published a report addressing the survival beneﬁt of radical prostatectomy compared with watchful waiting in patients with early-stage prostate cancer. A total of 348 men were assigned to watchful waiting and 347 to radical prostatectomy. After 8 yr of follow-up, the authors noted a 52% reduction in prostate cancer-speciﬁc mortality compared with those treated expectantly. Because the study cohort was diagnosed before the advent of PSA testing, the study participants had more advanced disease than is commonly seen in contemporary US practices. Approximately 76% of the patients enrolled in the trial had palpable disease, and only 12% of the cases were diagnosed as a result of an isolated elevation in PSA. A review of the cause-speciﬁc and all-cause survival curves reveals only a small difference between the two groups within the ﬁrst 5 yr after radical prostatectomy. The

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differences in disease-speciﬁc mortality and overall mortality between the two cohorts were only 2 and 1.5%, respectively, slightly favoring patients who had undergone radical prostatectomy. After 8 yr of follow-up, the difference in these categories increased to 6.6 and 6.3%, respectively, again slightly favoring patients treated with radical prostatectomy. These ﬁndings highlight the long follow-up required for a survival beneﬁt to emerge following surgery in men with prostate cancer. The lead time associated with PSA testing is likely to magnify this delay further.

SUMMARY Prostate cancer is a complex disease with an extraordinarily variable clinical outcome. The natural history of this disease is impacted by genetic factors, race, and environmental factors. Long-term outcomes are best predicted by tumor histology as measured by the Gleason scoring system. Based on information provided by randomized trials, population-based studies, and case series analyses, it appears that prostate cancer will inevitably progress to systemic disease and death if sufﬁcient time elapses. The competing risk analysis presented in Fig. 1 provides patients and clinicians with estimates of disease progression given a patient’s age and tumor histology at the time of diagnosis. These estimates are conservative and do not incorporate the lead time introduced by PSA testing. The advent of screening for prostate cancer using serum PSA has advanced the date of diagnosis for most patients diagnosed in the contemporary era. The lead time provided by PSA testing appears to be at least 5 yr and is similar for men with well-differentiated disease and poorly differentiated disease. Furthermore, PSA testing appears to have introduced a length bias that has dramatically increased the number of clinically insigniﬁcant tumors identiﬁed by transrectal ultrasound and prostate biopsy. The impact of treatment on the natural history of prostate cancer is uncertain and is best assessed through randomized clinical trials. Although case series and populationbased analyses suggest excellent outcomes for men with well-differentiated disease regardless of treatment, it is unclear how much aggressive intervention alters the natural history of this disease for men with well- and moderately differentiated disease. The recently published randomized trial conducted in Sweden suggests that intervention can decrease the incidence of disease progression for some men undergoing radical prostatectomy, but differences in overall survival compared with men receiving watchful waiting are not statistically different after 8 yr of follow-up. Men at high risk of dying from prostate cancer are those men diagnosed with Gleason score 7–10 tumors. These men have a 10-fold increased risk of dying from prostate cancer in the absence of treatment and therefore are the ones most likely to beneﬁt from treatment. By carefully documenting clinical outcomes and precisely stratifying patients by Gleason score and tumor volume as assessed using PSA measurements, clinicians and patients can obtain greater insights concerning how best to manage this complex disease. Carefully designed clinical trials such as the PIVOT trial in the United States and the Protect trial in the United Kingdom should provide important information concerning the impact of PSA screening and subsequent treatment on the natural history of this disease. Until then we are haunted by the words of the late Willet Whitmore, who ended his manuscript on the natural history of prostate cancer with the following comment: Only with better methods for deﬁning the natural history of the particular tumor, more sophisticated means for anticipating life expectancy of the individual host, and good

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data on the effects of various treatments on the quality and quantity of survival in patients with appropriately stratiﬁed tumors will it be possible to inject more science into the extant art of treatment of the prostatic cancer patient and substitute an era of cold fact for the present era of heated opinion (79).

Although written over 30 yr ago, these words still summarize the continued debate concerning the appropriate management of clinically localized prostate cancer. For now, observation is best reserved for men over age 75 yr, especially those men with signiﬁcant comorbidities who present with Gleason scores of ≤6 and whose PSA values suggest minimal tumor volume.

REFERENCES 1. Treatment and survival of patients with cancer of the prostate. The Veterans Administration Co-operative Urological Research Group. Surg Gynecol Obstet 1967;124:1011–1017. 2. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin 2003;53:5–26. 3. Holmberg L, Bill-Axelson A, Helegsen F, et al. for the Scandinavian Prostatic Cancer Group Study Number 4. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 2002;347:781–789. 4. Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC. Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci USA 1992;89:3367–3371. 5. Carter BS, Bova GS, Beaty TH, et al. Hereditary prostate cancer: epidemiologic and clinical features. J Urol 1993;150:797–802. 6. Narod SA, Dupont A, Cusan L, et al. The impact of family history on early detection of prostate cancer. Nat Med 1995;1:99–101. 7. Cerhan JR, Parker AS, Putnam SD, et al. Family history and prostate cancer risk in a population-based cohort of Iowa men. Cancer Epidemiol Biomarkers Prev 1999;8:53–60. 8. Lesko SM, Rosenberg L, Shapiro S. Family history and prostate cancer risk. Am J Epidemiol 1996;144:1041–1047. 9. Monroe KR, Yu MC, Kolonel LN, et al. Evidence of an X-linked or recessive genetic component to prostate cancer risk. Nat Med 1995;1:827–829. 10. Schaid DJ, McDonnell SK, Blute ML, Thibodeau SN. Evidence for autosomal dominant inheritance of prostate cancer. Am J Hum Genet 1998;62:1425–1438. 11. Matikainen MP, Schleutker J, Morsky P, Kallioniemi OP, Tammela TL. Detection of subclinical cancers by prostate-speciﬁc antigen screening in asymptomatic men from high-risk prostate cancer families. Clin Cancer Res 1999;5:1275–1279. 12. Gronberg H, Wiklund F, Damber JE. Age speciﬁc risks of familial prostate carcinoma: a basis for screening recommendations in high risk populations. Cancer 1999;86:477–483. 13. Smith JR, Freije D, Carpten JD, et al. Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 1996;274:1371–1374. 14. Berthon P, Valeri A, Cohen-Akenine A, et al. Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2-43. Am J Hum Genet 1998;62:1416–1424. 15. Xu J, Meyers D, Freije D, et al. Evidence for a prostate cancer susceptibility locus on the X chromosome. Nat Genet 1998;20:175–179. 16. Gibbs M, Stanford JL, McIndoe RA, et al. Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36. Am J Hum Genet 1999;64:776–787. 17. Bauer JJ, Srivastava S, Connelly RR, et al. Signiﬁcance of familial history of prostate cancer to traditional prognostic variables, genetic biomarkers, and recurrence after radical prostatectomy. Urology 1998;51:970–976. 18. Berry R, Schroeder JJ, French AJ, et al. Evidence for a prostate cancer-susceptibility locus on chromosome 20. Am J Hum Genet 2000;67:82–91. 19. Bratt O, Kristoffersson U, Lundgren R, Olsson H. Familial and hereditary prostate cancer in southern Sweden. A population-based case-control study. Eur J Cancer 1999;35:272–277. 20. Bastacky SI, Wojno KJ, Walsh PC, Carmichael MJ, Epstein JI. Pathological features of hereditary prostate cancer. J Urol 1995;153:987–992.

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21. Bratt O, Damber JE, Emanuelsson M, Gronberg H. Hereditary prostate cancer: clinical characteristics and survival. J Urol 2002;167:2423–2426. 22. Keetch DW, Humphrey PA, Smith DS, Stahl D, Catalona WJ. Clinical and pathological features of hereditary prostate cancer. J Urol 1996;155:1841–1843. 23. Valeri A, Azzouzi R, Drelon E, et al. Early-onset hereditary prostate cancer is not associated with speciﬁc clinical and biological features. Prostate 2000;45:66–71. 24. Gronberg H, Damber L, Tavelin B, Damber JE. No difference in survival between sporadic, familial and hereditary prostate cancer. Br J Urol 1998;82:564–567. 25. Bova GS, Partin AW, Isaacs SD, et al. Biological aggressiveness of hereditary prostate cancer: longterm evaluation following radical prostatectomy. J Urol 1998;160:660–663. 26. Hanus MC, Zagars GK, Pollack A. Familial prostate cancer: outcome following radiation therapy with or without adjuvant androgen ablation. Int J Radiat Oncol Biol Phys 1999;43:379–383. 27. Hanlon AL, Hanks GE. Patterns of inheritance and outcome in patients treated with external beam radiation for prostate cancer. Urology 1998;52:735–738. 28. Bratt O. Hereditary prostate cancer: clinical aspects. J Urol 2002;168:906–913. 29. von Eschenbach A, Ho R, Murphy GP, Cunningham M, Lins N. American Cancer Society guideline for the early detection of prostate cancer: update 1997. CA Cancer J Clin 1997;47:261–264. 30. Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin 2002;52:23–47. 31. Hsing AW, Tsao L, Devesa SS. International trends and patterns of prostate cancer incidence and mortality. Int J Cancer 2000;85:60–67. 32. Grossfeld GD, Latini DM, Downs T, Lubeck DP, Mehta SS, Carroll PR. Is ethnicity an independent predictor of prostate cancer recurrence after radical prostatectomy? J Urol 2002;168:2510–2515. 32a. Eastham JA, Kattan MW. Disease recurrence in black and white men undergoing radical prostatectomy for clinical stage T1–T2 prostate cancer. J Urol 2000;163:143–145. 33. Moul JW, Douglas TH, McCarthy WF, McLeod DG. Black race is an adverse prognostic factor for prostate cancer recurrence following radical prostatectomy in an equal access health care setting. J Urol 1996;155:1667–1673. 34. Schwartz KL, Severson RK, Gurney JG, Montie JE. Trends in the stage speciﬁc incidence of prostate carcinoma in the Detroit metropolitan area, 1973–1994. Cancer 1996;78:1260–1266. 35. Pienta KJ, Demers R, Hoff M, Kau TY, Montie JE, Severson RK. Effect of age and race on the survival of men with prostate cancer in the Metropolitan Detroit tricounty area, 1973 to 1987. Urology 1995;45:93–101; discussion 101–102. 36. Shimizu H, Ross RK, Bernstein L, Yatani R, Henderson BE, Mack TM. Cancers of the prostate and breast among Japanese and white immigrants in Los Angeles County. Br J Cancer 1991;63:963–966. 37. Kolonel LN. Fat, meat, and prostate cancer. Epidemiol Rev 2001;23:72–81. 38. Bruning PF, Bonfrer JM. Free fatty acid concentrations correlated with the available fraction of estradiol in human plasma. Cancer Res 1986;46:2606–2609. 39. Pusateri DJ, Roth WT, Ross JK, Shultz TD. Dietary and hormonal evaluation of men at different risks for prostate cancer: plasma and fecal hormone-nutrient interrelationships. Am J Clin Nutr 1990;51:371–377. 40. Kumar NB, Besterman-Dahan K. Nutrients in the chemoprevention of prostate cancer: current and future prospects. Cancer Control 1999;6:580–586. 41. Evans BA, Grifﬁths K, Morton MS. Inhibition of 5 alpha-reductase in genital skin ﬁbroblasts and prostate tissue by dietary lignans and isoﬂavonoids. J Endocrinol 1995;147:295–302. 42. Santibanez JF, Navarro A, Martinez J. Genistein inhibits proliferation and in vitro invasive potential of human prostatic cancer cell lines. Anticancer Res 1997;17:1199–1204. 43. Davis JN, Muqim N, Bhuiyan M, Kucuk O, Pienta KJ, Sarkar FH. Inhibition of prostate speciﬁc antigen expression by genistein in prostate cancer cells. Int J Oncol 2000;16:1091–1097. 44. Fotsis T, Pepper M, Adlercreutz H, et al. Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc Natl Acad Sci USA 1993;90:2690–2694. 45. Rosenberg Zand RS, Jenkins DJ, Brown TJ, Diamandis EP. Flavonoids can block PSA production by breast and prostate cancer cell lines. Clin Chim Acta 2002;317:17–26. 46. Kim H, Peterson TG, Barnes S. Mechanisms of action of the soy isoﬂavone genistein: emerging role for its effects via transforming growth factor beta signaling pathways. Am J Clin Nutr 1998;68(6 suppl):1418S–1425S. 47. Barnes RW. Survival with conservative therapy. JAMA 1969;210:331–332. 48. Albertsen PC, Fryback DG, Storer BE, Kolon TF, Fine J. Long-term survival among men with conservatively treated localized prostate cancer. JAMA 1995;274:626–631.

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49. Kaplan MH, Feinstein AR. The importance of classifying initial co-morbidity in evaluatin the outcome of diabetes mellitus. J Chron Dis 1974;27:387–404. 50. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–383. 51. Greenﬁeld S, Apolone G, McNeil BJ, Cleary PD. The importance of co-existent disease in the occurrence of postoperative complications and one-year recovery in patients undergoing total hip replacement. Comorbidity and outcomes after hip replacement. Med Care 1993;31:141–154. 52. Mellinger G, Gleason D, Bailar J. The histology and prognosis of prostatic cancer. J Urol 1967;97:331–337. 53. Weideranders R, Stuber RV, Mota C, O’Connell D, Haslam GJ. Prognostic value of grading prostatic carcinoma. J Urol 1963;89:881–888. 54. Gleason D. Histologic grading and clinical staging of prostatic carcinoma. In: Tannenbaum M, ed. Urologic Pathology: The Prostate. Lea & Febiger, Philadelphia, 1977, pp. 171–198. 55. McNeal JE, Bostwick DG, Kindrachuk RA, Redwine EA, Freiha FS, Stamey TA. Patterns of progression in prostate cancer. Lancet 1986;1:60–63. 56. Stamey TA, Yang N, Hay AR, McNeal JE, Freiha FS, Redwine E. Prostate-speciﬁc antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987;317:909–916. 57. Stamey TA, Freiha FS, McNeal JE, Redwine EA, Whittemore AS, Schmid HP. Localized prostate cancer. Relationship of tumor volume to clinical signiﬁcance for treatment of prostate cancer. Cancer 1993;71(3 suppl):933–938. 58. Catalona WJ, Smith DS, Ratliff TL, Basler JW. Detection of organ-conﬁned prostate cancer is increased through prostate-speciﬁc antigen-based screening. JAMA 1993;270:948–954. 59. Partin AW, Kattan MW, Subong EN, et al. Combination of prostate-speciﬁc antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA 1997;277:1445–1451. 60. Johansson JE, Adami HO, Andersson SO, Bergstrom R, Krusemo UB, Kraaz W. Natural history of localised prostatic cancer. A population-based study in 223 untreated patients. Lancet 1989;1:799–803. 61. Johansson JE, Adami HO, Andersson SO, Bergstrom R, Holmberg L, Krusemo UB. High 10-year survival rate in patients with early, untreated prostatic cancer. JAMA 1992;267:2191–2196. 62. Johansson JE, Holmberg L, Johansson S, Bergstrom R, Adami HO. Fifteen-year survival in prostate cancer. A prospective, population-based study in Sweden. JAMA 1997;277:467–471. 63. Chodak GW, Thisted RA, Gerber GS, et al. Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994;330:242–248. 64. Jones GW. Prospective, conservative management of localized prostate cancer. Cancer 1992;70(1 suppl):307–310. 65. Whitmore WF Jr, Warner JA, Thompson IM Jr. Expectant management of localized prostatic cancer. Cancer 1991;67:1091–1096. 66. Adolfsson J, Carstensen J, Lowhagen T. Deferred treatment in clinically localised prostatic carcinoma. Br J Urol 1992;69:183–187. 67. Goodman CM, Busuttil A, Chisholm GD. Age, and size and grade of tumour predict prognosis in incidentally diagnosed carcinoma of the prostate. Br J Urol 1988;62:576–580. 68. Moskovitz B, Nitecki S, Richter Levin D. Cancer of the prostate: is there a need for aggressive treatment? Urol Int 1987;42:49–52. 69. Lu-Yao GL, Yao SL. Population-based study of long-term survival in patients with clinically localised prostate cancer. Lancet 1997;349:906–910. 70. Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998;280:975–980. 71. Black WC, Welch HG. Advances in diagnostic imaging and overestimations of disease prevalence and the beneﬁts of therapy. N Engl J Med 1993;328:1237–1243. 72. Thompson IM, Goodman PJ, Tangen CT, et al. The inﬂuence of Finasteride on the development of prostate cancer. N Engl J Med 2003;349:213–222. 73. Lu-Yao GL, McLerran D, Wasson J, Wennberg JE. An assessment of radical prostatectomy. Time trends, geographic variation, and outcomes. The prostate patient outcomes research team. JAMA 1993;269:2633–2636. 74. Carter HB, Pearson JD, Metter EJ, et al. Longitudinal evaluation of prostate-speciﬁc antigen levels in men with and without prostate disease. JAMA 1992;267:2215–2220. 75. Gann PH, Hennekens CH, Stampfer MJ. A prospective evaluation of plasma prostate-speciﬁc antigen for detection of prostatic cancer. JAMA 1995;273:289–294.

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76. Gerber GS, Thisted RA, Scardino PT, et al. Results of radical prostatectomy in men with clinically localized prostate cancer. JAMA 1996;276:615–619. 77. Lu-Yao GL, Potosky AL, Albertsen PC, Wasson JH, Barry MJ, Wennberg JE. Follow-up prostate cancer treatments after radical prostatectomy: a population-based study. J Natl Cancer Inst 1996;88:166–173. 78. Sweat SD, Bergstralh EJ, Slezak J, Blute ML, Zincke H. Competing risk analysis after radical prostatectomy for clinically nonmetastatic prostate adenocarcinoma according to clinical Gleason score and patient age. J Urol 2002;168:525–529. 79. Whitmore WF Jr. Proceedings: the natural history of prostatic cancer. Cancer 1973;32:1104–1112.

11

Contemporary Technique of Radical Prostatectomy Open Approach

Eric A. Klein

INTRODUCTION Radical retropubic prostatectomy remains a popular therapy for localized prostate cancer and is frequently performed in most urologic practices. The current technique for this procedure, developed from watching many experienced surgeons, studying published descriptions, and a large surgical experience, is described. There are many ways to accomplish the goals of any operation, and what is described is what has worked best in terms of pathologic and functional results in more than 1500 patients.

PREOPERATIVE PREPARATION All patients undergo face-to-face preoperative counseling, preferably including spouses or other partners, for discussion of the general nature of the procedure, potential complications (including incontinence, impotence, and the potential need for transfusion), and the postoperative routine. Speciﬁc emphasis is placed on the use of epidural anesthesia, whether lymphadenectomy is to be performed, whether a nerve-sparing procedure is contemplated, and planned hospital length of stay. Patients donate 1 or 2 U of autologous blood at their option. A preoperative urinalysis should demonstrate no active infection. The diet is restricted to clear liquids on the day prior to surgery with a Fleet’s enema the evening before or the morning of surgery. Patients are admitted to the operating room (OR) on the day of surgery. A second-generation cephalosporin is given intravenously on call to the OR and for two doses postoperatively. Intermittent compression stockings are used for prophylaxis against deep venous thrombosis.

ANESTHETIC CONSIDERATIONS Epidural anesthesia alone is the preferred technique for all patients. The complete theoretic rationale and details of this technique are described in a separate chapter. From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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Klein Table 1 Comparison of Outcomes for Epidural Alone vs Epidural Plus General Anesthesia

Pain score (1–10) On arrival in recovery room Mean, ﬁrst 24 h Postoperative bupivacaine requirement (mg) Postoperative morphine sulfate requirement (mg) Highest sedation score Transfusion requirement (mean no. of units) Mean length of stay (d) Relative cost

General + epidural (n = 69)

Epidural alone (n = 119)

p value

2.6 2.6 195 10 2.2 1.2 2.9 1.07

1.0 1.5 111 7.4 1.5 0.8 2.7 1.00

<0.0001 0.0002 <0.0001 <0.0001 <0.0001 0.016 ns <0.0001

Briefly, the epidural catheters are placed in the low thoracic position preoperatively in an induction area by a dedicated team, and the patient is dosed with 0.1% bupivacaine and morphine sulfate 0.05 mg/mL upon arrival in the operating room. This combination of position and drugs has been demonstrated to promote early return of intestinal function by sympathetic blockade (1). Analgesia is maintained intra- and postoperatively with morphine sulfate or fentanyl, and low doses of anxiolytics are given parenterally throughout the procedure as needed. This regimen has been associated with a high degree of patient acceptance, few complications, and a conversion rate to general anesthesia of <3%. Epidural anesthesia avoids the need for ventilatory support and eliminates pulmonary and laryngeal complications. A comparison of epidural alone vs epidural plus general anesthesia demonstrates that epidural anesthesia alone results in better postoperative analgesia as assessed by patient self-report using validated instruments, causes less sedation, results in lower narcotic use, requires fewer transfusions, and is cheaper (Table 1).

PATIENT POSITIONING The patient is placed in the supine position with the table in mild reverse Trendelenburg position to facilitate exposure of the apex. Once the apical dissection is completed, the table is placed in mild Trendelenburg position to facilitate visualization and dissection of the bladder neck.

INCISION, EXPOSURE, AND RETRACTOR PLACEMENT An 18-F Foley catheter is placed transurethrally, and the balloon is inﬂated with 10mL of water prior to incision. A midline incision is made from below the umbilicus to the top of the pubis (Fig. 1), usually 4–6 inches in length depending on individual patient anatomy. The space of Retzius is developed bluntly, and the bladder is mobilized off the pelvic sidewall bilaterally. The peritoneum is also mobilized superiorly, exposing the psoas muscles bilaterally. The vas deferens is not routinely divided. A

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Fig. 1. An 18-F Foley catheter is placed transurethrally, and an extraperitoneal incision is made in the lower midline.

Bookwalter retractor with blades speciﬁcally modiﬁed for the performance of radical prostatectomy is placed (2), providing untiring retraction for the duration of the case (Fig. 2A and B). When pelvic lymphadenectomy is performed, a malleable blade is secured to the ring for lateral retraction of the bladder, permitting full visualization of the obturator fossa (Fig. 3).

PELVIC LYMPHADENECTOMY Based on published nomograms and our own experience, pelvic lymphadenectomy is omitted in selected patients at low risk for lymph node metastases based on preoperative serum prostate-speciﬁc antigen (PSA), tumor grade, and palpable tumor extent (3). Speciﬁcally, lymphadenectomy is omitted in patients with all three of the following criteria: preop PSA ≤ 10 ng/mL, biopsy Gleason sum ≤ 6, and clinical stage T1c (nonpalpable) or T2a (nodule involving < one-half of one lobe). Such patients have only a 0.3% likelihood of positive nodes, much less than the estimated 1% chance of a complication resulting from lymphadenectomy. Furthermore, we have recently demonstrated that omission of lymphadenectomy in men with these characteristics does not increase the likelihood of biochemical failure (4). Pelvic lymphadenectomy is routinely performed in

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Fig. 2. (A) A self-retaining, table-ﬁxed ring retractor is placed. The prostatic apex is to the left. (Figure continues)

any patient with preop PSA > 10 ng/mL (regardless of grade or stage), any Gleason sum ≥7 (regardless of PSA or stage), and for clinical stage ≥ T2b (regardless of PSA or grade). When performed, lymphadenectomy is limited to the obturator fossa bilaterally and is considered prognostic but not therapeutic. The limits of dissection include the undersurface of the external iliac vein superiorly, the pelvic sidewall laterally, the obturator nerve deep, the bifurcation of the common iliac vein cephalad, and the origin of the superﬁcial circumﬂex iliac vein caudally. Frozen section analysis is not routinely performed unless the nodes are grossly suspicious, as in our experience the overall rate of positive nodes is < 2%, and 50% of lymph node metastases seen on permanent histology are missed by frozen section (3).

ENDOPELVIC AND LATERAL PELVIC FASCIA, SANTORINI’S PLEXUS, AND THE DORSAL VEIN COMPLEX The apical dissection is the most challenging part of a radical prostatectomy, as the dorsal vein complex, neurovascular bundles, and the distal sphincter share a close

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Fig. 2. (continued) (B) Detail of blade placement. The two cephalad blades pull the bladder out of the pelvis and obviate the need to overinﬂate the Foley balloon.

anatomic relationship. Clinical experience has shown that a careful apical dissection can limit blood loss, preserve potency, and maintain high continence rates. Recent modifications in surgical technique during this portion of the procedure have had a significant impact on the approach to nerve sparing and improving the return of urinary control. In a standard retropubic approach, after incision of the endopelvic fascia, the puboprostatic ligaments are routinely divided along the posterior aspect of the pubis to obtain better exposure of the dorsal vein complex. Cadaveric studies have demonstrated that the puboprostatic ligaments support the proximal pendulous urethra and attach the membranous urethra and the striated sphincter to the underside of the pubis (5). This urethral suspensory mechanism may play an important role in maintaining effective distal sphincter function and suggests that preserving the puboprostatic ligaments may help return of continence. Two recent studies have demonstrated earlier return of urinary control, less blood loss, and no compromise of margin status in patients in whom the puboprostatic ligaments were preserved (Table 2) (6,7). Gaining control of the dorsal vein complex is critical for hemostasis as well as for exposure of the prostatic apex. Preservation of the striated urethral sphincter, which lies just underneath the dorsal vein and envelopes the urethra and prostatic apex, is essential for return of continence. A variety of methods have been proposed for division and control

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Fig. 3. A malleable blade is used for exposure of the obturator fossa when pelvic lymphadenectomy is performed.

Table 2 Effect of Sparing Puboprostatic Ligaments on Continence (% Continent) Lowe (6) Time after catheter removal (mo) Immediate 1 3 6 12

Poore et al. (7)

Ligaments divided a

Ligaments spared

Ligaments divided

Ligaments spared

0 15 51 79 89

26 49 80 96 100

11 15 51 75 94

28 39 82 94 100

a

Best result achieved in non-ligament-sparing groups. Adapted from refs. 7 and 8.

of the dorsal vein, with similar blood loss and ultimate functional results (Table 3) (8–10). Our experience has led us to the following modiﬁcations of the apical dissection, leading to a typical blood loss of 100–300 mL from the dorsal vein prior to suture ligation, excellent urethral exposure and preservation of urethral length, and excellent visualization of the neurovascular bundles at the apex prior to their dissection.

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Table 3 Effect of Various Techniques of Dorsal Vein Control on Continence % Continent Modiﬁcation Ligation and transection Creation of urethral hood Bunching technique

Immediate

1 mo

3 mo

12 mo

10 8 33

33 41 60

57 76 89

90 93 99

Adapted from ref. 10.

Fig. 4. The endopelvic fascia is incised bilaterally just lateral to the prostatic apex. The attachments of the levator muscles to the lateral surface of the prostate are taken down sharply with scissors. The puboprostatic ligaments are left intact.

The apical dissection begins in standard fashion with a vertical incision of the endopelvic fascia at the apex bilaterally (Fig. 4). The attachments of the levator muscles to the lateral surface of the prostate are taken down sharply with scissors. Blunt dissection of these attachments should be avoided to prevent shearing of small blood vessels, which may be difﬁcult to control. The puboprostatic ligaments are left intact. The urethral catheter will be easily palpable beyond the prostatic apex, when all the muscular attachments have been released.

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Fig. 5. The lateral pelvic fascia (the visceral layer of the endopelvic fascia covering the prostate) is elevated with a right-angled clamp and incised sharply with a knife (along the dotted line) from the apex to base of the prostate. This maneuver exposes the anterior prostatourethral junction and the position of the neurovascular bundles and facilitates control of the ramiﬁcations of the dorsal vein over the prostate. The maneuver is then repeated on the opposite side (not shown).

Next the lateral pelvic fascia (the visceral portion of the endopelvic fascia) covering the prostate is incised bilaterally beginning from the initial incision in the apical endopelvic fascia and extending to the base of the prostate (Fig. 5). The incision is performed high on the lateral surface of the prostate to avoid injuring the neurovascular bundles. When completed, this maneuver allows clear visualization of the prostatourethral junction, the location of the neurovascular bundles, and facilitates bunching of the ramifications of the dorsal vein over the prostate. The cut edges of the lateral fascia are then grasped with Turner-Babcock clamps, incorporating the branches of the venous plexus on the dorsolateral surface of the prostate (Fig. 6A). The plexus is suture-ligated with two individual figure-of-eight 0-chromic ligatures (Fig. 6B and C). This technique prevents back-bleeding when the dorsal vein is divided and helps identify the plane between the dorsal vein and urethra.

Fig. 6. Bunching technique for control of the dorsal venous complex. (A) Turner-Babcock clamps are used to bunch together the branches of the dorsal vein covering the dorsal surface of the prostate. (B) Two ﬁgure-of-eight sutures are used to ligate these branches, incorporating the cut edges of the endopelvic fascia. (Figure continues)

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Fig. 6. (continued) (C) Appearance after both sutures have been placed.

Incision and control of the dorsal vein varies by individual patient anatomy. In patients in whom a clear separation or notch is palpable between the posterior surface of the dorsal vein and the anterior surface of the urethra, a right-angled clamp is passed between them (Fig. 7A). Identiﬁcation of this plane is facilitated by ﬁnger palpation of the prostatic apex and urethral catheter, and in many patients this maneuver can be performed under direct vision. Precise placement behind the fascial sheath of the dorsal vein complex also will permit it to retract fully and help minimize bleeding. After passage of the clamp, the free end of a suture is grasped and pulled under the dorsal vein. The suture is then anchored anterior to the dorsal vein in the periosteum of the pubis and tied for distal control. The clamp is then repassed in the same plane, and the dorsal vein is divided sharply between the sutures (Fig. 7B). A ﬁgure-of-eight 0-

Fig. 7. Division and control of the dorsal vein. The prostatic apex is to the left. (A) A right-angled clamp is placed between the anterior surface of the urethra and posterior surface of the dorsal vein distal to the ﬁgure-of-eight sutures. The inset shows the correct plane between the dorsal vein and urethra. (B) The dorsal vein is divided sharply with a knife. (Figure continues)

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Fig. 7. (continued) (C) The cut surface of the dorsal vein is suture-ligated for hemostasis. (Figure continues)

chromic suture is placed for additional hemostasis (Fig. 7C). When correctly performed, this technique does not compromise the anterior prostatic margin and results in excellent visualization of the urethra (Fig. 7D). In some patients the dorsal vein and urethra are closely approximated, and passage of an instrument between them carries the risk of damaging the anterior striated sphincter. In such patients a distal stitch is placed around the dorsal vein and tied, and the dorsal vein is divided with scissors. This technique is usually associated with more bleeding than with passage of a clamp between the dorsal vein and urethra, but with experience does not compromise the anterior prostatic margin and is safer in some patients.

RELEASE OF THE NEUROVASCULAR BUNDLES For nerve-sparing procedures, the neurovascular bundles are next released from the prostate from the apex to the level of the vascular pedicle lateral to the seminal vesicles.

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Fig. 7. (continued) (D) Appearance of the urethra after division and ligation of the dorsal vein.

The dissection is performed with ﬁne-tipped scissors and begins at the midprostate with identiﬁcation of the most superior periprostatic vein, which marks the upper extent of the bundle. The dissection is carried sharply around the edge of the prostate bilaterally, entering the plane posterior to Denonvillier’s fascia and anterior to the rectum (Fig. 8). This plane is fully developed by sharp dissection, using a sponge stick for gentle rotation of the prostate (Fig. 8A). When this plane is fully developed, the prostate can be lifted off the rectal surface (Fig. 8B). This maneuver yields excellent visualization of the prostatourethral junction both anteriorly and posteriorly and allows precise transection of the urethra without risk of incision into the prostatic apex. For a non-nerve-sparing procedure, the incision in the lateral pelvic fascia is made lateral to the bundles to permit wide excision of all periprostatic tissue (Figs. 8C and D). The plane between the prostate and rectum is developed similarly. There are several advantages to the approach described. Initial release of the lateral pelvic fascia allows superior visualization of the junction between the rectum and prostate, with precise deﬁnition of the plane of dissection between these organs leav-

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Fig. 8. Release of the neurovascular bundles. The prostatic apex is to the left. (A) The left neurovascular bundle is exposed by rotating the prostate medially with a sponge stick and released from the prostate by sharp dissection from the apex to the posterior vascular pedicle. The inset shows the plane of dissection medial to the bundle and posterior to Denonvilliers’ fascia. A similar dissection is performed on the other side. (B) When the dissection is complete, the prostate can be lifted off the anterior surface of the rectum. The urethra remains intact at this point of the dissection. (C and D) The dissection is similar for non-nerve-sparing procedures, except that the lateral fascia is incised lateral to the neurovascular bundles. The plane between the prostate and rectum is developed similarly to the nerve-sparing technique.

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Klein Table 4 Margin Status As a Function of Surgical Technique Classical technique

Overall Nerve-sparing Non-nerve-sparing

Current technique a

No.

Positive margins (%)

No.

Positive margins (%)

p value

198 132 66

37 44 30

152 116 36

16 15 17

0.0013 0.0012 0.0046

a Current technique means that described in the text, with release of the lateral fascia and neurovascular bundles prior to urethral transection. Use of this technique was associated with more than double the likelihood of achieving negative margins (odds ratio 2.046, 95% CI 1.23–3.92), even when controlling for differences in rates of extracapsular extension and other pathologic features. In patients with favorable tumor characteristics (PSA < 10 ng/mL, Gleason sum ≤ 6, and clinical stage T1c or T2a), the positive margin rate with our current technique is 8%. Adapted from ref. 11.

ing all layers of Denonvillier’s fascia on the prostate. This reduces the likelihood of a positive margin along the posterior aspect of this fascia. Lifting the prostate off the rectum early in the dissection also permits precise delineation of the anatomy of the prostatic apex, especially posterior to the urethra, and prevents leaving small amounts of prostatic tissue attached to the urethra. Improved visualization of the apex using this technique also incorporates one of the main advantages of the perineal approach while still permitting adequate visualization and resection of the bladder neck and seminal vesicles. This technique also fully preserves the posterior fascial attachments of the urethra. Finally, dissection of the neurovascular bundles away from the prostate prior to transection of the urethra lowers the risk of traction injury when the apex is elevated. We have recently reported our results using this technique, demonstrating a lower incidence of positive margins and similar functional results to the classical approach (Table 4) (11).

DIVISION OF THE URETHRA AND PLACEMENT OF URETHROVESICAL SUTURES Following division of the dorsal vein complex and release of the lateral fascia and neurovascular bundles, the prostate remains attached at the apex only by the urethra. There are several important considerations in dividing the urethra. An attempt should be made to preserve as long a segment of urethra as possible without leaving prostate tissue attached. Walsh et al. (8) describe the tissue around the posterior aspect of the urethra as the lateral and posterior portions of the striated urethral sphincter at their attachment to Denonvilliers’ fascia. The posterior component of the sphincter is incorporated into the vesicourethral anastomosis. Considering this modification in technique as an extension of the earlier described preservation of the thicker anterior segment of the sphincter, the authors note an earlier return of urinary continence. We have described a similar approach to preserving the posterior attachments of the urethra (12). Without passing a clamp around the urethra, the anterior and then the posterior wall of the urethra is divided in situ while still attached to the underlying fascia. The fascia is then incised distal to the cut edge of the urethra under direct vision, and the divided fascia is included in the anastomosis. We ini-

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Fig. 9. Urethral division and placement of urethral sutures. (A) The anterior urethra is incised sharply from the 3- to 9-o’clock position, exposing the Foley catheter. (Figure continues)

tially reported early results using this technique in 83 patients (13). Complete continence without need for pads was attained in 88% using this technique. Seventeen percent of patients were dry by the first week after catheter removal, and all continent patients were dry by 4 mo. An extended experience in more than 1000 patients has confirmed these results, with approx 50% of patients dry within 2 wk of catheter removal. Division of the urethra begins with an incision of the anterior surface between 3- and 9 o’clock (Fig. 9A), exposing the Foley catheter. The catheter is next removed to allow placement of the vesicourethral anastomotic sutures. Placement of these sutures is facilitated by leaving the posterior urethra attached to the prostate in order to prevent urethral retraction (Fig. 9B). Five sutures of absorbable material are used for the anastomosis, placed at the 2-, 4-, 6-, 8-, and 10-o’clock positions, taking care to avoid the neurovascular bundles lying posterolaterally (Fig. 9C). The neurovascular bundles may be gently pushed out of the way with a ﬁnger to facilitate suture placement. With experience, placement of these sutures can usually be easily accomplished from outside to inside without the need for double-armed sutures or a urethral sound. The sutures with

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Fig. 9. (continued) (B) The Foley catheter is removed, and two anterior and three posterior anastomotic sutures are placed at the 2-, 4-, 6-, 8, and 10-o’clock positions. Leaving the posterior urethra attached facilitates suture placement by preventing urethral retraction. (C) The posterior urethra is divided sharply under direct vision, using gentle traction on the apex of the prostate for exposure. (D) Final appearance of the divided urethra with anastomotic sutures in place.

needles still attached are held with small hemostats labeled with the corresponding clock face position to avoid entanglement until the anastomosis is completed, as described subsequently. Urethral transection, including the underlying layers of Denonvilliers’ fascia, is next completed under direct vision using scissors and gentle traction on the prostatic apex for exposure (Fig. 9D). To minimize traction injury, the Foley catheter is not replaced into the prostate until the neurovascular bundles are fully released by division of the posterolateral pedicles.

POSTERIOR VASCULAR PEDICLES, BLADDER NECK, AND SEMINAL VESICLES Dissection of the posterior vascular pedicles is easily accomplished after completion of the apical dissection. Placing the table in mild Trendelenburg position and

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gentle traction on the prostate facilitates visualization for this portion of the procedure. It has generally been our approach to perform the bladder neck dissection prior to dissection of the seminal vesicles to permit leaving as much fascia as possible on both sides of these glands, although the “posterior peel” technique of seminal vesicle dissection prior to bladder neck dissection is occasionally used for glands with large median lobes. Dissection of the prostate base begins with complete release of the neurovascular bundle lateral to the posterolateral pedicle. In this area the neurovascular bundle is typically tethered to the prostate by a single branch, which is divided between small hemostatic clips. Next, a right-angled clamp is used to develop the plane between the posterolateral pedicle and the lateral surface of the seminal vesicle (Fig. 10). The pedicle should be ligated high to avoid damage to the neurovascular bundle and pelvic plexus, which lie just lateral to the tips of the seminal vesicles. Ligation of these pedicles allows good exposure of the junction of the prostate and bladder neck and facilitates passage of a right-angled clamp between the posterior bladder neck and anterior surface of the seminal vesicles (Fig. 11A). The bladder neck is then incised sharply in a direction that preserves its anatomic integrity as much as possible and that avoids cutting into the trigone near the ureteral oriﬁces (Fig. 11B). In cases of high-grade or large-volume tumor at the prostate base, a larger cuff of bladder neck is removed to ensure an adequate margin of normal tissue. Release of the prostate from the bladder neck exposes the posterior surface of the vas deferens and seminal vesicles (Fig. 11C). The vas are individually ligated with clips and divided, the remaining attachments of the seminal vesicles are then dissected sharply (Fig. 11D), ligating the small arterial branch at the tips of the glands, and the specimen is removed.

COMPLETION OF THE ANASTOMOSIS The ﬁnal step is completion of the vesicourethral anastomosis. The mucosa just inside the bladder neck is prolapsed over the bladder opening with interrupted 4-0 chromic sutures. When necessary, the bladder neck is reconstructed using 3-0 chromic suture. The anastomotic sutures previously placed in the urethra are placed in corresponding positions in the bladder neck (Fig. 12A). The cephalad two retractor blades (Fig. 2) are removed, releasing the bladder into the pelvis. The needles are removed from the sutures, and the sutures are tied sequentially, beginning with the posterior row and without a Foley catheter in place. The 4- or 8-o’clock suture is tied ﬁrst, followed by the 6-o’clock suture, followed by the remaining posterior suture. Omitting the Foley catheter while tying the anastomotic sutures allows the surgeon’s hands to descend fully into the pelvis to ensure full approximation of the urethra and bladder neck. A 20-F Foley catheter is next placed per urethra and guided into the bladder with a ﬁnger placed over the bladder neck opening. The two anterior sutures are then tied to complete the anastomosis (Fig. 12B), and the Foley balloon is inﬂated with 10mL of water. Use of a Foley with an overinﬂated balloon and traction on the bladder neck prior to tying the sutures is avoided, as the balloon simply ﬁlls up the already small space of the pelvis and may prevent good approximation of the bladder neck and urethra. The anastomosis is checked for water-tightness by irrigation via the Foley, and additional sutures are placed if necessary. Closed suction drains are placed through separate incisions through the body of the rectus muscle and left in the obturator fossa. Only a single drain is used in

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Fig. 10. The posterior vascular pedicles are divided bilaterally between clips. This exposes the junction of the bladder and prostate.

patients in whom no pelvic lymphadenectomy is performed. The incision is closed in a single layer with running nonabsorbable suture, and the skin is approximated with clips.

POSTOPERATIVE ROUTINE A detailed description of our postoperative regimen has been published elsewhere (14). Briefly, patients are ambulated on the evening of or morning following surgery. A clear liquid diet is begun on postoperative d 1 and advanced as tolerated. Analgesia is maintained with continuous and on-demand morphine sulphate plus bupivacaine via epidural catheter for 24 h, followed by iv/po ketorolac and ibuprofen as needed. The drains are removed after 48 h unless there is clinical suspicion of a urine leak. Ninety-nine percent of patients are discharged after two nights of hospitalization. Patients return 7 d after discharge for incisional staple and catheter removal. Cystograms are not routinely performed. We have previously demonstrated that this accelerated postop regimen is well tolerated by patients and reduces cost associated

Fig. 11. Bladder neck dissection. (A) A right-angled clamp is inserted in the plane between the posterior bladder neck and the seminal vesicles. This maneuver helps identify the correct plane for bladder neck dissection without injury to the trigone. (Figure continues)

Fig. 11. (continued) (C) Release of the prostate from the bladder neck exposes the posterior surface of the vas deferens and seminal vesicles. The vasa are ligated with clips and divided. (D) The attachments to the seminal vesicles are divided, and the specimen is removed.

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Fig. 12. Vesicourethral anastomosis. (A) The ﬁve urethral sutures are placed into the bladder neck at the corresponding positions after eversion of the bladder neck mucosa. The inset shows detail of bladder neck suture placement after mucosal eversion. (B) The vesicourethral sutures are tied circumferentially over a 22-F Foley catheter (left). The ﬁnal appearance of the completed anastomosis is illustrated (right).

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Table 5 Acute Complications After Radical Prostatectomy Complication

No.

%

Lymphatic or urine leak Catheter-related Wound Ileus Bleeding/pelvic hematoma Acute myocardial infarction Miscellaneous other Mortality Total

10 8 3 4 1 1 10 0 37

1.9 1.4 0.6 0.7 0.2 0.2 1.9 0 6.9

Data from most recent 540 consecutive cases.

with radical prostatectomy without compromising the quality of care based on acute complications, hospital readmissions, or mortality (14).

ACUTE COMPLICATIONS AND PATHOLOGIC AND FUNCTIONAL RESULTS The overall acute complication rate in a recent cohort of 540 consecutive cases was 6.9% (Table 5). Most of these were minor and resolved without further sequelae. Bladder neck contractures occur in 2% of patients and usually resolve with a single dilation under local anesthesia performed in the office. Overall continence as defined by the need for pads is 90%, with 10% requiring one or two pads per day for stressrelated leakage, and <1% requiring a sling or artificial urinary sphincter. Potency rates depend on age, ease of nerve sparing, number of bundles preserved, and comorbidity, with the best results achieved in healthy men aged ≤ 62 yr. In a recent unpublished tabulation, 66 of 100 consecutive men aged 41–62 yr with bilateral nerve sparing and no significant comorbidities reported an IIEF score ≥22 at 1 yr after surgery. Using the lateral fascial technique described, the positive margin rate for the most recent 600 consecutive tumors with favorable features (PSA <10, biopsy Gleason sum ≤ 6, and clinical stage T1c or T2a) was 8%.

CONCLUSIONS Experience with and modiﬁcations in the technique of radical retropubic prostatectomy have yielded improved functional and pathologic outcomes and continue to make this operation an excellent choice for men with localized disease.

REFERENCES 1. Scheinen B, Asantila R, Orko R. The effect of bupivacaine and morphine on pain and bowel function after colonic surgery. Acta Anaesthesiol Scand 1987;31:161–164. 2. Klein EA. Modification of the Bookwalter retractor for radical prostatectomy. Contemp Urol 1998;10:65–69. 3. Campbell SC, Klein EA, Piedmonte C. Open pelvic lymphadenectomy for prostate cancer: a reassessment. Urology 1995;46:352–355.

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4. Fergany A, Kupelian PA, Levin HS, Zippe CD, Reddy C, Klein EA. No difference in biochemical failure rates with or without pelvic lymph node dissection during radical prostatectomy in low risk patients. Urology 2000;56:92–95. 5. Steiner MS. The puboprostatic ligament and the male urethral suspensory mechanism: an anatomic study. Urology 1994;44:530–534. 6. Lowe BA. Preservation of the anterior urethral ligamentous attachments in maintaining post-prostatectomy urinary continence: a comparative study. J Urol 1997;158:2137–2141. 7. Poore RE. McCullough DL. Jarow JP. Puboprostatic ligament sparing improves urinary continence after radical retropubic prostatectomy. Urology 1998;51:67–72. 8. Walsh PC. Quinlan DM. Morton RA. Steiner MS. Radical retropubic prostatectomy. Improved anastomosis and urinary continence. Urol Clin North Am 1990;17:679–684. 9. Eastham JA, Kattan MW, Rogers E, et al. Risk factors for urinary incontinence after radical prostatectomy. J Urol 1996;156:1707–1713. 10. Kaye KW. Creed KE. Wilson GJ. D’Antuono M. Dawkins HJ. Urinary continence after radical retropubic prostatectomy. Analysis and synthesis of contributing factors: a uniﬁed concept. Br J Urol 1997;80:444–501. 11. Klein EA, Kupelian P, Tuason L, Levin HS. Initial dissection of the lateral fascia reduces the positive margin rate in radical prostatectomy. Urology 1998;51:766–773. 12. Klein EA. Early continence after radical prostatectomy. J Urol 1992;148:92–95. 13. Klein EA. Modified apical dissection for early continence after radical prostatectomy. Prostate 1993;22:217–223. 14. Klein EA, Grass JA, Calabrese DA, Kay RA, Sargeant MBA, O’Hara JF. Maintaining quality of care and patient satisfaction with radical prostatectomy in the era of cost containment. Urology 1996;48:269–276. 15. Gaker DL. Gaker LB. Stewart JF. Gillenwater JY. Radical prostatectomy with preservation of urinary continence. J Urol 1996;156:445–449.

12

Contemporary Technique of Radical Prostatectomy Laparoscopic Approach

Sidney C. Abreu, Andrew P. Steinberg, and Inderbir S. Gill

INTRODUCTION Once considered an unpopular operation with signiﬁcant morbidity, radical retropubic prostatectomy has evolved into a reﬁned, anatomically precise operation with satisfactory oncologic and functional outcomes (1). Recently, laparoscopy has been incorporated into the urologic armamentarium as an alternative technique for the treatment of localized prostate cancer. Laparoscopic radical prostatectomy (LRP) aims to simulate the open retropubic approach. Furthermore, owing to its enhanced visualization and magniﬁcation, the laparoscopic approach has the potential to impact favorably on the morbidity and functional sequelae related to this intricate operation. In 1991, Schuessler et al. (2) ﬁrst reported that the laparoscopic procedure was found to “offer no advantage over open surgery,” mainly because of the extreme length of operative time (mean 9.4 h) and technical difﬁculty (3). However, in the past few years improvement in laparoscopic skills, conﬁdence, and technology has turned LRP into an efﬁcient day-to-day practice at selected centers. Our single-center experience with LRP approaches 400 cases. We have been developing the technique of LRP to duplicate the principles of the open radical retropubic technique as practiced in the United States today. In this chapter, we describe our stepby-step LRP technique for both the transperitoneal and extraperitoneal approaches, highlighting some modiﬁcations incorporated by our team.

PATIENT SELECTION Oncologic principles established for open radical prostatectomy are followed. Therefore, if a patient with clinically organ-confined disease is considered a candiFrom: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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date for open radical prostatectomy, he is probably a candidate for laparoscopic surgery. Clear contraindications for LRP include prior failed external bean radiotherapy and prior open retropubic surgery. However, in our experience, the following are no longer formal contraindications for laparoscopic radical prostatectomy: prior luteinizing hormone-releasing hormone therapy, history of prostatitis, and prior transurethral resection of the prostate. A large prostate gland will also raise the level of technical difficulty. Nonetheless, it is not a contraindication for the laparoscopic approach. In fact, we have performed this procedure successfully in patients with a prostate gland weighing up to 220 g. Previous abdominal surgery, such as inguinal herniorraphy or appendectomy, is not an absolute contraindication for the laparoscopic technique either; however, extra care should be taken during initial trocar insertion to avoid inadvertent injury to intraperitoneal organs. Obesity is not, in itself, a contraindication to the laparoscopic approach. Although it significantly increases the level of technical difficulty of the procedure, it can be performed safely, and our heaviest patient has weighed 350 pounds. An acute intraperitoneal infectious process, uncorrected coagulopathy, and significant cardiopulmonary compromise represent formal contraindications for laparoscopy, as they are for open surgery.

PREOPERATIVE PREPARATION AND PATIENT POSITION Two bottles of magnesium citrate are self-administered by the patient at home on the afternoon before surgery. The patient reports to the hospital on the morning of the procedure and receives broad-spectrum intravenous antibiotics and subcutaneous heparin. Bilateral sequential compression devices are placed routinely. The patient is placed in a modiﬁed lithotomy position (thighs abducted), prepared with iodine-based disinfectant, and then draped. A Foley catheter is inserted, and the bladder is drained. The table is set in a Trendelenburg position; the degree of head-down inclination varies based on the proposed approach. If the Montsouris transperitoneal approach is employed (i.e., beginning with posterior dissection of the seminal vesicles), a greater head-down Trendelenburg position (30–40 degrees) is used. However, if our modified anterior transperitoneal approach or extraperitoneal approach is used, a lesser degree of Trendelenburg position is needed.

PORT PLACEMENT The Montsouris transperitoneal approach for LRP was described by Guillonneau and Vallencien (4), and the reader is referred to their pioneering article for an in-depth description. At the Cleveland Clinic, we have employed a modiﬁed approach: the “anterior” transperitoneal technique. Five ports are arranged in a “fan” conﬁguration in the pelvic area (Fig. 1). In this port conﬁguration the surgeon uses the 12-mm port and the 5-mm port inserted respectively along the right and left lateral borders of the rectus muscle, approx 2 ﬁngerbreadths below the umbilicus. Great care must be taken to avoid trocar injury to the inferior epigastric vessels, especially on the right side. Finally, two 5-mm ports are placed 2 ﬁngerbreadths medial to each anterior superior iliac spine and are used by the assistant for retraction and suction purposes.

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Fig. 1. Five ports are employed in a “fan” array for either the transperitoneal or the extraperitoneal approach.

LAPAROSCOPIC ROUTE SELECTION The laparoscopic technique for radical prostatectomy is evolving, and three different approaches to the prostate gland are currently available. Initially, Guilloneau and Vallencien (4) described a transperitoneal posterior approach in which the dissection commences at the rectovesical cul-de-sac. To obtain good exposure of the surgical ﬁeld, the sigmoid colon is retract cephalad with a fan retractor or with a stitch passed through an appendix epiploicae and brought out directly through the anterior abdominal wall. A transverse peritoneotomy is created at the second peritoneal fold in the rectovesical cul-de-sac, and the seminal vesicles and vas deferens are mobilized circumferentially using bipolar electrocautery (Fig. 2). The extraperitoneal approach offers some potential advantages compared with the transperitoneal approach: rapid access to the space of Retzius and endopelvic fascia, some decrease in operative time, and nonviolation of the peritoneum, minimizing the chances of intraperitoneal organ injury and paralytic ileus (5–7). However, in our hands, the extraperitoneal approach allows for a smaller working space and is often associated with inadvertent peritoneotomy, resulting in a concomitant pneumoperi-

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Fig. 2. Initial transverse peritoneotomy is made in the rectovesical cul-de-sac. The vas deferens and seminal vesicles are mobilized circumferentially.

toneum, with further compromise of the working space. Therefore, we found the extraperitoneal approach to be technically more demanding and skill-intensive (7). Moreover, since the bladder mobilization from its peritoneal attachments is limited, sometimes the bladder neck may be somewhat difficult to “bring down” during the urethrovesical anastomosis. Thus, at our institution, this approach is now reserved for patients with prior abdominal surgeries, such as colon surgery and aortobifemoral bypass. Currently, our approach of choice for LRP is the anterior transperitoneal approach (8). In this technique, no dissection is performed at the rectovesical cul-desac. Access to the Retzius space is gained after the bladder is mobilized anteriorly, and the seminal vesicles are approached anteriorly after transecting the bladder neck. Although this modified route transgresses the peritoneal cavity, it allows the urologist a view with familiar landmarks, a more physiologic patient positioning on the operative room table, minimal bowel manipulation, and an ample working space (8,9).

DEVELOPMENT OF THE RETZIUS SPACE Transperitoneal Approach The bladder is distended with 200 mL of saline through the indwelling Foley catheter. A wide inverted U-shaped incision is made, with both limbs of the U-incision located medial

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Fig. 3. Exposure of Retzius’ space during the transperitoneal anterior approach. Any kind of dissection is no longer performed at the rectovesical space.

to the ipsilateral medial umbilical ligament (Fig. 3). Care must be taken to avoid injury to the external iliac vessels. The horizontal part of the U-incision is located high on the undersurface of the anterior abdominal wall. This helps to prevent inadvertent bladder injury and also to preclude parietal peritoneum from hanging in front of, and compromising, the surgical view. Circumferential dissection of the bladder is performed in a virtually avascular plane, involving dissection of delicate ﬁbrofatty septae. If bleeding is encountered, one should suspect that dissection is being performed in the wrong plane, usually being too close to the bladder. Once the symphysis pubis has been visualized, the bladder is actively emptied using the bulb syringe. Dissection is initiated laterally on either side, completely exposing the endopelvic fascia bilaterally. A pad of fat remains in the midline in the vicinity of the puboprostatic ligaments; this area includes the superﬁcial dorsal vein, which is thoroughly coagulated with bipolar electrocautery or a harmonic scalpel and transected.

Extraperitoneal Approach A trocar-mounted balloon dissection device (US Surgical, Norwalk, CT) is used for rapid and atraumatic creation of a working space in the extraperitoneum (Fig. 4). It differs in shape from the trocar-mounted balloon used for retroperitoneoscopic surgery for the adrenal and kidney since it has an oblong, manta-ray shape, instead of a spherical format, which allows more lateral dissection of the extraperitoneal space.

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Fig. 4. Air is instilled into the balloon to develop the prevesical working space bluntly and rapidly.

An incision is made on the anterior rectus fascia just below the umbilicus, and the trocar-mounted balloon is inserted and advanced down toward the pelvis under the rectus aponeurosis until the pubic bone is reached. At this point the tip of the trocar is gently pushed underneath the pubic bone, between the two rectus muscle bellies, entering the transversalis fascia to reach the prevesical space. Typically, only 200–300 mL of air (10–15 pumps of the sphygmomanometer bulb) are instilled into the balloon for inﬂation. The laparoscope is inserted to ensure adequate positioning of the balloon. Alternatively, the extraperitoneal space can be developed by widening, circular movements of the laparoscope in a blunt fashion, without use of the balloon (6). Following dilation, the balloon is deﬂated and removed. A 10-mm Bluntip trocar (Origin Medsystems, Menlo Park, CA) is inserted as the primary port to ensure an airtight seal, which, in our experience, is more difﬁcult to achieve with a standard Hasson cannula (10). Further blunt dissection is always required to achieve a suitable extraperitoneal working space. This additional dissection is bluntly performed under laparoscopic visualization by gentle sweeping the laparoscope tip between the abdominal wall and the peritoneum membrane.

INCISION OF ENDOPELVIC FASCIA After the puboprostatic ligaments and the endopelvic fascia on either side are exposed, and the superficial dorsal vein is controlled, the prostate is retracted tautly

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Fig. 5. The endopelvic fascia is exposed and incised bilaterally.

to the left side, placing the right endopelvic fascia on stretch. The endopelvic fascia is incised distally up to the lateralmost puboprostatic ligament (Fig. 5). Visualization of the apex of the prostate is the endpoint of this dissection. We minimize any dissection distal to the prostate apex, so as to not compromise this nerve-rich, sphincter-active zone. A laparoscopic Kittner dissector is used to complete the dissection atraumatically.

DORSAL VEIN COMPLEX LIGATION The Foley catheter is replaced by an 18-F metallic urethral sound. A 2-0 vicryl stitch with a CT-1 needle is employed to ligate the dorsal vein. This stitch is placed in a backhand manner from the right to the left side, distal to the apex of the prostate, between the dorsal vein complex and the urethra (Fig. 6). To avoid inadvertent transgression of the urethra by the suture, the assistant pushes down the metallic sound, displacing the urethra posteriorly. We routinely place two stitches across the dorsal vein complex in an attempt to achieve a safe ligation. Also, we secure the dorsal vein stitch to the puboprostatic ligaments, aiming to achieve a retropubic urethropexy suspension in order to possibly enhance continence outcomes. A back-bleeding stitch is placed across the anterior surface of the base of the prostate. The tails of this stitch are cut somewhat long and are used subsequently to provide anterior countertraction of the prostate base during bladder neck transection.

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Fig. 6. Two 2-0 vicryl sutures in a CT-1 needle are used to ligate the dorsal vein complex effectively.

BLADDER NECK TRANSECTION Anterior Bladder Neck The long tails of the previously placed back-bleeding stitch are grasped and tautly retracted anteriorly, thus elevating and “ﬁxing” the base of the prostate. The bladder is tautly retracted cephalad, thereby placing the anterior bladder neck on traction (Fig. 7). The precise anatomic location of the junction between the prostate and the bladder neck is not well deﬁned under laparoscopic visualization. A combination of maneuvers can be performed to overcome the absence of landmarks for the bladder neck identiﬁcation: Close laparoscopic visualization usually identiﬁes the area where the prevesical fat ends, signifying the prostatovesical junction. Gentle blunt dissection with the elbow of the J-hook eletrocautery also aids to deﬁne this junctional area. Repeated in-and-out movements of the metallic urethral dilator, with its curved tip pointing anteriorly, provides another indication of where the prostate ends and where the bladder begins. At the presumed prostatovesical junction, a horizontal incision is created using Jhook eletrocautery. The initial dissection aims to develop the plane laterally on each side of the bladder neck. The anterior bladder neck is divided in the midline, and the tip of the urethral dilator is delivered through the cystotomy into the space of Retzius. The prostate is now tented anteriorly using the urethral dilator.

Posterior Bladder Neck Incision of the posterior bladder neck is a crucial step to set up properly the dissection of the seminal vesicles and vas deferens. Upon transecting the anterior bladder

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Fig. 7. A J-hook electrocautery is used to transect the anterior bladder neck. Anterior traction on the back-bleeding stitch helps to identify the appropriate plane of dissection between the prostate base and the bladder.

neck, the remaining posterior bladder neck is clearly seen. Using a J-hook electrocautery, the posterior bladder neck is scored away from the ureteral oriﬁces. The posterior bladder neck is then grasped in the midline with a laparoscopic Allis and gently retracted cephalad. The plane between the posterior bladder neck and the prostate is developed with a J-hook electrocautery. Care should be taken to avoid inadvertent creation of a “buttonhole” on the posterior bladder wall. We do not make a major effort to spare the bladder neck, which may result in a positive surgical margin at this location. However, a carefully dissected bladder neck can avoid the extra step of bladder neck reconstruction. Furthermore, we incise the bladder neck somewhat obliquely, such that the anterior lip becomes slightly shorter than the posterior. This maneuver is helpful to provide a better visualization of the posterior suture line during urethrovesical anastomosis.

VAS DEFERENS AND SEMINAL VESICLES The incision on the posterior bladder neck is deepened for approx 2–4 mm until the anterior layer of Denonvilliers’ fascia is encountered. The surgeon must create a wide enough transverse incision to avoid “digging into a hole.” The anterior layer of Denonvilliers’ fascia is incised, and the vasa deferentia are identiﬁed, grasped with a laparoscopic Allis clamp, and retracted cephalad (Fig. 8). Dissection is carried along its lateral border to identify the ipsilateral seminal vesicle, which is mobilized circumferentially. The curved harmonic scalpel (Ethicon, Cincinnati, OH) signiﬁcantly aids in this dissection. The vesicular vessels are carefully secured using a combination of har-

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Fig. 8. The posterior bladder neck is incised. The posterior layer of Denonvilliers’ fascia is entered, and the vas deferens are identiﬁed.

monic scalpel and Hemolock clips. The seminal vesicles are “hugged,” and this dissection is carried distally to its junction with the prostate. Similarly, the contralateral vas deferens and seminal vesicles are mobilized.

INCISION OF POSTERIOR DENONVILIERS’ FASCIA The mobilized vas deferens and seminal vesicles are tautly retracted anteriorly, which places the posterior layer of Denonvilliers’ fascia under traction (Fig. 9). A small horizontal incision is created and enlarged with blunt dissection. Making this incision approx 2–3 mm posterior to the junction of the seminal vesicles with the prostate allows proper entry into the prerectal plane posterior to the prostate. Visualization of prerectal fat conﬁrms the correct plane. Creating the Denonvilliers’ fascia incision more anteriorly may increase the risk of a positive surgical margin at this location. Conversely, if the incision is too posterior, inadvertent entry into the rectum is possible.

TRANSECTION OF LATERAL PEDICLES AND NEUROVASCULAR BUNDLES (NON-NERVE-SPARING) In a non-nerve-sparing procedure, while placing the adjacent lateral pedicle on traction, an articulating Endo-GIA stapler (vascular cartridge, 2.5 mm) is ﬁred across each pedicle. A second Endo-GIA cartridge is employed to detach completely the lateral border of the prostate and the neurovascular bundle from the perirectal fat (Fig. 10). A

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Fig. 9. After the vas deferens and seminal vesicles are dissected up to the prostate base, a cold-cut scissors is used to incised the anterior Denonvilliers’ fascia.

similar maneuver is performed on the contralateral side, leaving the prostate attached only near its apex.

NERVE-SPARING: COMBINED ANTEGRADE-RETROGRADE TECHNIQUE The optimal laparoscopic technique of nerve-sparing continues to evolve. We currently employ a combined antegrade-retrograde technique. A few technical maneuvers in this regard include the following: 1. Upon opening the endopelvic fascia, while releasing the levator muscles from the apex and lateral aspect of the prostate, no thermal or electrical energy is used near the neurovascular bundle. A laparoscopic Kittner or “cold” cut scissors is used to complete the dissection. 2. Following dorsal vein ligation, the lateral fascia over the prostate is bilaterally incised superﬁcially with “cold” Endoshears to release the tethering of the neurovascular bundle. 3. With the aim of minimizing eletrocautery trauma to the neurovascular bundle near the tip of the seminal vesicles, the vesicular artery is secured with hemostatic locking clips (Weck Systems, Triangle Park, NC).

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Fig. 10. In a non-nerve-sparing procedure, an articulated Endo-GIA is used to transect the lateral pedicle widely and ipsilateral neurovascular bundle en bloc.

The nerve-sparing technique itself is performed in a combined antegrade-retrograde fashion. After the posterior bladder neck is transected, the seminal vesicles and vas deferens are dissected, and attention is turned to the prostate apex, where the dorsal vein complex is divided, the neurovascular bundle is gently mobilized away from the prostatourethral junction, and the anterior wall of the urethra is transected adjacent to the prostate apex, maintaining a generous urethral stump. Once the proximal urethra and prostate apex have been thus prepared, and the neurovascular bundle has been deﬁned and dissected bilaterally, attention is returned to the bladder neck (see steps above), and the lateral pedicles are addressed. Initially, the lateral pedicles of the prostate are controlled with one or two 10-mm Hemolock clips (Weck Systems, Triangle Park, NC) (Fig. 11). The posterolateral edge of the prostate base is identiﬁed. Once this anatomic landmark is encountered, the magniﬁed laparoscopic vision allows the surgeon to identify the neurovascular bundle. The harmonic scalpel is employed to develop a plane between the gland and the neurovascular bundle, approx 2 mm away from the prostate. The harmonic scalpel is preferred because of its limited spread of thermal energy (1–2 mm). Furthermore, no electric energy is involved, which could potentially disrupt nerve integrity and conduction. In comparison, bipolar electrocoagulation, in addition to employing electrical energy, has a lateral thermal scatter of 3–5 mm.

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Fig. 11. During a nerve-sparing procedure, the lateral pedicles are deﬁned and controlled with nonmetallic locking clips.

DORSAL VEIN COMPLEX TRANSECTION With the use of a laparoscopic Allis clamp, the transected base of the prostate is grasped with signiﬁcant cephalad traction, placing the urethra and the dorsal vein complex on stretch. Subsequently, the harmonic scalpel is used to divide the dorsal vein complex along the curvature of the apex of the prostate. Occasionally the dorsal vein stitch may loosen, leading to venous bleed. However, owing to the tamponade effect of the CO2 pneumoperitoneum, the degree of hemorrhage is usually not signiﬁcant, and is readily controlled by placing another stitch (2-0 vicryl, CT-1 needle) around the transected dorsal vein.

APICAL DISSECTION AND URETHRAL TRANSECTION Since every apex is different, meticulous apical dissection is probably the most challenging step of this operation. During this step technical shortcomings can lead to incontinence (compromised urethral stump length), impotency (damage to the neurovascular bundle), and positive surgical margins (iatrogenic entry into the prostate apex). After the dorsal venous complex is divided, the anterior urethral wall is identiﬁed with the aid of the metallic urethral sound. The neurovascular bundles, located posterolateral to the urethra near the pelvic ﬂoor, are mobilized laterally from the prostatourethral junction using the ﬁne, gently curved tip of the harmonic scalpel without activation. At this point, cold Endoshears are used to transect the anterior urethral wall close to the concave notch of

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the prostate, which ensures preservation of an excellent urethral stump. The tip of the intraurethral metallic sound is delivered through the urethral opening. The posterior urethral wall and the rectourethralis muscles are divided. During this maneuver, which completely detaches the prostate, extreme care is taken to avoid inadvertent entry into the prostatic apex and rectum. In this regard, visualizing the prostate apex laterally from either side by placing selective countertraction on the prostate is of signiﬁcant help. The prostate is entrapped immediately in a 10-mm Endocatch bag (US Surgical) and placed in the abdomen until extraction at the end of the case.

BLADDER NECK RECONSTRUCTION The bladder neck is evaluated closely and biopsied if one suspects that prostatic tissue was left behind. The ureteric oriﬁces are assessed, and if there is any doubt as to their integrity, intravenous indigo carmine can be administered. A running suture (UR6 needle, 2-0 vicryl) is employed to tighten the posterior bladder neck, which is necessary in 15–20% of cases.

URETHROVESICAL ANASTOMOSIS During open retropubic radical prostatectomy, the pubic bone may impair visibility and access to the urethral stump, and the surgeon must tie the knots in a blind ﬁeld, relying on tactile sensation alone. In comparison, during laparoscopic radical prostatectomy, all sutures are meticulously placed and tied under complete visual control (11). In our early experience, the urethrovesical anastomosis was performed with six to eight interrupted sutures. Despite technically adequate mucosa-to-mucosa approximation, urinary leak on cystogram was noted in approx 40% of the patients on postoperative d 7. We have recently adopted a continuous running technique based on Van Velthoven’s approach. A double-armed stitch is prepared by tying two 2-0 sutures on a UR-6 needle, one dyed Monocryl and the other undyed Caprosyn, each 10 inches in length, thus creating a double-armed stitch. Both these needles are initially passed from outside to inside on the posterior bladder neck, thus placing the knot outside the bladder and anchoring the stitch at this position. The ﬁrst stitch is run up in a clockwise direction from 6 o’clock to 9 o’clock. Similarly, the second stitch is run up in a counterclockwise direction from 6 o’clock to 3 o’clock. At this point, both stitches are placed on traction. Because of the low friction characteristics of the Monocryl and Caprosyn, the sutures glide smoothly under traction, thus anchoring the entire posterior half of the bladder neck to the urethral stump. Upon creation of this posterior plate, a 22-F urethral Foley catheter is easily advanced into the bladder. Anastomosis is completed by running both stitches to 12 o’clock, where they are tied together (Fig. 12). Our preliminary results with this technique indicate a <10% rate of urinary leak on postoperative d 3, allowing catheter removal at that time. Moreover, only one intracorporeal knot is tied. It is helpful to have the two stitches be of different colors to avoid confusion during the suturing process.

LAPAROSCOPIC EXIT A Jackson-Pratt drain is inserted through one of the 5-mm port sites. The specimen is extracted through an extension of the umbilical incision. Fascial closure of the 12mm port site is achieved with a Carter-Thomason needle device and a 0 vicryl suture.

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Fig. 12. Under laparoscopic visualization, a precise mucosa-to-mucosa approximation is completed during the urethrovesical anastomosis using a running suture technique.

INTRA- AND PERIOPERATIVE DATA Laparoscopic radical prostatectomy, owing to the tamponading effect of the 15-mm Hg pressure of CO2 pneumoperitoneum, results in decreased blood loss (Table 1). In a review of 1228 LRPs at six European centers, average blood loss was 488 mL, with a transfusion rate of only 3.5% (12). At the Cleveland Clinic, the average blood loss of our ﬁrst 100 patients was 322 mL (13), resulting in transfusion of only two patients. In a review of 813 laparoscopic radical prostatectomies, Vallancien et al. (14) reported a major complication rate of only 1%. Among these major complications, three were rectal injuries requiring temporary colostomy. These rectal injuries mainly occurred during apical dissection during which the rectourethralis muscle is divided. At the Cleveland Clinic, we have had experienced 1 case of rectal injury out of 250 patients, which was immediately recognized and laparoscopically repaired without further consequences. Conversion to open surgery is rare during LRP. Vallancien and colleagues (14) reported a conversion rate of 0.9% (7 cases out of 813), highlighting that all these conversions occurred in the authors’ initial experience during the first 100 cases. At the Cleveland Clinic, only 1 case out of 250 patients required conversion to open surgery (0.4%). This case also occurred in our very early experience (case 3), and conversion to open surgery was necessary owing to the lack of progression with the laparoscopic technique.

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Abreu, Steinberg, and Gill Table 1 Intraoperative Data

Author

Guillonneau and Turk et al. Hoznek et al. Rassweiler et al. Bollens et al. Vallancien (4) (22) (21) (8) (6)

No. of patients OR time (h) Blood loss (mL) Transfusion rate (%) Open conversion (%) a

350 3.6 354 5.7 2

125 4.25 185 2 0

134 3.5a — 3 0

180 4.5 1230 31 4.4

50 4.4 680 13 2

Excludes the ﬁrst 20 patients.

Table 2 Oncologic Outcome Rassweiler et al. (8) No. of patients pT2 (%) pT3 (%) (+) surgical margins (%) Overall pT2 pT3 Biochemical failure (%) Follow-up (mo)

180 49 45 16 2.3 23 5 12

Hoznek et al. (21) 134 75 24 24.5 16.8 48.8 11.4 11

Turk et al. (22) 125 61.6 38.4 26.4 0b 6.8

Susler et al. (23)a 1228 71 24 16.25 13.6 26.8 — —

Guillonneau et al. (24) 240 86.6 12.5 13.75 10.5 36.6 6.6c —

a

Experience from six European centers. 65 patients followed. c Among 208 patients with pT2. b

ONCOLOGIC OUTCOME Concerns about positive surgical margins after LRP have been raised (15). We believe that laparoscopy will probably be comparable to open surgery in regard to positive surgical margins (Table 2). In our experience, an approx 50% decline in the positive surgical margin occurred from our ﬁrst 50 cases to our third 50 cases (13). Technique reﬁnements, especially during the apical dissection, were inherently related to this reduction in our positive surgical margins rate. In addition to this, we believe that a considerable number of positive surgical margins present in our series may be related to the laparoscopic manipulation of the prostate with traumatic instruments. In fact, the laparoscopic Allis forceps used to tautly retract the prostate cephalad and laterally during various steps of the procedure has a propensity to create divots on the gland, perhaps creating false-positive surgical margins. Because deﬁnitive cure of prostate cancer needs a long follow-up, current available data are still quite immature. However, LRP is likely to emerge as a solid oncologic alternative. Guillonneau and colleagues (16) recently reported an oncologic midterm

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Table 3 Postoperative Continencea Author Continence at 1 mo 3 mo 6 mo 1 yr Mean catheter duration (d)

Hoznek et al. (21) 18 (21.9) 31 (59.6) 27 (64.3) 25 (86.2) 4

Bollens et al. (6)

Rassweiler et al. (8)

20 (39) 42 (85) 5.5b

65 (36%) 97 (54%) 127 (74%) 85 (97%) 7

Turk et al. (22)

93 (75%) 108 (86%) 5.5c

a

Data are numbers of patients, with percents in parentheses. For the last 10 patients. c For the last 45 patients. b

evaluation of 1000 patients who underwent LRP. In this study, the overall actuarial biochemical progression-free survival was 90.5% at 3 yr. According to the pathologic stage, the progression-free survival was 91.8% for pT2aN0, 88% for pT2bN0, 77% for pT3aN0, and 44% for pT3bN0. Patients with negative surgical margins had 94% progression-free survival, and those with positive margin status had 80% (p < 0.001) (16).

FUNCTIONAL OUTCOME The combination of a bloodless ﬁeld and an enhanced view confers on the laparoscopic technique the potential to have a favorable impact on the functional outcome of radical prostatectomy.

Continence The laparoscopic technique has the potential to improve the postoperative continence rates owing to the ability to perform a water-tight urethrovesical anastomosis under direct laparoscopic visualization (Table 3). Guillonneau et al. (17) reported on their ﬁrst 133 patients with at least a 1-yr follow-up and found that 85.5% were totally continent (no protection needed during day or night). Five patients (3.8%) were classiﬁed as severely incontinent. Nadu et al. (12) have reported continence rates > 93% in a median follow-up of 7 mo (range, 1–15 mo). In this particular study, the authors reported that only 15.1% of the patients had anastomotic leak on postoperative d 2–4 cystography. Despite the use of a single circular running stitch technique, no anastomotic stricture, pelvic abscess, or urinoma were noticed in this series (12).

Potency Laparoscopic magnification allows precise identification and handling of the neurovascular bundles. Therefore, the potential to improve on postoperative potency rates exists, yet outcome data with laparoscopic nerve-sparing techniques are sparse (Table 4). Guillonneau et al. (18) reviewed 73 of their patients who had either bilateral (46 patients) or unilateral (27 patients) nerve-sparing LRP. A remarkable 74% spontaneous erection rate was reported in the bilateral nerve-sparing group and 51%

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Author No. of patients Unilateral nerve sparing % Patients % Spontaneous erection % Intercourse Bilateral nerve sparing % Patients % Spontaneus erection % Intercourse % Overall spontaneous erection with or without intercourse % Postoperative oral medication Follow-up (mo) a

Guillonneau et al. (24)

Turk et al. (22)

Hoznek et al. (21)

Salomon et al. (20)

73a

44a

47

104

37 51.8 3.7

89 — —

56 — 28

— 22.2 —

63 73.9 41.3 —

11 — — 59

44 — 46 —

— 40 — 25.6

— 2–12

30.8 —

0 1

0 1

All patients preoperatively potent.

in the unilateral group with a follow-up ranging from 2 to 12 mo. More recently, Katz et al. (19) reported a postoperative potency rate at 1 yr of 87.5% in patients with bilateral nerve sparing. However, out of group of 46 patients that underwent bilateral nerve sparing and answered the sexual function questionnaire at 1 mo, only 8 patients responded to the survey at the 1-yr mark (19). These authors found that the overall rate of patients who had erections preoperatively and maintained erections after surgery (53.8%) was comparable to the results for open surgery.

REFERENCES 1. Walsh PC, Donker PJ. Impotency following radical prostatectomy: insight into etiology and prevention. J Urol 1982;128:492–497. 2. Schuessler WW, Kavoussi LR, Clayman RV, Vancaille T. Laparoscopic radical prostatectomy: initial case report. J Urol 1992;147:246A. 3. Schluesser W, Shulman P, Clayman RV. Laparoscopic radical prostatectomy: initial short-term experience. Urology 1997;50:854. 4. Guillenneau B, Vallancien G. Laparoscopic radical prostatectomy: the Mountsouris technique. J Urol 2000;163:1643–1649. 5. Raboy A, Ferzli G, Albert P. Initial experience with extraperitoneal endoscopic radical retropubic prostatectomy. Urology 1997;50:849–853. 6. Bollens R, Bossche MV, Roumeguere T, et al. Extraperitoneal laparoscopic radical prostatectomy. Eur Urol 2001;40:65–69. 7. Abreu S, Gill I, Kaouk J, et al. Laparoscopic radical prostatectomy: comparison of transperitoneal vs extraperitoneal approach. J Urol Suppl 2002;167:19. 8. Rassweiler J, Sentker L, Seemann O, Hatzinger M, Rumpelt HJ. Laparoscopic radical prostatectomy with the Heilbronn technique: an analysis of the ﬁrst 180 cases. J Urol 2001;166:2101–2108. 9. Steinberg A, Gill I. Laparoscopic radical prostatectomy. Contemp Urol 2002;14:34–49. 10. Gill S. Retroperitoneal laparoscopic nephrectomy. Urol Clin North Am 1998;25:343. 11. Hoznek A, Salomon L, Rabii R, et al. Vesicourethral anastomosis during laparoscopic radical prostatectomy: the running suture method. J Endourol 2000;14:749–753.

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12. Nadu A, Salomon L, Hoznek A, et al. Early removal of the catheter after laparoscopic radical prostatectomy. J Urol 2001;166:1662–1664. 13. Farouk A, Gill I, Kaouk J, et al. 150 laparoscopic radical prostatectomy (LRP): learning curve in the United States. J Endourol 2002;16(suppl 1):A33, P9-2. 14. Vallancien G, Cathelineau X, Baumert H, Doublet JD, Guillonneau B. Complications of transperitoneal laparoscopic surgery in urology: review of 1,311 procedures at a single center. J Urol 2002;168:23–26. 15. Walsh PC. Minimally invasive treatment of prostate cancer. J Endourol 2001;15:447–448. 16. Guillonneau B, El Fettouh H, Baumert HC. Laparoscopic radical prostatectomy: oncological midterm evaluation of 1000 patients at Montsouris Institute. J Endourol 2002;16(suppl 1):A36, P9-13. 17. Guillonneau B, Cathelineau X, Doublet JD, Vallancien G. Laparoscopic radical prostatectomy: the lessons learned. J Endourol 2001;15:441–445. 18. Guillonneau B, Cathelineau X, Doublet JD, et al. Prospective assessment of functional results after laparoscopic radical prostatectomy. J Urol 2001;165(suppl):614A. 19. Katz R, Salomon L, Hoznek A. Patient reported sexual function following laparoscopic radical prostatectomy. J Urol 2002;168:2078–2082. 20. Salomon L, Olsson LE, Hoznek A, et al. Continence and potency after laparoscopic radical prostatectomy. J Urol Suppl 2001;165:390. 21. Hoznek A, Salomon L, Olsson LE, et al. Laparoscopic radical prostatectomy. Eur Urol 2001;40:38–45. 22. Turk I, Serdar D, Winkelmann B, Schonberger B, Loening SA. Laparoscopic radical prostatectomy. Eur Urol 2001;40:46–53. 23. Susler T, Guillenneau B, Vallancien G, et al. Complications and initial experience with 1228 laparoscopic radical prostatectomy at 6 European centers. J Urol Suppl 2001;165:150. 24. Guillenneau B, Rozet F, Barret E, Cathelineau X, Vallencien G. Laparoscopic radical prostatectomy: assessment after 240 procedures. Urol Clin North Am 2001;28:189–202.

13

Contemporary Technique of Radical Prostatectomy Perineal Approach

Vernon E. Weldon

INTRODUCTION Perineal access is the least invasive and least costly approach to radical prostatectomy. Perineal rates of negative specimen margins, relapse-free survival, continence, and potency are equivalent to those with the retropubic approach (1–10). Contemporary radical perineal prostatectomy is associated with no need to routinely have blood available for transfusion (10), a single overnight hospital stay in 87–91% of patients with 95% patient satisfaction (9,11), and a similar learning curve (12) but a 42% cost saving compared with the retropubic approach (11). Laparoscopic and robotic learning curves and costs are much steeper, without providing less morbidity.

PELVIC LYMPHADENECTOMY Most candidates for radical prostatectomy in the United States do not need lymph node sampling. Pathologic stage migration in populations under prostate-specific antigen (PSA) surveillance has brought the risk of lymph node metastases in current surgical cases to as low as 1% (13). A decision analysis model shows that pelvic lymphadenectomy is justified when a positive finding would abort the prostatectomy and when the risk of nodal metastases is >18% (14). Currently, both of these criteria are rarely present together. Radical prostatectomy is rarely aborted in the presence of microscopic lymph node metastases, as 10% of such patients have a 10-yr relapsefree survival (15) and local control is improved; only cases with Gleason scores of 8–10 and either PSA levels > 20 ng/mL or large palpable tumors have a >18% risk of nodal metastases (16). Routine pelvic lymphadenectomy is costly. In the mid-1990s, the estimated added charge per case was $1750, with yearly costs in the United States of $222 million (17). The estimated cost for each metastasis discovered was $43,600 (18).

From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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If pelvic lymphadenectomy was never done with radical prostatectomy in the United States, then an additional 1% of patients would have an immediate or early detectable PSA level postoperatively. They would at least have gained better local disease control; they would be assumed to have metastatic disease and could be treated with androgen deprivation (19).

ANATOMY Pelvic Fascia Execution of the contemporary nerve-sparing (20) and extended radical (21) modiﬁcations of radical perineal prostatectomy requires a clear understanding of the anatomy of the pelvic fascia. The erroneous concept of “layers” of Denonvilliers’ fascia was corrected by Tobin and Benjamin (22). The pelvic fascia is a single continuous layer of ﬁbroareolar and variably fatty tissue, with variable thickness and parietal and visceral surfaces. It is derived from and surrounds all the pelvic organs above the pelvic levator muscles (23). Denonvilliers’ membrane, the single and densely ﬁbrous membrane that he called the “prostatoperitoneal membrane” (24) (colloquially, the “anterior layer”), is derived from the embryonic fusion of the most caudal portion of the peritoneal sac within the pelvis (Fig. 1). After fusion, Denonvilliers’ membrane extends caudally from the vesicorectal peritoneal cul-de-sac for a variable distance but often down to the prostatic apex (Fig. 2). The neurovascular bundles mark its lateral margins (25,26). It loosely covers the dorsal surface of the seminal vesicles, but it is densely adherent to the dorsal prostatic capsule. It is separated from the rectum by the ventral rectal fascia (colloquially, the “posterior layer”), the portion of the continuous areolar and fatty pelvic fascia surrounding the rectum that extends in a frontal plane across the pelvis ventral to the rectum (Figs. 2 and 3). The ventral rectal fascia was given no designation by Denonvilliers (24), and it differs from Denonvilliers’ prostatoperitoneal membrane in both histologic composition and embryologic origin.

Neurovascular Bundles The paired neurovascular bundles are composed of cavernous nerves intertwined with branches of the ipsilateral middle rectal artery and vein and embedded in a variable amount of fat. The cavernous nerves are unmyelinated autonomic nerves that originate in the pelvic nerve plexuses located on each side within the lateral rectal fascia at the level of the tips of the seminal vesicles. Myers (27) described the neuroanatomy of a single bundle as consisting of 64 nerves with a mean diameter of 0.12 mm (range 0.04–0.37 mm). The 10 largest nerves had a diameter of 0.20–0.37 mm. The bundles lie vertically within the lateral pelvic fascia at its junction with the ventral rectal fascia and over the dorsolateral aspects of the prostate and membranous urethra (Fig. 3). The prostatic nerve branches of the neurovascular bundles are concentrated into superior and inferior neural pedicles located at the prostatic base and apex (28). Variable amounts of fat enclose the neurovascular elements and increase the bulk of the bundles. Lying within the fascia, the bundles are flattened by the firm prostate on the prostatic surface of the fascia, but the softer rectum allows them to bulge into the rectal surface of the fascia, thus providing easy identification from the perineal approach.

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Fig. 1. Histologic transverse section through the pelvis of a 161.4-mm human embryo with the prostate and its urethra (U.) superior and the rectum (R.) inferior. The caudal extension of the peritoneal cavity (P.C.) is located between these organs. Note the large neural ﬁbers in the lateral rectal fascia extending to the posterolateral prostate that constitute the fetal neurovascular bundles. (Reproduced with permission from Tobin CE, Benjamin JA. Anatomical and surgical restudy of Denonvilliers’ fascia. Surg Gynecol Obstet 1945;80:373.)

Related Anorectal Anatomy The three bands of longitudinal smooth muscle of the intra-abdominal colon, the taenia coli, become concentrated beneath the peritoneal reflection on the rectum into two broad anterior and posterior bands. The rectourethralis muscle is composed of fascicles of the anterior band of longitudinal smooth rectal muscle that insert into the perineal body that is formed by the midline junction of the transverse perineal and bulbocavernosus muscles (29). Some striated muscle bands of the medial levator ani, the puboperinealis muscle, extend anterior to the rectum on each side and also insert into the perineal body (30). Caudal to the puboperinealis muscle, the striated external anal sphincter surrounds the anal canal. It is innervated by branches of the internal pudendal nerves that cross the ischiorectal fossa and enter the sphincter posterior to the 3 and 9 o’clock positions

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Fig. 2. Histologic sagittal section through an adult male rectovesical peritoneal cul-de-sac (P.). Seminal vesicle (S.V.), ampulla of vas deferens and bladder (B.) at left and rectum (R.) at right. Note Denonvilliers’ prostatoperitoneal membrane (P.P.M.) extending from the cul-de-sac “dimple” over the dorsal wall of the seminal vesicle. Also note the areolar ventral rectal fascia between Denonvilliers’ membrane and the rectal wall. (Reproduced with permission from Tobin CE, Benjamin JA. Anatomical and surgical restudy of Denonvilliers’ fascia. Surg Gynecol Obstet 1945;80:373.)

relative to the anal canal. These nerves can be injured by excessive posterior extensions of the perineal incision.

NERVE-SPARING VS EXTENDED DISSECTION The modern radical prostatectomy era is deﬁned by the description of the paired neurovascular bundles and their relevance to potency preservation (31) and the local spread of prostate cancer (28). Although perineal nerve sparing has preserved unassisted potency in 70% of men with good preoperative potency (bilateral 72% and unilateral 68%) (10), a dilemma results from the demonstration that the primary route of cancer penetration of the prostatic capsule is through the perineural spaces of the nerve branches from the neurovascular bundles that penetrate the prostatic capsule at the lateral edge of Denonvilliers’ membrane (28). In our early series before stage migration, 18% of specimens had solitary posterolateral capsular penetration but still had negative

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Fig. 3. Transverse section through the prostate at the level of the verumontanum. Note the continuous nature of the pelvic fascia. The lateral prostatic fascia and the lateral rectal fascia comprise the lateral pelvic fascia. The solid line indicates the nerve-sparing dissection plane on Denonvilliers’ membrane and the prostatic capsule. The broken line indicates the extended radical dissection plane excising the neurovascular bundle and the periprostatic fascia and located on the rectal wall and the levator ani muscle. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Das S, Crawford ED, eds. Cancer of the Prostate. Marcel Dekker, New York, 1993, pp. 225–226.)

margins because of an extended dissection sacriﬁcing the ipsilateral neurovascular bundle (1). Having negative surgical margins with capsular penetration confers an inverse grade-related 25–35% advantage in the 15-yr freedom from PSA relapse (15). Remembering that few things reduce concern about potency more than a rising PSA level and that the unilateral perineal nerve sparing has had relatively high success, there are reasonable guidelines for sparing a neurovascular bundle. Clinical stage T1b tumors without significant peripheral zone involvement and T1c tumors with low PSA levels, medium grade, and limited volume on systematic biopsy are often ideal cases for bilateral nerve sparing. A neurovascular bundle may be spared if it overlies a lobe with no palpable or sonographically detected tumor and if systematic biopsy of that lobe reveals little or no tumor. A neurovascular bundle may also be spared if it is adjacent to a small palpable tumor (T2a) with a Gleason score of 6 or less and if it can be easily and cleanly dissected free. A neurovascular bundle that is adjacent to any larger or higher grade tumor, associated with ipsilateral perineural space invasion on biopsy, or unusually adherent to the capsule should be sacrificed.

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Fig. 4. Operative view with vertical incision of the ventral rectal fascia. The black arrow indicates the nerve-sparing dissection plane on the prostatic capsule with mobilization of the left neurovascular bundle. The white arrow indicates the extended radical dissection plane on the levator ani muscle sacriﬁcing the right neurovascular bundle. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Das S, Crawford Ed, eds. Cancer of the Prostate. Marcel Dekker, New York, 1993, pp. 225–226.)

Bilateral extended dissection is indicated for all men with significant erectile dysfunction, those who consider potency unimportant, and those unwilling to accept any discretionary risk in the treatment of their cancer. With this selective approach, 7% of patients undergoing nerve sparing had an apparently related positive margin, but all of them were only focal (1). Performing a nerve-sparing or extended dissection requires a clear understanding of the different dissection planes within the pelvic fascia. The initial approach is within the envelope of the rectal fascia. The decision to proceed through or around the ventral rectal fascia determines the type of dissection on each side. The nerve-sparing dissection plane is through the ventral rectal fascia onto Denonvilliers’ membrane. It continues ventrally on the prostate inside the lateral prostatic fascia and beneath Santorini’s venous plexus (Figs. 3 and 4).

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The extended radical dissection plane with wide excision of the neurovascular bundle and the periprostatic fascia is outside the ventral rectal fascia on the rectal wall. It extends laterally around the neurovascular bundle and through the lateral rectal fascia onto the levator ani muscle. It then turns ventrally between the lateral prostatic fascia and the levator ani muscle and onto the anterior prostatic capsule beneath Santorini’s venous plexus (Figs. 3 and 4). This dissection achieves the widest possible margins, located on the rectal wall and the levator ani muscle.

PREOPERATIVE PREPARATION We have demonstrated a median and maximal blood loss of 600 and 2000 ml respectively (95% lost 1200 mL or less) (10). Therefore, we routinely obtain blood type and antibody screening but not autologous or allogenic blood for transfusion. Bowel cleansing with oral laxatives and a rectal suppository (e.g., Fleet Prep Kit No. 1; C.B. Fleet, Lynchburg, VA) efficiently empties the rectum. Antibiotic prophylaxis appropriate for colorectal operations (e.g., cefotetan 2 g) is given intravenously at the time of induction of general anesthesia. Preliminary cystoscopy helps to avoid unusual but potentially troublesome surprises from bladder stones and tumors, urethral strictures, and unusual locations or configurations of the ureteral orifices. Useful special instruments include the prostatic tractors designed by Lowsley and Young (Fig. 5), a self-retaining retractor (e.g., Mini-Crescent, Omni-Tract Surgical, Minneapolis, MN [Fig. 6]), and a bright headlight. The long, curved Lowsley tractor is placed transurethrally prior to the incision.

OPERATIVE PROCEDURE Patient Position Only a moderately exaggerated lithotomy position is required, with the plane of the perineum at a 45° angle relative to the floor. “Candy cane” stirrups positioned at 90° relative to the long axis of the table will support the legs without ever touching them. To avoid stretching the sciatic and femoral nerves, the proper position of the pelvis should be achieved solely by placing pads (e.g., folded sheets) under the sacrum, while avoiding torque on the legs from forceful cephalad rotation of the stirrup poles (Fig. 7). Frequent intraoperative adjustment of the tilt and elevation of the table will assist optimal exposure of different areas, including the membranous urethra and the seminal vesicles. Position requirements exclude some patients from the perineal approach, such as those with severe ankylosis of the hips or spine. Other skeletal deformities, including leg amputation and hemipelvectomy, can usually be adapted to the position. The common degenerative spine and disc problems are not a contraindication since the ﬂexedspine position is often beneﬁcial for them. The perineal approach to radical prostatectomy is often preferred for very obese patients, as most men have a disproportionate abdominal fat concentration. However, those with extreme obesity may not tolerate the position if the weight on the diaphragm requires excessive ventilatory pressure (>40 cm H2O) that restricts cardiac ﬁlling. Antithrombosis stockings are unnecessary, as the position provides maximal venous drainage of the legs and pelvis.

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Fig. 5. Prostatic tractors of Young (left) and Lowsley (right) closed for transurethral passage and opened for specimen traction. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Crawford ED, Das S, eds. Current Genitourinary Cancer Surgery, 2nd ed. Williams & Wilkins, Baltimore, 1997, pp. 258–287.)

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Fig. 6. Table-mounted Omni-tract surgical mini-crescent retractor with retractor mounted ﬁber-light. Note position of the ring with table connection at 8 o’clock and ring opening at 2 o’clock. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Das S, Crawford ED, eds. Cancer of the Prostate. Marcel Dekker, New York, 1993, pp. 225–266.)

Incision Before skin preparation, the anus should be opened digitally to expel any ﬂuid remaining in the rectum. If more than a little residual rectal ﬂuid is discovered, temporary insertion of a rectal tube with simultaneous pressure on the lower abdomen is useful. With an empty rectum, and prophylactic antibiotics, no special draping to isolate the anus is required. This allows intraoperative insertion of a ﬁnger, temporarily covered by a second glove, into the rectum if needed. An inverted U incision is made outside the anal sphincter and inside the ischial tuberosities, as described by Young (32) (Fig. 8). The subsphincteric approach of Belt et al. (33) provides more restricted exposure, and it does not allow the intact sphincter to prevent soiling of the operative field. The apex of the incision can be located by noting the increased pigmentation of the skin over the sphincter in White patients, palpating the soft midline spot just ventral to the sphincter, or placing it 3 cm ventral to the anal orifice. The vertical limbs of the incision should not extend

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Fig. 7. Exaggerated lithotomy position. All weight is borne on the cotton ﬂannel sheets under the sacrum. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Das S, Crawford ED, eds. Cancer of the Prostate. Marcel Dekker, New York, 1993, pp. 225–266.)

posteriorly beyond the 3 and 9 o’clock positions relative to the anus, to avoid damaging the internal pudendal nerve branches to the external anal sphincter. This minimal access can cause some difficulty with large prostates, but intact specimens up to 180 g have been removed (20). Full development of the incision requires transecting the central tendon of the perineum, opening the ischiorectal fossae, and exposing the ventral rectal wall. The central tendon is the vertical, midline, anterior, striated muscle extension of the external anal sphincter that attaches it to the perineal body (Fig. 8). Lateral incisions through the subcutaneous fascia allow digital development of the fossae and the plane between the rectal wall and the central tendon (Fig. 9). If a ﬁnger cannot be insinuated into this plane with relative ease, it should not be forced. Instead, direct transverse dissection should proceed through the overlying structures, including any red, striated remnants of the puboperinealis and upper external anal sphincter muscles, down to the white smooth muscle of the rectal wall.

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Fig. 8. The perineal body, located at the center of the perineum, is the site of attachment of the transverse perineal muscles laterally, the bulbocavernosus muscle ventrally, and the central tendon dorsally. The broken line indicates the position of the skin incision and the site of division of the central tendon. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Das S, Crawford ED, eds. Cancer of the Prostate. Marcel Dekker, New York, 1993, pp. 225–266.)

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Fig. 9. Digital insinuation over the rectal wall, cephalad to the external anal sphincter and beneath the central tendon connects each ischiorectal fossa. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Das S, Crawford ED, eds. Cancer of the Prostate. Marcel Dekker, New York, 1993, pp. 225–266.)

Rectal Mobilization Cephalad dissection on the anterior longitudinal smooth muscle band of the rectum leads to the rectourethralis muscle, formed by fascicles of this muscle that connect the rectum to the perineal body (29). The rectourethralis muscle must be visualized as a strap suspending the tent of the anterior rectal wall. Skeletonizing this strap and placing it on tension assists safe, complete transection (Fig. 10). The rectourethralis muscle must be completely divided. Any broad and indeﬁnite remnant is best divided after scissors penetration and spreading in the midline. Each remaining half is then completely incised, beginning at the newly created medial edge and extending laterally (Fig. 11). Division of the rectourethralis muscle gives entry to the key space between the rectum and its ventral fascia (Fig. 12). The plane of dissection now turns at a right angle from the horizontal to the vertical, and this space is best developed by blunt, digital,

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Fig. 10. The rectourethralis muscle, composed of fascicles of the anterior band of longitudinal smooth rectal muscle that connects the rectum to the perineal body, is isolated for division. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Das S, Crawford ED, eds. Cancer of the prostate. Marcel Dekker, New York, 1993, pp. 225–266.)

cephalad, and lateral dissection while keeping the ﬁngernail on the prostate and avoiding pressure on the rectum (Fig. 13). Retracting the rectal wall exposes the ventral rectal fascia and both laterally located neurovascular bundles (34).

Nerve-Sparing Dissection The ventral rectal fascia is incised vertically, medial to the neurovascular bundle. A midline incision with inverted Y extensions at the prostatic base is used for a bilateral nerve-sparing dissection. This fascia and the enclosed neurovascular bundle are carefully separated from the prostatic capsule, primarily with scissors spreading and cutting and beginning over the midbody of the prostate (Fig. 14). The main areas of attachment of the neurovascular bundles are the superior and inferior neural pedicles penetrating the prostate capsule at the base and apex (28). They must be divided

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Fig. 11. Complete division of the rectourethralis muscle. After dividing any discrete central or lateral edge, any remaining broad and indeﬁnite muscle is completely penetrated and split longitudinally by scissors-spreading in the midline. Inset: Each remaining half is then completely incised beginning at the newly created medial edge and extending laterally. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Crawford ED, Das S, eds. Current Genitourinary Cancer Surgery, 2nd ed. Williams & Wilkins, Baltimore, 1997, pp. 258–287.)

sharply, with hemoclip control of the superior pedicle to avoid bleeding (Fig. 15). The neurovascular bundles must be mobilized at least 1 cm over the membranous urethra and sufﬁciently proximal at the base to allow them to slip to the side and avoid stretching during removal of the prostate. Mobilization of the bundles is facilitated by two maneuvers: (1) scissors dissection with coordination between the surgeon and assistant in simultaneously lifting the medial edge of the ventral rectal fascia and rotating the prostate contralaterally with a Kitner dissector; and (2) as a ﬁnal step after otherwise maximal bundle mobilization, the superior neural pedicle is isolated for division between clips by pulling back on the handle of Lowsley’s tractor, which pushes the prostate base ventrally and away from the neurovascular bundle.

Extended Radical Dissection The ventral rectal fascia and the neurovascular bundle remain on the prostate, and the thin lateral rectal fascia is opened vertically by scissors penetration just lateral to

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Fig. 12. After transecting the rectourethralis muscle, the key space (arrow) between the rectal wall and its ventral fascia is entered. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Crawford ED, Das S, eds. Current Genitourinary Cancer Surgery, 2nd ed. Williams & Wilkins, Baltimore, 1997, pp. 258–287.)

the bundle, exposing the levator ani muscle (Fig. 4). The avascular plane between the red, striated levator muscle and the white lateral prostatic fascia is then opened with blunt, digital dissection. The ventral rectal fascia and the enclosed neurovascular bundle are transected transversely at the level of the base and apex of the prostate. The lateral prostatic fascia also remains on the prostate and is later incised around the bladder neck.

Early Vascular Pedicle Division If the vascular pedicles are accessible without stretching the neurovascular bundles, dividing them at this early stage provides maximal arterial hemostasis and specimen mobility. Otherwise, it is accomplished during continued retrograde dissection after mobilizing the apex when addressing the posterior bladder neck. The space between the cephalad cuff of ventral rectal fascia at the base of the prostate and the underlying

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Fig. 13. Digital dissection develops the vertical plane between the rectal wall and its ventral fascia. The neurovascular bundles are within the lateral aspects of the fascia. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Das S, Crawford ED, eds. Cancer of the Prostate. Marcel Dekker, New York, 1993, pp. 225–266.)

Denonvilliers’ membrane is bluntly developed cephalad before incising Denonvilliers’ membrane transversely over the seminal vesicles. In this plane deep to the neurovascular bundles, a closed Mixter right-angle forceps is inserted between the lateral edge of the seminal vesicle and the laterally adjacent vascular pedicle to “hook” the pedicle and pull it caudally and medially to allow securing and division. Dissection of the vesicles and the vasal ampullae can be partially or completely accomplished through this posterior access, or it can be deferred until the bladder neck is circumcised to allow both anterior and posterior access.

Apical Dissection Shifting to the apex, the dissection proceeds inside the neurovascular bundles onto the wall of the proximal membranous urethra. The urethra is encircled with a

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Fig. 14. Vertical incision of the ventral rectal fascia medial to the neurovascular bundles exposes Denonvilliers’ membrane. Inset: Beginning mobilization of the left neurovascular bundle at the lateral edge of Denonvilliers’ membrane. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Das S, Crawford ED, eds. Cancer of the Prostate. Marcel Dekker, New York, 1993, pp. 225–266.)

right-angle forceps and divided precisely at its junction with the apex of the prostate (Fig. 16). After removing Lowsley’s tractor, the ventral urethral wall is transected with Pott’s angled scissors just beneath the encircling forceps. Easy perineal access and direct posterior visualization of the asymmetric caudal extension of the posterior prostatic apex opposite the anterior notch (35) facilitates precise dissection with both optimal membranous urethral preservation and avoidance of inadvertent incisions into the prostate.

Puboprostatic Ligament Division Young’s short tractor (Fig. 5) is inserted through the apical urethra, and the prostate is rotated dorsally, exposing the anterior prostatic capsule and the puboprostatic ligaments beneath Santorini’s venous plexus (Fig. 17). These ligaments must be divided sharply rather than avulsed to reduce the risk of a positive margin if cancer is present in the transition zone (1).

Bladder Neck Division The anterior bladder neck can be palpated lateral and cephalad to the puboprostatic ligaments. After those ligaments are divided, Santorini’s venous plexus can be pushed cephalad in the midline, where the anterior 180° of the bladder neck muscularis is then

Fig. 15

Fig. 16

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Fig. 15. (left, top) Left nerve sparing dissection showing the superior (basal) and inferior (apical) neural pedicles and the ﬁbrous attachment at the prostatourethral junction. Inset: Division of the long and broad superior neural pedicle. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Crawford ED, Das S, eds. Current Genitourinary Cancer Surgery, 2nd ed. Williams & Wilkins, Baltimore, 1997, pp. 258–287.) Fig. 16. (left, bottom) Division of the dorsal urethral wall, with a right extended radical and left nerve-sparing dissection. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Das S, Crawford ED, eds. Cancer of the Prostate. Marcel Dekker, New York, 1993, pp. 225–266.)

Fig. 17. Anterior prostate dissection with right extended radical and left nerve-sparing dissection. Young’s short tractor enters the apical urethra and is rotated dorsally. The puboprostatic ligaments are divided sharply. Broken line indicates the site of division of the right lateral pelvic fascia at the bladder neck. (Reproduced with permission from Weldon VE, Tavel FR, Neuwirth H. Patterns of positive specimen margins and detectable prostate speciﬁc antigen after radical perineal prostatectomy. J Urol 1995;153:1565–1569).

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Fig. 18. Anterior bladder neck dissection with a right extended radical and left nerve-sparing dissection. The circular bladder neck muscle is completely separated from the prostate, exposing the mucosa. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Das S, Crawford ED, eds. Cancer of the Prostate. Marcel Dekker, New York, 1993, pp. 115–266.)

separated from the prostate (Fig. 18). This dissection preserves most of the bladder neck, although it will be trimmed later to avoid preserving invisible, microscopic benign prostate glands. Routine wide excision of the bladder neck is both unnecessary and futile since cancer invasion of the bladder neck is unusual (3%) and when it occurs it is a marker for large tumor volume that is almost always accompanied by a positive margin at another site (1). If an extended dissection has been performed on either side, the lateral prostatic fascia on that side is incised around the bladder neck (Fig. 17). Any significant diffuse bleeding from Santorini’s venous plexus can be controlled by packing an opened 4 × 4-inch sponge against the plexus, compressing it against the intact endopelvic fascia. Focal bleeding vessels are grasped with a vascular forceps and clipped. The anterior bladder neck mucosa is then opened, and further specimen traction is provided by a 0.5-inch Penrose drain looped through the prostatic urethra around the

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Fig. 19. Complete division of the bladder neck with a right extended radical and left nerve-sparing dissection. Specimen traction is provided by a 0.5-inch Penrose drain looped through the urethra around the anterior lobe. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Das S, Crawford ED, eds. Cancer of the Prostate. Marcel Dekker, New York, 1993, pp. 225–266.)

anterior lobe (Fig. 19). To accomplish this, a right-angle forceps is inserted retrograde through the apical prostatic urethra and out the anterior bladder neck opening. It is then used to pull the Penrose drain antegrade through the prostatic urethra. If not previously accomplished, the vascular pedicles must now be divided to allow complete circumcision of the bladder neck (Figs. 19 and 20). If a pedunculated prostatic middle lobe impedes visualization of the posterior bladder neck mucosa, risking injury to the ureteral orifices, it can be grasped with a single-toothed uterine tenaculum and pulled out to allow safe incision behind it but caudal to the trigone. Identifying the plane immediately anterior to the laterally visible seminal vesicle facilitates division of the thick posterior bladder neck muscularis (Fig. 20). When dividing the posterior bladder neck, injury to the ureteral orifices can be avoided by palpating the interureteric ridge and visualizing the trigone and orifices. Occasionally, use of intravenous indigo carmine may be needed to visualize the ureteral orifices.

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Fig. 20. Late vascular pedicle division with a right extended radical dissection. A right-angle forceps “hooks” the pedicle for proximal clamping and division. Inset: After the vascular pedicle is completely divided and the lateral edge of the seminal vesicle is exposed, an advantageous view of the plane of transection of the posterior bladder neck is achieved and developed with a right-angle forceps. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Das S, Crawford ED, eds. Cancer of the Prostate. Marcel Dekker, New York, 1993, pp. 225–266.)

Seminal Vesicle Dissection If not completed earlier from the posterior approach, complete dissection of the seminal vesicles and division of the vasal ampullae is now performed using both anterior and posterior access. Key steps include: (1) opening the cleft between the vesicle and the adjacent vas (Fig. 21); (2) scissors spreading on the wall of the vesicle; (3) traction and countertraction to expose the vesicle arteries serially for division beneath clips (Fig. 22).

Vesicourethral Anastomosis The bladder neck is inspected and trimmed. Bladder neck preservation does not enhance continence, but it may reduce anastomotic tension in some cases and contribute to the very low incidence of anastomotic strictures (10). However, microscopic benign prostate glands are retained on 44% of preserved bladder necks (36,37), and

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Fig. 21. Anterior seminal vesicle dissection with a right extended dissection. The cleft between the left vasal ampulla and the seminal vesicle is developed. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Das S, Crawford ED, eds. Cancer of the Prostate. Marcel Dekker, New York, 1993, pp. 225–266.)

trimming the neck will reduce the risk of a benign source of PSA postoperatively. It also provides enhanced microscopic assessment of the proximal margin. The anterior bladder neck is approximated to the circumference of the membranous urethra around a 20-Ch silicone Foley catheter with 9 or 10 interrupted, synthetic, absorbable 2-0 sutures (Figs. 23 and 24). If desired, continuous sutures can be used. Precise mucosal approximation is achieved with each stitch, without separately everting the bladder neck mucosa or attempting to tighten the anastomosis. Any redundant posterior bladder neck is closed vertically as a “racquet handle” (Fig. 24 ). Using a second layer closure of the “racquet handle” has virtually eliminated the previous 2% incidence of prolonged urinary drainage.

Closure The rectum is inspected prior to closure. Any proctotomy is meticulously closed in two layers with synthetic, absorbable sutures. The anterior band of longitudinal smooth

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Fig. 22. Complete bilateral seminal vesicle dissection using traction and countertraction to isolate, clip, and divide the numerous small arteries. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Crawford ED, Das S, eds. Current Genitourinary Cancer Surgery, 2nd ed. Williams & Wilkins, Baltimore, 1997, pp. 258–287.)

muscle usually provides a secure second layer. A 0.25-inch Penrose drain is placed with its center looped into the wound, and each end is separately brought out the opposite corners of the incision and sutured to the skin. A drain placed in this manner will not be pulled out with friction when the patient is sitting. The perineal wound is closed in two layers, with continuous, synthetic, absorbable, subcutaneous and intradermal skin sutures. This closure will adequately resist the shearing force associated with sitting. Disposable stretch-mesh pants hold the absorbent dressings in place and allow easy changing if the dressings become saturated.

VARIATIONS WITH LARGE PROSTATES With bilateral perineal nerve sparing, the prostate must be removed from between the neurovascular bundles, and prostates larger than 50 g make this difﬁcult to accomplish with-

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Fig. 23. Anastomosis of the anterior bladder neck to the anterior membranous urethra with the three initial sutures. In this case the catheter is pulled through the urethra and lifted up to expose the anterior urethral wall. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Das S, Crawford ED, eds. Cancer of the Prostate. Marcel Dekker, New York, 1993, pp. 225–266.)

out stretching the bundles. Since postoperative potency is related to quantitative neural preservation rather than simply bilateral or unilateral, it is preferable to preserve one bundle completely rather than compromise both bundles. Removing one bundle with a large prostate will usually provide the space necessary to preserve the other bundle maximally. Although intact prostates up to 180 g have been removed, the space under the pubic arch and between the ischial tuberosities is limited, and there should be concern about using the perineal approach when the base of the prostate cannot be reached during digital rectal examination. When removing a large prostate through the perineal approach, the vascular pedicles should be divided as early as possible to achieve maximum specimen mobility. When continuous outward traction on the large specimen ﬁlls the space between the tuberosities, thus preventing adjacent dissection, the partially mobilized specimen should be pushed back into the wound (and sometimes rotated into the open bladder neck) and elevated with ribbon retractors to expose the posterolateral

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Fig. 24. After the catheter tip is placed into the bladder, the anterior bladder neck is approximated around the membranous urethra. Any redundant posterior bladder neck is closed vertically. (Reproduced with permission from Weldon VE. Radical perineal prostatectomy. In: Das S, Crawford ED, eds. Cancer of the Prostate. Marcel Dekker, New York, 1993, pp. 225–266.)

prostatic base. It may also be necessary to transect the seminal vesicles and remove them separately after the prostate is removed.

POSTOPERATIVE CARE Oral liquids to a regular diet as desired are given on the day of surgery. If rectal repair was required, a minimal residue liquid diet with full nutrition (e.g., Ensure, Abbott Laboratories, Columbus, OH) is used for 1 wk. Full ambulation is resumed on the ﬁrst postoperative day. The Penrose drain is removed on the ﬁrst day unless unusual urinary drainage occurs. Regular administration of nonsteroidal anti-inﬂammatory agents for the initial 24 h provides most of the necessary analgesia, with minimal additional oral or parenteral narcotics as needed. Because no muscles pull on the incision, patients move freely without pain, and 90% of patients are ready for discharge the following day. With a negative cystogram and treatment of any catheterrelated urinary infection, the catheter can be removed after 7 d. Earlier removal has a

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Table 1 Morbidity after Radical Perineal Prostatectomy in 220 Consecutive Patientsa No. of patients

%

3 3 2 1 1 1 2 4 4 4 3 5 2 1 3 1 40

1 1 1 0.5 0.5 0.5 1 2 2 2 1 3 1 0.5 1 0.5 18

Anastomotic strictures Inadvertent proctotomy Pulmonary embolus Deep venous thrombosis only Necrotizing pancreatitis Myocardial infarction Atrial ﬁbrillation Transient peripheral neuropathy Prolonged urinary extravasation Prolonged lymph drainagea Transient genital edemaa Lymphocelea Clostridium difﬁcile colitis Obstructed catheter (clots) Perineal cellulitis Pneumonia Total a

Concomitant pelvic lymphadenectomy in 181 patients. Reproduced with permission from Weldon VE, Tavel FR, Neuwirth H. Continence, potency and morbidity after radical perineal prostatectomy. J Urol 1997;158:1470–1475.

troublesome incidence of nonstrictured urinary retention related to edema and requiring recatheterization.

COMPLICATIONS Morbidity Complications that occurred in this author’s initial 220 cases (concomitant mini-lap pelvic lymphadenectomy in 181) are listed in Table 1. There have been no deaths. Serious complications including venous thrombosis or embolism, myocardial infarction, and necrotizing pancreatitis occurred in 2%. In that early series, venous thrombosis or embolism occurred only in men who underwent concomitant pelvic lymphadenectomy. Now that pelvic lymphadenectomy is rarely done, the incidence of venous thrombosis or embolism is 0.3%, and the 7% incidence of directly related complications has been eliminated. The 2% incidence of prolonged urinary drainage has been eliminated by using two layers for the “racquet handle” closure of any posterior bladder neck redundancy. Anastomotic strictures in 1% occur primarily in men receiving salvage radiation therapy, and they have never required more than simple dilation. As many as 39% of carefully questioned patients may be found to have at least minimal evidence of ﬂeeting neurapraxia (38), but only 2% of our series complained of it. Blood loss in those cases (rounded to the nearest 100 mL) is shown in Fig. 25. Median operative blood loss was 600 mL, and 95% lost 1200 mL or less. In a nationwide survey of retired military men, Bishoff and associates (39) found a 15% incidence of at least monthly fecal incontinence occurring 1 yr after radical per-

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Fig. 25. Operative blood loss during radical perineal prostatectomy in 220 consecutive patients. (Reproduced with permission from Weldon VE, Tavel FR, Neuwirth H. Continence, potency and morbidity after radical perineal prostatectomy. J Urol 1977;158:1470–1475.)

ineal prostatectomy, compared with 10% of retropubic cases. They also had an unacceptably high incidence of urinary incontinence (39% perineal vs 56% retropubic) (39). However, experienced perineal surgeons have reported a questionnaire-determined change in bowel habits after 1 yr in 7% and new-onset fecal incontinence (usually only staining underwear and not requiring pads) after 1 yr in 3% (11,40). Our 1% incidence of inadvertent proctotomy has not been associated with any sequelae. However, if a rectourethral or rectocutaneous ﬁstula is manifest in the ﬁrst few days after prostatectomy, the perineal wound should be reopened and the rectum repaired. If delayed manifestation occurs and persists, transanal repair with a rectal wall ﬂap has a high success rate. In the absence of pelvic cellulitis, abscess, sepsis, or a very large ﬁstula, diverting colostomy is rarely necessary.

Continence Continence (no daily pads) rates related to postoperative time are shown in Figure 26. After 10 mo, 95% were continent. Of the 5% who were incontinent, 25% had mild (one pad daily), 42% had moderate (two to three pads daily), and 33% had severe (four to six pads daily) incontinence. None were totally incontinent. Poor bladder compliance or instability ameliorated by anticholinergic medication was a major factor in 17% of the incontinent men. Patient age was the only signiﬁcant related variable, with incontinence occurring almost solely in men age 70 or older (occurring in 12% of that age group) (10). There is likely to be an irreducible minimum incontinence rate in older men related to an aging-acquired deﬁciency of the distal sphincter mechanism. Injection of bulking agents for sphincteric insufﬁciency has been very helpful. It may be more effective after the perineal approach since incontinence was never total and the precise apical dissection and anastomosis leaves a relatively long and pliable membranous urethra that more easily accepts the injected material.

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Fig. 26. Cumulative postoperative continence as a function of time after radical perineal prostatectomy in 220 consecutive patients. (Reproduced with permission from Weldon VE, Tavel FR, Neuwirth H. Continence, potency and morbidity after radical perineal prostatectomy. J Urol 1997;158:1470–1475.)

Fig. 27. Cumulative postoperative potency as a function of time after nerve-sparing radical perineal prostatectomy in 50 patients. (Reproduced with permission from Weldon VE, Tavel FR, Neuwirth H. Continence, potency and morbidity after radical perineal prostatectomy. J Urol 1997;158:1470–1475.)

Potency Unassisted potency (prospectively assessed, repeated and prolonged vaginal penetration) related to postoperative time in our initial 50 patients who had good preoperative potency and a minimum 18 mo of follow-up and who were otherwise candidates for nerve sparing is shown in Fig. 27. Preoperative potency status and patient age were the only related variables. Potency returned in all men younger than age 50 but in only

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29% age 70 or older. Bilateral nerve sparing was successful in 73% and unilateral in 68% (10). The high success rate with unilateral perineal nerve sparing is related to both direct access and visualization of the posterolaterally located bundle and the added space available to avoid nerve stretching.

Health-Related Quality of Life Validated questionnaire assessment of the quality of life after treatment for prostate cancer has provided essential information. There are several studies assessing the quality of life associated with an individual treatment. However, Wei and associates (41) reported a concurrent study, with outcomes after 1 yr, comparing radical prostatectomy, external radiation, brachytherapy, and controls. They also noted the effects of adjuvant androgen deprivation. Compared with controls, each treatment group reported bothersome sexual dysfunction. Radical prostatectomy was associated with adverse urinary continence but improved urinary irritative symptoms. External radiation was associated with adverse bowel function. Brachytherapy was associated with averse urinary, bowel, and sexual function (p ≤ 0.0002 for each). Adjuvant androgen deprivation was associated with significant impairment. After 1 yr, patients who had had brachytherapy continued to have worse urinary, bowel, and sexual function than those who had radical prostatectomy or external radiation.

CANCER CONTROL Intermediate and long-term data on freedom from PSA relapse after both perineal (42,43) and retropubic (13,15,44) radical prostatectomy demonstrate that approx 70% of men with clinically localized prostate cancer are cured. The chance of cure in an individual patient is independently related to his clinical stage (TNM), biopsy grade (Gleason score), PSA level, year of treatment (reflecting PSA screening-related pathologic stage migration), and volume of tumor or number of involved cores in systematic biopsies (15,45). With the data from 2091 radical prostatectomy patients, Han and colleagues (46) generated tables using clinical stage, biopsy grade, and broad groups of PSA levels to estimate the chance of a 10-yr PSA relapse-free survival, with 95% confidence intervals, for an individual patient. They also generated tables using pathologic stage and grade, with preoperative PSA level, to give a more precise prediction when the specimen is available for analysis (46). Comparison of relapse-free and survival rates for radical prostatectomy vs external radiation or brachytherapy is hindered by many factors including absence of randomization, difference in cohort characteristics and deﬁnitions of PSA relapse, and changing methods of radiation therapy and stages of cases discovered with PSA over time. As an example of this confusion, when American Society for Therapeutic Radiology and Oncology (ASTRO) criteria for PSA failure after radiation therapy were used to assess the outcome of radical prostatectomy at 15 yr, the surgical success rate increased by 22%. Almost 50% of surgical patients with known biochemical failure were missed using ASTRO criteria (47). Nonetheless, Kupelian and associates (48) reported a large, nonrandomized study comparing the PSA outcomes of T1 and T2 patients treated with radical prostatectomy and external radiation at a single institution and using a nadir or rising PSA >0.5 ng/mL to identify radiation failure. They found that the 8-yr actuarial relapse-free survival for high-dose external radiation (≥72 Gy) was statistically similar to that with

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radical prostatectomy. Lower radiation doses were distinctly inferior. Polascik and associates (49), using a case-matched method controlling for favorable characteristics, compared the outcomes of radical prostatectomy and brachytherapy. They found a 19% PSA relapse-free advantage after 7 yr for radical prostatectomy (98% vs 79%). The best available comparison of survival data is the large population-based National Cancer Institute Surveillance, Epidemiology and End Results (SEER) study of 59,576 patients treated from 1983 to 1992 and reported by Lu-Yao and Yao (50). They demonstrated a substantial survival advantage for radical prostatectomy vs external radiation that increased with increasing grade. The 10-yr survival rates with Gleason score 2–4 cancers were 98% with surgery, 74% with radiation, and 76% with palliation. With Gleason scores 5–7, the 10-yr survival rates were 91% with surgery, 74% with radiation, and 76% with palliation. With Gleason scores 8–10, the 10-yr survival rates were 76% with surgery, 52% with radiation, and 43% with palliation. In this context it is reasonable to conclude that radical prostatectomy is unsurpassed in the control of localized prostate cancer.

SALVAGE THERAPY The use of radical prostatectomy for primary treatment of clinically localized prostate cancer also allows the use of low morbidity and reasonably effective salvage external radiation to the prostate bed for probable local failure. This contrasts with attempts to salvage primary radiation failures, which have much higher morbidity (51,52). With a rising PSA level after radical prostatectomy, optimal identification of probable local recurrence amenable to more local treatment is achieved using Gleason score and pathologic stage, but primarily PSA kinetics. Patients with low-grade disease are more likely to have local failure, whereas those with seminal vesicle invasion are more likely to have distant metastases. However, PSA levels detected more than 2 yr after surgery and with a velocity less than 0.75 ng/mL/yr were observed in 94% of patients with local recurrence (53). Levantis and colleagues (54) found that postrecurrence PSA doubling time and preradiation PSA levels were the only predictors of successful salvage. An ASTRO consensus panel advocated instituting salvage radiation with postoperative PSA levels between 0.5 and 1.5 ng/mL, using doses of ≥64 Gy (55). Others have noted a beneﬁt to instituting salvage before the PSA level reached 1 ng/mL (56). With reasonable patient selection, salvage external radiation for apparent local failure after radical prostatectomy results in approx 50% with an undetectable PSA level 5 yr after salvage, with very low morbidity (56–58). The combination of primary radical prostatectomy and low-morbidity salvage radiation therapy provides unequaled control of localized prostate cancer.

CONCLUSIONS Contemporary radical perineal prostatectomy is safe and effective and is the least invasive surgical approach. It is unnecessary to have blood available for transfusion routinely. Ninety percent of patients stay 1 d in the hospital. Continence and potency rates in selected men are equal to more invasive approaches at lower cost. Alone, radical prostatectomy is unsurpassed in the control of localized prostate cancer. With available low-morbidity salvage therapy, it is unequaled.

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REFERENCES 1. Weldon VE, Tavel FR, Neuwirth H, Cohen R. Patterns of positive specimen margins and detectable prostate speciﬁc antigen after radical perineal prostatectomy. J Urol 1995;153:1565–1569. 2. Haab F, Boccon-Gibod L, Delmas V, Boccon-Gibod L, Toublanc M. Perineal versus retropubic radical prostatectomy for T1, T2 prostate cancer. Br J Urol 1994;74:626–629. 3. Sullivan LD, Weir MJ, Kinahan JF, Taylor DL. A comparison of the relative merits of radical perineal and radical retropubic prostatectomy. BJU Int 2000;85:95–100. 4. Boccon-Gibod L, Ravery V, Vordos D, Toublanc M, Delmas V, Boccon-Gibod L. Radical prostatectomy for prostate cancer: the perineal approach increases the risk of surgically induced positive margins and capsular incisions. J Urol 1998;160:1383–1385. 5. Weldon VE. Re: Radical prostatectomy for prostate cancer: the perineal approach increases the risk of surgically induced positive margins and capsular incisions (letter). J Urol 1999;161:1287. 6. Korman HJ, Leu PB, Huang RR, Goldstein NS. A centralized comparison of radical perineal and retropubic prostatectomy specimens: is there a difference according to the surgical approach? J Urol 2002;168:991–994. 7. Salmon L, Anastasiadis AG, Levrel O, et al. Location of positive surgical margins after retropubic, perineal and laparoscopic radical prostatectomy for organ-confined prostate cancer. Urology 2003;61:386–390. 8. Frazier HA, Robertson JE, Paulson DF. Radical prostatectomy: the pros and cons of the perineal versus retropubic approach. J Urol 1992;147:888–890. 9. Parra RO. Analysis of an experience with 500 radical perineal prostatectomies in localized prostate cancer (abstract). J Urol 2000;163(suppl):284–285. 10. Weldon VE, Tavel FR, Neuwirth H. Continence, potency and morbidity after radical perineal prostatectomy. J Urol 1997;158:1470–1475. 11. Ruiz-Deya G, Davis R, Srivastav SR, Wise AM, Thomas R. Outpatient radical prostatectomy: impact of standard perineal approach on patient outcome. J Urol 2001;166:581–586. 12. Mokulis J, Thompson I. Radical prostatectomy: is the perineal approach more difﬁcult to learn? J Urol 1997;157:230–232. 13. Catalona WJ, Smith DS. Cancer recurrence and survival rates after anatomic radical retropubic prostatectomy for prostate cancer: intermediate term results. J Urol 1998;160:2428–2434. 14. Meng MV, Carroll PR. When is pelvic lymph node dissection necessary before radical prostatectomy? Decision analysis. J Urol 2000;164:1235–1240. 15. Han M, Partin AW, Pound CR, Epstein JI, Walsh PC. Long-term biochemical disease free and cancerspeciﬁc survival following anatomic retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am 2001;28:555–556. 16. Partin AW, Kattan MW, Subon MS, et al. Combination of prostate-speciﬁc antigen, clinical stage and Gleason score to predict pathologic stage of localized prostate cancer: a multi-institutional update. JAMA 1997;277:1445–1451. 17. Rees MA, Resnick MI, Oesterling JE. Use of prostate speciﬁc antigen, Gleason score and digital rectal examination in staging patients with newly diagnosed prostate cancer. Urol Clin North Am 1997;24:379–388. 18. Campbell SC, Klein EA, Levin HS, Piedmonte MR. Open pelvic lymph node dissection for prostate cancer: a reassessment. Urology 1995;46:352–355. 19. Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 1999;341:1781–1788. 20. Weldon VE, Tavel FR. Potency-sparing radical perineal prostatectomy: anatomy, surgical technique and initial results. J Urol 1988;140:559–562. 21. Weldon VE. Extended radical perineal prostatectomy: an anatomical and surgical study (abstract). J Urol 1988;139(suppl):488A. 22. Tobin CE, Benjamin JA. Anatomical and surgical restudy of Denonvilliers’ fascia. Surg Gynecol Obstet 1945;80:272–288. 23. Tobin CE, Benjamin JA, Wells JC. Continuity of the fasciae lining the abdomen, pelvis and spermatic cord. Surg Gynecol Obstet 1946;83:575–596. 24. Denonvilliers C-PD. Anatomie du périnée. Bull Soc Anat Paris 1836;11:105–107. 25. Villers A, McNeal JE, Freiha F, Boccon-Gibod L, Stamey TA. Invasion of Denonvilliers’ fascia in radical prostatectomy specimens. J Urol 1993;149:793–798.

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26. Lepor H, Gregerman M, Crosby R, Mostoﬁ FK, Walsh PC. Precise localization of the anatomic nerves from the pelvic plexus to the corpora cavernosa: a detailed anatomic study of the adult male pelvis. J Urol 1985;133:207–212. 27. Myers RP. Gross and applied anatomy of the prostate. In: Kantoff PW, Carroll PR, D’Amico AV, eds. Prostate Cancer: Principles and Practice. Lipincott Williams & Wilkins, Philadelphia, 2002, p. 12. 28. Villers A, McNeal JE, Redwine EA, Freiha FS, Stamey TA. The role of perineural space invasion in the local spread of prostatic adenocarcinoma. J Urol 1989;142:763–768. 29. Myers RP, Cahill DR, Devine RM, King BF. Anatomy of radical prostatectomy as deﬁned by magnetic resonance imaging. J Urol 1998;159:2148–2158. 30. Myers RP, Cahill DR, Kay PA, et al. Puboperineales: muscular boundries of the male urogenital hiatus in 3D from magnetic resonance imaging. J Urol 2000;164:1412–1415. 31. Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and prevention. J Urol 1982;128:492–497. 32. Young HH. The early diagnosis and radical cure of carcinoma of the prostate: being a study of 40 cases and a presentation of a radical operation which was carried out in 4 cases. Bull Johns Hopkins Hosp 1905;16:315–321. 33. Belt E, Ebert CE, Surber AC Jr. A new anatomic approach in perineal prostatectomy. J Urol 1939;41:482–497. 34. Weldon VE. Radical perineal prostatectomy. In: Carroll PR, Grossfeld GD, eds. American Cancer Society Atlas of Clinical Oncology: Prostate Cancer. BC Decker, Hamilton, Ontario, 2002, p. 193. 35. Myers RP, Goellner JR, Cahill DR. Prostate shape, external striated urethral sphincter and radical prostatectomy: the apical dissection. J Urol 1987;138:543–550. 36. Lepor H, Chan S, Melamed J. The role of bladder neck biopsy in men undergoing radical retropubic prostatectomy with preservation of the bladder neck. J Urol 1998;160:2435–2439. 37. Weldon VE, Neuwirth H, Bennett PM. Bladder neck sparing during radical perineal prostatectomy risks preserving benign prostate glands. Abstracts of the Western Section AUA Annual Meeting, 1998, p. 37. 38. Price DT, Vieweg J, Roland F, et al. Transient lower extremity neurapraxia associated with radical perineal prostatectomy: a complication of the exaggerated lithotomy position. J Urol 1998;160:1375–1378. 39. Bishoff JT, Motley G, Optenberg SA, et al. Incidence of fecal and urinary incontinence following radical perineal and retropubic prostatectomy in a national population. J Urol 1998;160:454–458. 40. Dahm P, Silverstein AD, Weizer AZ, et al. A longitudinal assessment of bowel related symptoms and fecal incontinence following radical perineal prostatectomy. J Urol 2003;169:2220–2224. 41. Wei JT, Dunn RL, Sandler HM, et al. Comprehensive comparison of health-related quality of life after contemporary therapies for localized prostate cancer. J Clin Oncol 2002;20:557–566. 42. Paulson DF. Impact of radical prostatectomy in the management of clinically localized disease. J Urol 1994;152:1826–1830. 43. Iselin CE, Robertson JE, Paulson DF. Radical perineal prostatectomy: oncological outcome during a 20-year period. J Urol 1999;161:163–168. 44. Dilloglugh O, Leibman BD, Katan MW, Seale-Hawkins C, Wheeler TM, Scardino PT. Hazard rates for progression after radical prostatectomy for clinically localized prostate cancer. Urology 1997;50:93–99. 45. Freedland SJ, Aronson WJ, Terris MK, et al. Percent of prostate needle biopsy cores with cancer is a signiﬁcant independent predictor of prostate speciﬁc antigen recurrence following radical prostatectomy: results from the SEARCH Database. J Urol 2003;169:2136–2141. 46. Han M, Partin AW, Zahurak M, et al. Biochemical (prostate speciﬁc antigen) recurrence probability following radical prostatectomy for clinically localized prostate cancer. J Urol 2003;169:517–523. 47. Gretzer MB, Trock BJ, Han M, Walsh PC. Critical analysis of the interpretation of biochemical failure in surgically treated patients using the American Society for Therapeutic Radiology and Oncology criteria. J Urol 2002;168:1419–1422. 48. Kupelian PA, Elshaikh M, Reddy CA, Zippe C, Klein EA. Comparison of the efﬁcacy of local therapies for localized prostate cancer in the prostate-speciﬁc antigen era: a large single-institution experience with radical prostatectomy and external-beam radiotherapy. J Clin Oncol 2002;20:3376–3385. 49. Polascik TJ, Pound CR, DeWeese TL, Walsh PC. Comparison of radical prostatectomy and iodine-125 interstitial radio-therapy for clinically localized prostate cancer: a 7-year biochemical (PSA) progression analysis. Urology 1998;51:884–890. 50. Lu-Yao GL, Yao SL. Population based study for long term survival in patients with clinically localized prostate cancer. Lancet 1997;349:906–910. 51. Garzotto M, Wajsman Z. Androgen deprivation with salvage surgery for radiorecurrent prostate cancer: results at 5-year follow up. J Urol 1998;159:950–955.

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52. Pisters LL, von Eschenbach AC, Scott SM, et al. The efﬁcacy and complications of salvage cryotherapy of the prostate: J Urol 1997;157:921–925. 53. Partin AW, Pearson JD, Landis PK, et al. Evaluation of serum prostate-speciﬁc antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases. Urology 1993;43:649–659. 54. Leventis AK, Shariat SF, Kattan MW, et al. Prediction of response to salvage radiation therapy in patients with prostate cancer recurrence after radical prostatectomy. J Clin Oncol 2001;19:1030–1039. 55. Cox JD, Gallagher MJ, Hammond EH, et al. Consensus Statement on radiation therapy of prostate cancer: guidelines for prostate re-biopsy after radiation and for radiation therapy with rising prostate-speciﬁc antigen levels after radical prostatectomy. American Society for Therapeutic Radiology and Oncology Consensus Panel. J Clin Oncol 1999;17:1155–1163. 56. Schild SE, Buskirk SJ, Won WW, et al. The use of radiotherapy for patients with isolated elevation of serum prostate speciﬁc antigen following radical prostatectomy. J Urol 1996;156:1725–1729. 57. vander Kooy MJ, Pisanski TM, Cha SS, Blute ML. Irradiation for locally recurrent carcinoma of the prostate following radical prostatectomy. Urology 1997;49:65–70. 58. Pisansky TM, Kozelsky TF, Myers RP, et al. Radiotherapy for isolated serum prostate speciﬁc antigen elevation after prostatectomy for prostate cancer. J Urol 2000;163:845–850.

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Anesthetic Considerations for Contemporary Radical Prostatectomy Jerome F. O’Hara, Jr. and David Whalley

INTRODUCTION Anesthetic management for patients presenting for radical prostatectomy can be challenging. The different anesthetic techniques utilized in caring for these patients are inﬂuenced by whether an open or laparoscopic surgical approach is planned. Surgeon expertise, anesthetic technique, and method of postoperative pain control can affect the patient’s postoperative course. We review the anesthesia-related literature speciﬁc to this surgery and describe how our anesthetic management of these patients has evolved over the last decade.

ANESTHETIC PREOPERATIVE PREPARATION With the availability of a blood test to detect prostate-speciﬁc antigen levels, patients often present for radical prostate surgery earlier in life. Even so, many patients often present with multiple pre-existing medical problems that require medical evaluation and optimization before proceeding with anesthesia and surgery. Preoperatively, patients should be informed of the different anesthetic options for surgery. The likelihood of perioperative blood transfusion is discussed with the patient, together with the option of preoperative autologous blood donation (ABD) for open procedures. Additional perioperative issues associated with laparoscopic prostatectomy are addressed later in the chapter. Patients with known coronary artery disease or signiﬁcant cardiac risk factors should have cardiac clearance prior to undergoing prostatectomy. Generally our policy is to screen any patient with known coronary artery disease, a history of angioplasty or coronary artery bypass grafting, or multiple risk factors for coronary artery disease with a stress test prior to surgery.

ANESTHETIC CONSIDERATIONS FOR OPEN PERINEAL AND RETROPUBIC PROSTATECTOMY: GENERAL VS REGIONAL ANESTHESIA The potential of moderate to signiﬁcant intraoperative surgical bleeding is real. The type of anesthetic technique and need for invasive monitoring (arterial and central

From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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venous pressure) should be considered if a larger blood loss is expected based on size of gland, body habitus, and individual surgeon experience. A blood loss of several liters under the effect of a sympathetic block with regional anesthesia may lead to extreme hypotension and may require aggressive volume resuscitation with emergent tracheal intubation for airway management. This is more of a concern for retropubic radical prostatectomy (RRP) than for the perineal approach. Anesthesia for the perineal approach can be provided with either a general or regional (spinal or epidural) anesthetic technique. In these cases perioperative blood loss can usually be safely managed provided there is adequate intravenous access. Invasive monitoring is usually reserved for the patient who has coexisting cardiopulmonary disease. A complication of the perineal approach is lower extremity nerve injury owing to intraoperative positioning of extreme lithotomy positioning. For RRP there has been much discussion of the relative merits of regional anesthesia (spinal or epidural) over general anesthesia. Epidural anesthesia and analgesia has been described to impact favorably on operative blood loss, postoperative pain control, and patient activity level after surgery; however, some studies have reported no difference in patient mortality outcomes between regional vs general anesthesia for RRP (1,2). In comparing the anesthetic techniques of general anesthesia vs epidural anesthesia for RRP, several studies report that a signiﬁcant decrease in operative blood loss occurs with an epidural anesthetic technique (2–5). Stevens et al. (5) reported a decreased intraoperative blood loss when a combined technique of general anesthesia and a thoracic epidural anesthetic was compared with a general anesthetic alone. An important observation of this study was that the group of patients who had the combined technique breathed spontaneously intraoperatively. Controlled positive pressure ventilation during surgery increases thoracic pressure, which is hypothesized to impede venous return, compromise cardiac output, and increase peripheral venous pressure. This increase in venous pressure could be transmitted to resected veins surrounding the prostate and result in an increased operative blood loss. Several studies have demonstrated improved pain control when epidural anesthesia is used pre-emptively and then continued for analgesia postoperatively (6,7). This technique has also been shown to decrease the time needed for patients to resume normal activity levels after surgery (4,7). The conclusion from these studies was that epidural anesthesia and analgesia for RRP provided a decreased intraoperative blood loss, better postoperative analgesia, and improved patient activity sooner after surgery. When epidural anesthesia and analgesia were provided for patients undergoing RRP, the effect on the return of bowel function has been evaluated. An earlier return of bowel function has been reported, but this did not result in a difference in time to hospital discharge (5). The patients in this study remained hospitalized for 5–7 d, but the current trend is for the patient to be evaluated for discharge on postoperative d 2 or 3. A significant factor in determining patient discharge readiness may be whether bowel function returns earlier with an epidural anesthetic.

ANESTHETIC CONSIDERATIONS FOR LAPAROSCOPIC PROSTATECTOMY This section explores concerns of the anesthesiologist in the management of patients undergoing laparoscopic prostatectomy. We review the cardiovascular and respiratory

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effects of pneumoperitoneum (PP) along with the anesthetic management for this surgical approach. The advent of laparoscopic techniques in gynecologic practice by Steptoe (8) in 1967 presented the anesthesiologists with their ﬁrst exposure to the challenges posed by the physiologic effects and complications of laparoscopy. It was not until the reports of successful laparoscopic cholecystectomy from France in the latter part of the 1980s that the practice of anesthesia for laparoscopic minimally invasive surgery became a recognized subspecialty among multiple surgical disciplines. This recognition brought with it the obligation to be aware of the peculiarities of this particular type of surgery and the physiologic disturbances that accompany it.

Cardiovascular Effects The laparoscopic gynecologic procedures of 25 yr ago were associated with few cardiovascular disturbances. This was attributed to the short diagnostic character of the procedures, which were performed mainly in a young, healthy patient population. The impact of the PP and modest head-down position was identiﬁed and described by a number of investigators (9,10). These early studies showed that there were consistent, although transitory, hemodynamic changes associated with laparoscopy. This was a result of the interaction between the head-down position, increase in intra-abdominal pressure secondary to the PP, and physiologic effects of absorbed CO2 from the abdominal cavity. The laparoscopy of modern minimally invasive urologic surgery induces cardiovascular changes that reﬂect those of the induced PP and the position in which the patient is placed. Minute ventilation can usually be increased to accommodate the progressive increase in absorbed CO2 without undue increases in intrathoracic pressure. Abdominal insufﬂation in the supine position is associated with an increase in mean arterial pressure as a result of an increase in systemic vascular resistance, increase in ﬁlling pressures, and increased preload (11–13). Increase in preload and cardiac index and decrease in systemic vascular resistance have been described during laparoscopic urologic surgery in the lateral position. This appears to be more pronounced in the right vs left lateral position (14). Release of PP is accompanied by a hyperdynamic state (13). Changes in preload and afterload are usually well tolerated in healthy, young individuals but may compromise cardiac function in the patient with limited cardiac reserve such as in the population undergoing prostatectomy. Catastrophic cardiovascular complications of a PP with CO2 include arrhythmias and CO2 embolism; constant vigilance for these complications is required (15).

Respiratory Effects The respiratory effects of PP and positioning are superimposed on the effects of the anesthetic itself. They consist of decreased lung volumes and compliance together with the need to excrete an increased CO2 load secondary to absorption from the peritoneal cavity or retroperitoneal space (16). The cephalad movement of the abdominal contents is partially responsible for the decrease in lung volumes and alteration in compliance (C). These changes are more evident in the obese patient. The consequence of a decreased functional residual capacity (FRC) is microatelectasis in the lung bases and ventilation-perfusion mismatching. In the head-down position during laparoscopic prostatectomy, a further decrease in lung volumes and C occurs secondarily to the weight of the abdominal contents

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displacing the diaphragm cephalad. Insufflation of the abdomen causes a decrease in FRC of approx 20%, a decrease in C of at least 30%, and an unpredictable effect on physiologic dead space (16,17). The effect on oxygenation and CO2 elimination in this setting can be minimal if managed properly (18). The implications for the anesthesiologist are first, that an elevated airway pressure increases the likelihood for barotrauma and second, that the decrease in C is a function primarily of a decrease in chest wall compliance. Carbon dioxide is absorbed from the peritoneal cavity during laparoscopy, and this added CO2 load is excreted through the lungs. A small respiratory acidosis is usually well tolerated in most patients, but it is often necessary to compensate for the absorption of CO2 by increasing minute ventilation. It has been suggested that retroperitoneoscopic renal and adrenal surgery are associated with greater absorption of CO2 than the transperitoneal approach (19), but recent work has challenged that conclusion (20). Subcutaneous emphysema may be more common with the retroperitoneal approach owing to increased CO2 absorption. In the absence of any complications, the maintenance of arterial oxygenation is rarely a problem. Numerous studies have attested to the maintenance of arterial PO2 (PaO2) or oxygen saturation during laparoscopy in different patient populations. This includes ASA III patients and those in whom a substantial decrease in cardiac output has been observed (12,21,22). It is likely that the impact of ventilation-perfusion (V/Q) mismatching on oxygenation is minimized by the increased ventilation needed to maintain normocapnia. The end-tidal PCO2 ( PETCO2) is commonly used to monitor the adequacy of ventilation and has a close relationship (3–5 mmHg) to the arterial PCO2 (PETCO2). In summary, the respiratory implications for the anesthesiologist of laparoscopy in the patient undergoing prostatectomy include management of the decreased compliance and excretion of the increased CO2 load. This implies careful attention to the change in airway pressure and PETCO2, as well as frequent monitoring of PaCO2 during prolonged surgery, particularly in those patients with cardiorespiratory compromise.

Preoperative Evaluation and Preparation The impetus for the explosion of minimally invasive surgery (MIS) has been the demonstration that laparoscopic techniques, although often taking longer to perform, are often associated with less blood loss, shorter hospital stay, and quicker return of normal patient function compared with conventional open surgery. Laparoscopic prostatectomy appears to be a safe, effective, and precise technique that offers some advantages over open surgery. This surgical approach offers a dry, magniﬁed operative site and lower likelihood of blood transfusion. Laparoscopic MIS is associated with a postoperative course that is demonstrably less protracted, which can lead to a trivialization of the preoperative workup that must be firmly discouraged. Despite the term “minimally invasive” the physiologic disturbances associated with PP, positioning, and CO2 absorption, as we have described, can be substantial. This implies a full preoperative assessment and optimization of any systemic disease before anesthesia is undertaken, with the patient presenting for surgery in optimum condition. A decrease in blood loss should be expected compared with open prostatectomy, but uncontrollable hemorrhage can occur (23), and at least one large-bore intravenous catheter should be inserted to accommodate a major blood loss.

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Monitoring Routine monitoring should include PETCO2. It is advisable to insert a radial artery catheter to facilitate arterial blood gas measurement and to monitor the arterial pressure directly during longer laparoscopic procedures (24). The effects of PP and positioning render the measurements of central venous pressure almost meaningless as a measure of myocardial ﬁlling because of their impact on intrathoracic pressure. The use of transesophageal echocardiography has been described in the patient population undergoing laparoscopy and is a more suitable monitor of preload and ejection fraction (12,13). The suitability of the transesophageal echocardiography is, however, limited by the availability of equipment and appropriately trained personnel.

Anesthetic Technique General anesthesia with endotracheal intubation is the technique of choice for laparoscopic prostatectomy. Regional anesthesia is not a practical option, although it has been described for other types of MIS such as laparoscopic cholecystectomy (25). and inguinal hernia repair (26). General anesthesia with endotracheal intubation provides a secure airway, controlled ventilation, and the use of muscle relaxation to facilitate surgery and maintain the PP.

Anesthetic Agents The surgical requirements for laparoscopy demand profound muscle relaxation and a nondistended bowel. Postoperative goals are to have a patient who is awake, painfree, and without nausea or vomiting. The challenge to the anesthesiologist is to provide these conditions while maintaining hemodynamic and respiratory stability during surgery and in the immediate postoperative period. The intravenous anesthetic propofol and the inhalational anesthetics desﬂurane and sevoﬂurane have unique properties that have made them especially useful for general anesthetics that demand rapid emergence. In laparoscopic procedures of short duration, nitrous oxide probably makes no difference to surgical exposure, but with long surgery, such as that encountered during prostatectomy, nitrous oxide is associated with dilation of the bowel. This can compromise the surgical exposure and may be one of the factors in causing postoperative nausea and vomiting. Preferably the muscle relaxant chosen should have cardiovascularly stability, predictable recovery/reversal, no accumulation, no histamine release and should not be expensive. We often use muscle relaxants that have intermediate duration of action (atracurium or rocuronium) either by intermittent bolus or by constant infusion. A continued challenge in modern anesthesia for laparoscopic procedures such as prostatectomy is to solve the problem of perioperative pain that traditionally demands the administration of narcotics without prolonging stay in the Postoperative Anesthesia Care Unit owing to somnolence or emesis. Pre-emptive multimodal analgesic techniques can be employed that incorporate opiates, nonsteroidal anti-inﬂammatory drugs, and local anesthesia inﬁltrated at the site of incisions or applied topically in the peritoneal cavity to manage postoperative pain (27). Despite the high prevalence of postoperative nausea and vomiting after MIS, much can be done to decrease its occurrence. Adequate hydration of the patient (28) and a postoperative analgesia regimen that de-emphasizes opiates may help obviate the problem. A recent quantitative systematic review of the safety and efﬁcacy of dexamethasone

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for the prevention of nausea concluded that it is very likely that the best prophylaxis of nausea currently available is achieved by combining dexamethasone with a 5-HT3 receptor antagonist such as dolasetron (29).

Complications The most common complication of any laparoscopic procedure is subcutaneous emphysema. It is more frequently observed late in the procedure and is heralded by an increase in the end-expired CO2. The diagnosis is conﬁrmed by feeling for crepitus. The surgeon should be notiﬁed of its occurrence and the ventilation suitably adjusted. More serious complications of laparoscopic prostatectomy include perforation of the bowel and uncontrollable hemorrhage (30,31). Complications associated with the PP include pneumothorax and massive CO2 embolism. These events may lead to a decrease in the O2 saturation and acute cardiovascular compromise. CO2 embolism is more frequently associated with a decrease in end-expired CO2 rather than the increase that can accompany pneumothorax. Fortunately, these latter complications are rare, but their occurrence can be devastating in an otherwise healthy patient population.

PERIOPERATIVE BLOOD CONSERVATION TECHNIQUES With the potential for significant intraoperative blood loss during open RRP, many strategies have been recommended perioperatively to avoid allogenic blood transfusion. These include preoperative administration of erythropoietin, preoperative ABD, acute normovolemic hemodilution (ANH), and use of intraoperative cell savage (ICS) techniques. A preoperative pharmacologic therapy to avoid allogenic blood transfusion is the injection of erythropoietin. Chun et al. (32) described this therapy as safe, well tolerated, and equally effective as preoperative ABD in decreasing the need for allogenic blood transfusion in RRP. The cost was described as similar to that of preoperative ABD and offered patients greater convenience with less time commitment to perform. Monk et al. (33) prospectively compared preoperative ABD of 3 U vs preoperative erythropoietin and ANH vs ANH alone to determine which of these three blood conservation strategies for RRP was the most efﬁcient. The authors concluded that all three blood conservation strategies resulted in similar allogenic blood exposure but that ANH was the least costly technique. Preoperative erythropoietin and ANH prevented postoperative anemia but resulted in the highest cost. ABD has gained popularity as a method to prevent allogenic blood transfusion for RRP. Autologous blood transfusion eliminates the risk of transmitting infectious diseases but still has the potential for adverse reactions. The complications described with autologous blood transfusion include misidentiﬁcation of the patient unit, bacterial contamination, hemolysis, delaying surgery for collection, vasovagal reactions during donation, relative anemia pre- and postoperatively, and volume overload (34). In the early 1990s, ABD for this surgical procedure was strongly suggested. Over the last decade improved surgical techniques have led to less intraoperative blood loss for RRP, which does challenge whether ABD for this surgery is always needed. There is an inverse correlation of the number of autologous donation units available for a patient and the need for an allogenic blood transfusion. The need for allogenic blood transfusion in patients who participate in ABD is reported to be between 0 and 14% (35–37) and is similar to that in patients who do not donate blood (2.4–11%)

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(37–40). Two of the factors that determine the suitability of the patient for autologous blood transfusion are the preoperative hematocrit and the projected intraoperative blood loss. If healthy patients have normal hemoglobin levels preoperatively and the predictable blood loss pattern of the individual surgeon is less than 1500 mL, then ABD should be left as an option for the patient rather than a standard for this surgery. ABD for RRP is associated with a high incidence of wasted or inappropriately transfused units (42–81%), which does raise the question of the cost of procurement and effectiveness of this practice (34–36,39,40). ANH is another alternative to avoid allogenic blood transfusion during RRP. The advantage of ANH is that it preserves blood components more effectively than preoperative ABD and also avoids risks associated with autologous blood transfusion. Both ABD and ANH are reported to decrease the need for allogenic blood transfusions, but ANH is less expensive and more convenient for patients (33,41). ANH offers some advantages over preoperative ABD, but successful performance does require an additional intraoperative effort. It has been suggested that 3–4 U of blood should be harvested to decrease signiﬁcantly the need for allogenic blood transfusion (42). Therefore ANH is one option that can be considered to replace or be an adjunct to preoperative ABD for use in RRP to decrease the need for allogenic blood transfusion. A newer strategy to prevent allogenic blood transfusion for RRP is the use of ICS. Gray et al. (43) evaluated the safety in this technique compared with preoperative ABD. They concluded that ICS using leucocyte reduction ﬁlters in RRP resulted in higher preoperative hematocrit levels and a low rate (3% vs 14%) of allogenic blood transfusion. The investigators commented that ICS did not appear to be associated with an increased risk of any early biochemical cancer progression, but a review by Thomas (44) concluded that the safety of ICS in malignant ﬁelds is not clearly established. In vitro studies using ﬁlters appear to provide nearly 100% protection from reinfusion of tumor cells, which does suggest that the use of ﬁlters is clinically safe. However, in vivo studies to support this practice are lacking owing in part to the ethical issues involved. Some other factors have been identiﬁed that may affect intraoperative blood loss for RRP. Controlled hypotensive anesthesia (45) and Trendelenburg position (46) have been reported to result in a decreased blood loss during RRP, whereas intermittent pneumatic compression devices utilized to help prevent lower extremity deep vein thrombosis have been reported to increase blood loss during radical pelvic operations (47).

PERIOPERATIVE ANESTHETIC CONCERNS One of the most important aspects in providing anesthesia for RRP surgery is being prepared for acute and signiﬁcant intraoperative blood loss. Other perioperative anesthetic concerns include the risk of air embolism via the venous plexus surrounding the prostate gland, the occurrence of thromboembolism from deep vein thrombosis, and the possibility of obturator nerve injury from retractor trauma or transection. As previously discussed, postoperative recovery of bowel function after RRP may be affected by the choice of anesthetic technique (5). The infusion of intravenous lidocaine has been reported to result in a faster return of bowel function, less postoperative pain, and a shorter hospital stay in patients who had a general anesthetic for RRP (48).

POSTOPERATIVE PAIN CONTROL The anesthetic technique selected for RRP may affect the degree of postoperative pain that the patient experiences. It appears that use of epidural anesthesia followed by

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epidural analgesia decreases pain in the immediate postoperative period as well as in the weeks to months following surgery (6,7). Epidural analgesia compared with intravenous morphine patient-controlled analgesia has been reported to decrease postoperative pain and result in a greater proportion of patients experiencing complete pain relief postoperatively (49). Ketorolac has been described as a beneﬁcial adjunct for postoperative pain management after RRP, resulting in an earlier recovery of bowel function and earlier discharge from the hospital (50,51).

CURRENT ANESTHETIC TECHNIQUE FOR RADICAL RETROPUBIC PROSTATECTOMY Our initial technique at The Cleveland Clinic Foundation for RRP was general anesthesia. Subsequently we provided a combined technique of general and epidural anesthesia. Currently our technique is epidural anesthesia and analgesia for the procedure. After preoperative evaluation most patients present on the day of surgery expecting an epidural anesthetic. A high lumbar epidural catheter is placed after appropriate sedation prior to the patient entering the operating room. The epidural catheter is usually dosed with 2% mepivacaine or 2% lidocaine with the goal of obtaining a T6 level sensory block. Two large-bore intravenous catheters are routinely introduced. A phenylephrine infusion is utilized to counteract hypotension from the sympathetic block. This can be significant owing to venous pooling in the lower extremities, especially when the patient is placed in the reverse Trendelenburg position to facilitate surgical exposure of the prostate. If an inadequate sensory epidural anesthetic is experienced, we attempt conversion to a general anesthetic using a laryngeal mask airway and spontaneous ventilation. Spontaneous, rather than mechanical, ventilation is felt to be a factor in decreasing intraoperative blood loss. A patient with a stable cardiac history or several cardiac risk factors will have an arterial catheter inserted for invasive blood pressure monitoring and blood sampling. Postoperatively, patients are continued on an epidural patient-controlled analgesia infusion. Typically, on postoperative d 1, the epidural catheter is removed, and the patient is started on oral analgesics such as ketorolac. With this analgesic regimen, patients have rated their feelings on postoperative pain control as “satisﬁed” or “very satisﬁed” 89.2% of the time (52). To prevent allogenic blood transfusion, patients are offered the opportunity for ABD. If ABD is selected, it is arranged as early as possible prior to surgery. These patients are then routinely placed on an oral iron supplement to improve hemoglobin levels post donation. In addition, an epidural anesthetic technique facilitates a degree of hypotensive anesthesia in an attempt to decrease intraoperative blood loss. Another technique used by some surgeons to prevent allogenic blood transfusion is ICS with leukocyte-depleting ﬁlters. These two techniques, along with a low transfusion threshold in healthy patients (hematocrit ≤ 25), have dramatically reduced the need for allogenic blood transfusion to approx 5%. For patients undergoing laparoscopic radical prostatectomy, our anesthetic technique is that of a general anesthetic, two large-bore intravenous catheters, and invasive arterial blood pressure monitoring. Arterial blood pressure monitoring is utilized owing to the length of the procedure, extreme Trendelenburg positioning, effect on ventilation, and need for arterial blood gas sampling. Postoperatively, these patients do well

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with a regimen of intravenous and oral analgesics that include ketorolac after local anesthesia is injected at the incision sites at the end of the surgical procedure.

CONCLUSIONS The perioperative anesthetic management of patients undergoing RRP can be challenging. The anesthetic and surgical technique selected inﬂuences intraoperative blood loss, return of bowel function postoperatively, degree of postoperative pain, time to return of normal activity levels, and patient satisfaction. These are factors that can potentially affect morbidity and inﬂuence length of hospital stay. Hospitalization for RRP is now expected to be 2–3 d with an open procedure and 1–2 d with a laparoscopic approach. We are observing decreased surgical times for laparoscopic radical prostatectomy. If this surgical technique becomes the standard of care, then all patients would be expected to receive a general anesthetic. The anesthetic technique chosen for future radical prostatectomy surgeries will depend on whether a speciﬁc surgical approach (open vs laparoscopic) is discovered to be superior for patient outcome.

REFERENCES 1. Shir Y, Frank SM, Brendler CB, Raja SN. Postoperative morbidity is similar in patients anesthetized with epidural and general anesthesia for radical prostatectomy. Urology 1994;44:232–236. 2. Frank E, Sood OP, Torjman M, et al. Postoperative epidural analgesia following radical retropubic prostatectomy: outcome assessment. J Surg Oncol 1998;67:117–120. 3. Shir Y, Raja SN, Frank SM, et al. Intraoperative blood loss during radical retropubic prostatectomy: epidural versus general anesthesia. Urology 1995;45:993–999. 4. Malhotra V. A comparision of epidural anesthesia, general anesthesia, and combined epidural general anesthesia for radical prostatectomy. Anesthesiology 1994;81(3A):A973. 5. Stevens RA, Mikat-Stevens M, Flanigan R, et al. Does the choice of anesthetic technique affect the recovery of bowel function after radical prostatectomy? Urology 1998;52:213. 6. Shir Y, Raja SN, Frank SM. The effect of epidural versus general anesthesia on postoperative pain and analgesic requirements in patients undergoing radical prostatectomy. Anesthesiology 1994;80:49–56. 7. Gottschalk A, Smith DS, Jobes DR, et al. Preemptive epidural analgesia and recovery from radical prostatectomy: a randomized controlled trial. JAMA 1988;279:1076–1082. 8. Steptoe PC. Laparoscopy in Gynaecology. ES Livingstone, London, 1967. 9. Marshall RL, Jebson PJR, Davie IT, Scott DB. Circulatory effects of carbon dioxide insufﬂation of the peritoneal cavity for laparoscopy. Br J Anaesth 1972;44:680–684. 10. Smith I, Benzie RJ, Gordon NLM, Kelman GR, Swapp GH. Cardiovascular effect of peritoneal insufﬂation of carbon dioxide for laparoscopy. BMJ 1971;3:410–411. 11. Kelman GR, Swapp GH, Benzie RJ, Gordon NL. Cardiac output and arterial blood-gas tension during laparoscopy. Br J Anaesth 1972;44:1155–1162. 12. Gannedahl P, Odeberg S, Brodin L, Sollevi A. Effects of posture and pneumoperitoneum during anaesthesia on the indices of left ventricular ﬁlling. Acta Anaesthesiol Scand 1996;40:160–166. 13. Harris SN, Ballantyne GH, Luther MA, Perrino AC. Alterations of cardiovascular performance during laparoscopic colectomy: a combined hemodynamic and echocardiographic analysis. Anesth Analg 1996;83:482–487. 14. Fujise K, Shingu K, Matsumoto S, et al. The effects of the lateral position on cardiopulmonary function during laparoscopic urological surgery. Anesth Analg 1998;87:925–930. 15. Morison DH, Riggs JRA. Cardiovascular collapse in laparoscopy. Can Med Assoc J 1974;111:433–437. 16. Wahba RWM, Beique F, Kleiman SF. Cardiopulmonary function and laparoscopic cholecystectomy. Can J Anaesth 1995;42:51–63. 17. Bardoczky GI, Engleman E, Levarlet M, Simon P. Ventilatory effects of pneumoperitoneum monitored with continuous spirometry. Anaesthesia 1993;48:309–311. 18. Scott DB, Slawson KB. Respiratory effects of prolonged Trendelenburg position. Br J Anaesth 1968;40:103–107.

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19. Wolf JS, Monk TG, McDougall EM, et al. The extraperitoneal approach and subcutaneous emphysema are associated with greater absorption of carbon dioxide during laparoscopic renal surgery. J Urol 1995;154:959–963. 20. Ng CS, Gill IS, Sung GT, et al. Retroperitoneoscopic surgery is not associated with increased carbon dioxide absorption. J Urol 1999;162:1268–1272. 21. Joris JL, Noirot DP, Legrand MJ, et al. Hemodynamic changes during laparoscopic cholecystectomy. Anesth Analg 1993;76:1067–1071. 22. Dhoste K, Lacoste L, Karayan J, et al. Haemodynamic and ventilatory changes during laparoscopic cholecystectomy in elderly ASA III patients. Can J Anaesth 1996;43:783–788. 23. Tan PL, Lee TL, Tweed WA. Carbon dioxide absorption and gas exchange during pelvic laparoscopy. Can J Anaesth 1992;39:677–681. 24. Wittgen CM, Andrus CH, Fitzgerald SD, et al. Analysis of the hemodynamic and ventilatory effects of laparoscopic cholecystectomy. Arch Surg 1991;126:997–1001. 25. Hanley ES. Anesthesia for laparoscopic surgery. Surg Clin North Am 1992;72:1014–1018. 26. Azurin DJ, LS, Cwik JC, et al. The efﬁcacy of epidural anesthesia for endoscopic preperitoneal herniorrhaphy. J Laparosc Surg 1996;6:369–373. 27. Michaloliakou C, Chung F, Sharma S. Preoperative multimodal analgesia facilitates recovery after ambulatory laparoscopic cholecystectomy. Anesth Analg 1996;82:244–251. 28. Yogendran Y, Asokumar B, Cheng DCH, et al. A prospective randomized double-blinded study of the effect of intravenous fluid therapy on adverse outcomes on outpatient surgery. Anesth Analg 1995;80:682–686. 29. Henzi I, Walder B, Tramer MR. Dexamethasone for the prevention of postoperative nausea and vomiting: a quantitative systematic review. Anesth Analg 2000;90:186–194. 30. Sprung J, O’Hara JF, Gill IS, et al. Anesthetic aspects of laparoscopic and open adrenalectomy for pheochromocytoma. Urology 2000;55:339–343. 31. Hynson JM, Sessler DI. Intraoperative warming therapies: a comparison of three devices. J Clin Anesth 1992;4:194–199. 32. Chun TY, Martin S, Lepor H. Preoperative recombinant human erythropoietin injection versus preoperative autologous blood donation in patients undergoing radical retropubic prostatectomy. Urology 1997;50:727. 33. Monk TG, Goodnough LT, Brecher ME, et al. A prospective randomized comparison of three blood conservation strategies for radical prostatectomy. Anesthesiology 1999;91:24–33. 34. O’Hara JF Jr, Sprung J, Klein EA, et al. Use of preoperative autologous blood donation in patients undergoing radical retropubic prostatectomy. Urology 1999;54:130–134. 35. Goh M, Kleer CG, Kielczewski P, et al. Autologous blood donation prior to anatomical radical retropubic prostatectomy: is it necessary? Urology 1997;49:569–573. 36. Das A, Strup S, Canﬁeld S, et al. Utilization of autologous blood donation during radical retropubic prostatectomy. Tech Urol 1998;4:131–135. 37. Goldschlag B, Afzal N, Carter HB, et al. Is preoperative donation of autologous blood rational for radical retropubic prostatectomy? J Urol 2000;164:1968–1972. 38. Koch MO, Smith JA Jr. Blood loss during radical retropubic prostatectomy: is preoperative autologous blood donation indicated? J Urol 1996;156:1077–1079. 39. Goad JR, Eastham JA, Fitzgerald KB, et al. Radical retropubic prostatectomy: limited beneﬁt of autologous blood donation. J Urol 1995;154:2103–2109. 40. Goodnough LM, Grishaber JE, Birkmeyer JD, et al. Efficacy and cost-effectiveness of autologous blood predeposit in patients undergoing radical prostatectomy procedures. Urology 1994;44:226–231. 41. Terada N, Arai Y, Matsuta Y, et al. Acute normovolemic hemodilution for radical prostatectomy: can it replace preoperative autologous blood transfusion? Int J Urol 2001;8:149–152. 42. Monk TG, Goodnough LT, Birkmeyer JD, et al. Acute normovolemic hemodilution is a cost-effective alternative to preoperative autologous blood donation by patients undergoing radical retropubic prostatectomy. Transfusion 1995;35:559–565. 43. Gray CL, Amling CL, Polston GR, et al. Intraoperative cell salvage in radical retropubic prostatectomy. Urology 2001;58:740–745. 44. Thomas MJ. Infected and malignant ﬁelds are an absolute contraindication to intraoperative cell salvage: fact or ﬁction? Transfus Med 1999;9:269–278. 45. Boldt J, Weber A, Mailer K, et al. Acute normovolaemic haemodilution vs controlled hypotension for reducing the use of allogeneic blood in patients undergoing radical prostatectomy. Br J Anaesth 1999;82:170–174.

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46. Barre C, Pocholle P, Chauveau P. Minimal blood loss in patients undergoing radical retropubic prostatectomy. World J Surg 2002;26:1094–1098. 47. Strup SE, Gudziak M, Mulholland SG, et al. The effect of intermittent pneumatic compression devices on intraoperative blood loss during radical prostatectomy and radical cystectomy. J Urol 1993;150:1176–1178. 48. Groudine SB, Fisher HA. Intravenous lidocaine speeds the return of bowel function, decreases postoperative pain, and shortens hospital stay in patients undergoing radical retropubic prostatectomy. Anesth Analg 1998;86:235–239. 49. Allaire PH, Messick JM Jr, Oesterling JE, et al. A prospective randomized comparison of epidural infusion of fentanyl and intravenous administration of morphine by patient-controlled analgesia after radical retropubic prostatectomy. Mayo Clin Proc 1992;67:1031–1041. 50. Grass JA, Sakima NT, Valley M, et al. Assessment of ketorolac as an adjuvant to fentanyl patient-controlled epidural analgesia after radical retropubic prostatectomy. Anesthesiology 1993;78:642–648. 51. See WA, Fuller JR, Toner ML. An outcome study of patient-controlled morphine analgesia, with or without ketorolac, following radical retropubic prostatectomy. J Urol 1995;154:1429–1432. 52. Klein EA, Grass JA, Calabrese DA, Kay RA, Sargeant W, O’Hara JF. Maintaining quality of care and patient satisfaction with radical prostatectomy in the era of cost containment. Urology 1996;269–276.

15

Conformal External Beam Radiation Therapy Arul Mahadevan and Patrick A. Kupelian

INTRODUCTION External beam radiation therapy (RT) has been an essential component in the curative treatment of prostrate cancer for several decades. During the early clinical applications of cobalt beam teletherapy, the methods used to treat prostrate cancer relied on broad anatomic and physical principles that were applied in a general fashion to all patients with presumed localized disease. The target tissues (including the prostate, seminal vesicles, and pelvic lymph nodes) were not differentiated from the surrounding organs such as the bladder and the rectum, limiting the application of high radiation doses. The higher the radiation dose administered to a given volume of cancer, the more likely it is that the cancer will be permanently controlled—this is a basic tenet in radiation biology that has been clinically validated in several reports, both retrospective and prospective (1–7). In the last decade or so, the availability of high-energy megavoltage X-ray machines and the incorporation of cross-sectional imaging modalities and computerized treatment planning systems have been instrumental in the evolution of external radiation beam therapy as a safer and more effective option for men with localized prostate cancer. This chapter highlights the relevant clinical applied anatomy, the technical aspects of conformal external beam radiation therapy techniques, and the current disease control and quality of life outcome expectations.

APPLIED CLINICAL ANATOMY The major advances in external beam radiation therapy of prostate cancer have resulted from recognizing the importance of differentiation of doses delivered to target tissues (prostate, seminal vesicles, and lymph nodes) and surrounding normal organs (bladder and rectum). An essential step in this direction is to obtain three-dimensional images to plan radiation treatments. Currently the most widely used technique involves cross-sectional computed tomography (CT) images. More recently, magnetic reso-

From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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nance imaging (MRI) has been utilized to reﬁne further target and normal tissue delineation (8–10).

Organ Motion The location of the prostate in the middle of the pelvis between two expansile normal structures (bladder and the rectum) makes organ motion a major confounding factor in the targeting of modern external beam radiation therapy. Over the last decade, prostate motion has been evaluated extensively (11–19). The magnitude of the motion is most pronounced in the anterior/posterior dimension (range 1–1.5 cm), is signiﬁcant in the superior/inferior dimensions (range 0.75–1.5 cm), and is least in the lateral dimension (range 0.5–1 cm). The rotational changes have been less studied. To improve the differential doses delivered to the target and normal tissues at risk, it is essential to reduce organ motion on a daily basis. The currently available techniques to achieve this include: 1. Implantation of radio-opaque seeds in the prostate and tracking the daily position using orthogonal X-rays or electronic portal imaging devices (19). 2. Daily transabdominal utrasonography (12,20). 3. Daily CT scans (21,22). 4. Tomotherapy (23,24).

At the Cleveland Clinic we currently use daily transabdominal ultrasonography to compensate for interfraction motion of the prostate gland.

Target Volume Prostate cancer is frequently multifocal in the gland; therefore the entire gland is considered a target for external beam radiation therapy. More recently the use of MRI and MR spectroscopy has suggested a role for an additional boost to a dominant intraprostatic lesion. The most common location of the disease within the gland is in the peripheral zone, and the least common is the central zone. Prostate cancer cells also have a tendency to track along the nerves, and hence extraprostatic extension is most frequent at the apex, base, and posterolateral aspect of the gland. Microscopic extension to the extraprostatic tissue occurs in around 30–40% of the cases with clinically organ-conﬁned disease (stages T1 and T2) (25,26). More than half (53%) of extraprostatic extension cases are posterolateral, 24% are lateral, 13% are posterior, and 10% are at the base. Extraprostatic extension is usually within 3–4 mm of the gland in 90% of the cases (26). Involvement of the seminal vesicles is mainly owing to direct extension from the prostate base. However, a small percentage of patients’ microscopic tumor can be found within the seminal vesicles without obvious extraprostatic extension. In patients with pretreatment prostate-speciﬁc antigen (PSA) levels of <10 ng/mL and biopsy Gleason score (bGS) ≤6, the rate of seminal vesicle involvement is about 5–6% vs 30–35% with pretreatment PSA levels > 10 ng/mL or bGS of ≥ 7(27). The most common involvement is found in the proximal half of the seminal vesicles in direct contact with the base of the prostate gland.

Pelvic Lymph Nodes The inclusion of pelvic lymph nodes as a target is controversial. Earlier Radiation Therapy Oncology Group (RTOG) studies have failed to show any difference in survival in patients who had pelvic radiation as opposed to prostate radiation alone

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(28). However, two important criticisms of these studies include the following: the patient population most likely to benefit was not studied, and the doses delivered were not adequate. More recently a randomized study has been completed for patients determined to be at high risk for pelvic lymph node metastasis (29). The study randomized patients to receive either whole pelvic radiation plus a prostate boost or prostate-alone radiation. A second randomization assigned patients to receive 4 mo of androgen deprivation either neoadjuvantly or adjuvantly. Preliminary results have shown an advantage to whole pelvic radiation when combined with neoadjuvant androgen deprivation therapy. The ﬁnal results are expected soon. In this study, patients received a total dose of 70.2 Gy. Whether this dose is sufﬁcient for high-risk prostate cancer patients and whether more radiation can be delivered safely along with whole pelvic radiation remains to be seen. At the Cleveland Clinic, the target volume includes the prostate gland only for lowrisk disease (T1, T2a/b, bGS ≤ 6, PSA ≤ 10 ng/mL); prostate gland plus seminal vesicles for intermediate-risk disease (T2c or bGS 7or PSA > 10 ≤ 20); and prostate gland plus seminal vesicles and preiprostatic lymph node regions for higher risk patients (T3, T4, bGS ≥ 8 and/or PSA > 20).

CONFORMAL EXTERNAL BEAM RADIATION THERAPY TECHNIQUES Limitations of Conventional Radiation Therapy Techniques Conventional radiation implies delivery of radiation therapy using a simple four-ﬁeld approach. No signiﬁcant effort was made to differentiate between target tissue and normal organs at risk. Conventional dosimetry included dose computations limited to the plane of beam intersection. This resulted in imprecise dose evaluations at the remainder of the target, resulting in geographic misses, tumor underdosage, and potentially high doses to normal organs at risk. Uncertainty regarding patient positioning and organ motion also contributed to the ineffectiveness of conventional radiation techniques.

Three-Dimensional Conformal Radiation Therapy Conformal radiation therapy (CRT) is a broad term applied to a variety of radiation therapy techniques designed to “conform” the radiation fields to the individual patient’s speciﬁc target volume. It also facilitates conformal avoidance of normal organs at risk. This is accomplished by obtaining cross-sectional imaging (most commonly CT scans) and using sophisticated software to compute dose distributions across the whole target volume and organs at risk. Typically, after obtaining cross-sectional images in the treatment position, the target organs (prostate, seminal vesicals, and lymph node regions, if appropriate) and normal organs at risk (rectum, bladder, and penile bulb) are outlined. The prostate (and the seminal vesicals) constitute the gross tumor volume (GTV). A margin is added to this to account for microscopic spread of disease, thus making up the clinical target volume (CTV). (Note: normally GTV applies to visualized tumor volume only. In the case of prostate cancer, the GTV and CTV are usually the same, as the whole gland is considered a target because of the multifocality of prostate cancer.) Additional margins are added to account for daily setup errors and prostate motion, constituting the planning target volume (PTV). Beams are shaped to conform to the target volumes and to avoid, as much as possible, the normal organs at risk. Either multileaf collimator or Cerrobend blocks are used to

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shape the beams. Multiple beams are designed to distribute doses to normal tissues while the target volume remains the focus in all beams. Figure 13 compares the radiation dose distribution between conventional and conformal treatment plans.

Intensity-Modulated Radiation Therapy Intensity-modulated radiation therapy (IMRT) is an advanced form of conformal radiation therapy that can further conform doses to the target and avoid doses to normal organs at risk. A computer generates the treatment plan after the assignment of doses to the target (maximize) and organs at risk (minimize) by the radiation oncologist. The treatments are delivered by modifying the intensity of the beam, within each beam, to limit doses to normal organs. This may be achieved by using moving leafs of a multileaf collimator while delivering radiation through a beam (either dynamic or static) or by changing the beam opening during an arc therapy. Figure 14 compares the radiation intensity patterns between CRT/IMRT.

Particle Beam Therapy Thus far in this chapter, radiation utilizing X-ray photons has been discussed. The limitations of X-ray photons include the depth-dose proﬁle, which delivers large doses to points beyond the target. The depth-dose proﬁles of some charged particles, like protons, show a dramatic fall-off of dose beyond a certain depth at which energy deposition is maximum. (This depth of maximum energy deposition depends on energy of the proton beam.) This physical property of protons has been used to escalate doses differentially to the prostate gland and spare the normal organs at risk (30). Neutron beam therapy has been studied (31–33) in prostate cancer. The purported advantages of neutrons over photons include the low oxygen enhancement ratios, decreased potentially lethal and sublethal damage repair, and the direct effect of neutron radiation on DNA— potential radiobiologic advantages.

OUTCOMES: WHAT TO EXPECT Disease Control Traditionally, local control, distant control, and cancer-related deaths as endpoints have been used to deﬁne disease control. Now, with PSA testing resulting in earlier diagnosis and treatments, PSA control is commonly being used as an endpoint to report outcomes (bNED—biochemical no evidence of disease). In clinical trials, it is used as a marker for when to initiate salvage treatments for PSA failures (bF—biochemical failures). Since there is no uniformly accepted deﬁnition to assess disease control using PSA that can be applied in the clinical setting of prostatectomy, external beam radiation therapy, brachytherapy, and androgen derivation, it should only be used as an early endpoint for studies and clinical trials. The ultimate outcome endpoint should remain overall survival. In 1997, the American Society for Therapeutic Radiology and Oncology (ASTRO) developed guidelines for PSA outcome reporting, to eliminate variability in reporting of PSA-based outcomes. A summary of the guidelines is as follows (34): • A PSA recurrence after radiation therapy is deﬁned as three consecutive increases in PSA or a single rise so great as to trigger the initiation of hormone therapy. The date of PSA failure should be the midpoint between the postirradiation nadir PSA and the ﬁrst of the three consecutive rises.

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Fig. 1. Biochemical relapse-free survival (bRFS) by clinical T stage—conventional technique.

• It was recommended that published series be presented with a minimum observation period of 24 mo. It was also recommended that PSA determinations be obtained at 3- or 4-mo intervals during the ﬁrst 2 yr after the completion of RT, and every 6 mo thereafter. • No level of PSA failure has, as yet, been shown to be a surrogate for clinical progression or survival. • Although the PSA nadir is a strong prognostic factor, no absolute level is a valid cutoff point for separating successful and unsuccessful treatments. Nadir PSA is similar in prognostic value to pretreatment prognostic variables.

OUTCOME WITH CONVENTIONAL EXTERNAL BEAM RADIATION Most conventional radiation outcome data report clinical outcomes (without PSA data). However, in this chapter, PSA outcomes following conventional radiation therapy will be highlighted in order to compare them with the more recent outcomes from CRT and IMRT. At the Cleveland Clinic, 536 patients were treated by conventional radiation therapy (CON) from 1986 to 2000. The 5- and 10-yr bNED rates for all patients were 42 and 35%, respectively (Figs. 1, 2, and 5). The 5-yr bNED rates for T1/T2A, T2B/C, and T3 were 51, 33, and 21%, respectively (p < 0.0001). The 5- and 10-yr bNED rates for patients with bGS ≤6 were 47 and 39%, and for patients with bGS ≥ 7 they were 33 and 31%, respectively (p = 0.0004). Zagars et al. (35) have reported the 6-yr biochemical outcome for 938 patients with stages T1–T4 disease; >90% of them were treated with conventional external beam radiation therapy. The 6-yr relapse/rising PSA-free survival rates for patients with pretreatment PSA levels of 0–4 ng/mL, >4–10 ng/mL, >10–20 ng/mL, and >20 ng/mL were 84, 64, 49, and 11%, respectively. The 6-yr relapse/rising PSA-free survival for stages T1/T2 was 66%, and that for T3/T4 was 37%. Zietman et al. (36) have reported long-term outcome of 1044 men with T1–T4 prostate cancer treated by conventional radiation therapy. Failure was deﬁned as two

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Fig. 2. Biochemical relapse-free survival by biopsy Gleason score (bGS)—Conventional technique.

sequential rises in serum PSA level or PSA > 1 ng/mL, 2 or more years after radiation; or any clinical failure. At 10 yr only 40% of the T1/T2 group and 33% of the T3/T4 group remained disease-free. The failure of conventional RT to eradicate localized prostate cancer results, in part, from intrinsic resistance of subpopulations of tumor cells to the traditional radiation dose levels of 65–70 Gy. DOSE ESCALATION At the Cleveland Clinic, from 1986 to 2001, 1267 patients have been treated with external beam radiation therapy with at least 2-yr follow-up. At 7 yr, the bRFS biochemical relapse-free survival (bRFS) rate for all patients was 59% (Fig. 3). For those who received a dose of ≥ 72Gy vs < 72 Gy, the bRFS rates were 79% vs 41% (p < 0.0001; Fig. 4). For patients with favorable-risk localized prostate cancer (stage T1–2, bGS ≤ 6, PSA ≤ 10 ng/mL) receiving ≥ 72 Gy, the 5-yr bRFS rate was 95% vs 77% for those receiving < 72 Gy (p = 0.01) (37). (The updated 5-yr bRFS for this group of patients is 93% vs 71% for those receiving ≥ 72 Gy vs < 72 Gy, respectively; p < 0.0001). Several other retrospective and a few prospective studies have demonstrated a doseresponse relationship in the treatment of prostate cancer (Tables 1–3). Pollack et al. (2) has recently reported results of a randomized study comparing the efﬁcacy of 70 Gy vs 78 Gy in patients with stage T1–3 disease. The freedom from clinical and/or biochemical failure (FFF) for the 70- and 78-Gy arms at 6 yr were 64 and 70%, respectively (p = 0.03). Dose escalation preferentially beneﬁted those patients with a pretreatment PSA > 10 ng/mL; the FFF rate was 62% for the 78-Gy arm vs 43% for the 70-Gy arm (p = 0.01). Valicenti et al. (5) have reported a survival advantage from higher dose radiation therapy for clinically localized prostate cancer patients treated on the RTOG trials. In patients who had bGS of 8–10, a signiﬁcantly better overall survival, disease-speciﬁc

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Fig. 3. Biochemical relapse-free survival (bRFS) for external beam patients: 1986–2001.

Fig. 4. Biochemical relapse-free survival (bRFS) by <72 Gy vs ≥72 Gy.

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Study Fiveash et al. (1) Pollack et al. (2)

No. of patients 102 301

Kupelian et al. (3)

1041

Zelefsky et al. (4)

743

Subset

Dose (Gy)

bNED

p value

>70 <70 78 70 ≥72 <72 >75.6 <70.2 >75.6 <70.2

88%a

0.02

T1–2, GS 8–10 T1–3, PSA > 10 ng/mL All subsets Intermediate risk High risk

65%a 62%b 43%b 87c 51c 79%d 55%d 58%d 32%d

0.01 <0.001 0.04 0.03

Abbreviations: bNED, biochemical no evidence of disease; GS, Gleason score; PSA, prostate-speciﬁc antigen. a Five-year survival. b Freedom from failure, biochemical and local; 6-yr survival. c Eight-year survival. d Four-year survival; estimates from graph.

Table 2 Effect of Radiation Dose on Survival Study

No. of patients

Subset

Dose (Gy) 75–80 70–75 <70 ≥ 66 <66 ≥ 74 < 74

Fiveash et al. (1)

180

bGS 8–10

Valicenti et al. (5)

1465

bGS 8–10

Hanks et al. (6)

714

T2C–T3

Overall survival (%) 80.5a 70.8a 59.3a 27b 16b 88 73

p value 0.04

0.012 0.039

Abbreviations: bGS, biopsy Gleason score. a Five-year survival. b Ten-year survival.

Table 3 Effect of Radiation Dose on Local Control Study Hanks et al. (38)

No. of patients 1516

Subset Stage B Stage C

Shipley et al. (7)

202

Abbreviation: GS, Gleason score. a Cobalt Gray equivalent.

T3–4, GS 8–10

Dose (Gy) ≥60 <60 ≥ 70 < 70 75.6a 67.2

Local control (%) 86 76 83 75 84 19

p value 0.004 0.01 0.0014

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survival, and local control were seen in those receiving ≥ 66 Gy. Hanks et al. (6) reported an overall survival advantage in patients with T2c–T3 disease getting ≥ 74Gy. In a multi-institutional review by Fiveash et al. (1), an overall survival advantage in patients with bGS ≥ 8 getting ≥ 75Gy was reported (Table 2). Studies demonstrating a direct relationship between local control and dose in carcinoma of the prostate are listed in Table 3. Hanks et al. (38) combined three prostate cancer patterns of care outcome surveys totaling 1516 patients and analyzed them for the effect of dose on inﬁeld recurrence. Signiﬁcant dose effects were observed in the overall data (p = 0.003), in stage B cancers (725 patients, p = 0.004), and in stage C cancers (624 patients, p = 0.059). No dose effect was observed for stage A cancers (168 patients, p = 0.217). Shipley et al. (7) reported the results of a randomized trial comparing proton vs conventional boosting for locally advanced prostate cancer. The local control at 8 yr in the proton boost arm receiving 75.6 cobalt Gray equivalent (CGE) in patients with poorly differentiated tumors was 84% vs 19% (p = 0.0014) in the conventional arm receiving 67.2 Gy. These studies provide evidence that the dose levels necessary for controlling prostate cancer exceed 70 Gy. The ability to deliver higher doses with conventional megavoltage techniques has been limited because of high rates of rectal and bladder complications. This results from the inability of conventional radiation techniques to exclude a sufﬁcient volume of normal tissue from the high-dose regions. A report from the patterns of care study demonstrated that the rate of severe (grade 3–4) complications nearly doubled (from 3.5 to 6.9%) when doses of >70 Gy were administered with conventional techniques (39). Pollack et al. (2) reported higher rectal toxicities in the dose escalation randomized study. Grade 2 or higher rectal toxicities at 6 yr were 12 and 26% for the 70- and 78-Gy arms, respectively. In this trial, all patients were initially treated with a conventional four-ﬁeld box to 46 Gy. For the patients in the 78-Gy arm, grade 2 or higher toxicity correlated highly with the proportion of the rectum treated to >70 Gy. OUTCOMES WITH CRT FOR PROSTATE CANCER In a nonrandomized comparison of CRT with conventional RT, Perez et al. (40) reported improved outcomes with CRT in patients treated with 68–70 Gy (p ≤ 0.0001). Higher 5-yr bRFS was observed with CRT (91% for T1c and 96% for T2 tumors) compared with conventional RT (53 and 58%, respectively). In patients with a pretreatment of PSA of ≤10 ng/mL who were treated with CRT, bRFS was 96% vs 65% in the patients treated with conventional RT (p ≤ 0.01). In patients with a PSA of 10–20 ng/mL, the bRFS with CRT was 88% compared with 40% for patients treated with conventional RT (p = 0.05%). The corresponding values were 71 and 26%, respectively, for patients with PSA levels > 20 ng/mL. On multivariate analysis, CRT was an important prognostic factor (p = 0.033). Zelefsky et al. (4) reported the results of dose escalation with three-dimensional CRT. The 5-yr actuarial PSA relapse-free survival for patients with favorable prognostic indicators (stage T1–2, pretreatment PSA ≤ 10 ng/mL, and GS ≤ 6) was 85%, compared with 65% for those with intermediate prognosis (one of the prognostic indicators with a higher value) and 35% for the group with unfavorable prognosis (two or more indicators with higher values; p < 0.01). PSA relapse-free survival was significantly improved in patients with intermediate and unfavorable prognosis receiving ≥ 75.6 Gy (p < 0.05).

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Fig. 5. Biochemical relapse free survival (bRFS) by treatment technique. IMRT, intensity-modulated radiation therapy; CRT, 3-D conformal radiation therapy; CON, conventional radiation therapy.

Fig. 6. Biochemical relapse free survival (bRFS) by initial prostate-speciﬁc antigen (PSA)—conformal technique. iPSA, initial (pretreatment) PSA.

The biochemical outcomes for 1267 Cleveland Clinic patients by treatment technique are given in Fig. 5. Since 1997, nearly all patients have been treated by CRT. More than 90% of these patients were treated to doses of ≥72 Gy. The biochemical outcomes for these 731 patients with a minimum 2-yr follow-up are given in Figs. 6–8. On

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Fig. 7. Biochemical relapse-free survival (bRFS) by biopsy Gleason score (bGS)—conformal technique.

Fig. 8. Biochemical relapse-free survival (bRFS) by clinical T stage—conformal technique.

multivariate analysis, the signiﬁcant predictors for outcome were clinical T stage, pretreatment PSA, bGS, and radiation dose. OUTCOMES WITH IMRT IMRT is a new paradigm in the delivery of radiation treatments, and clinical experience is limited. However, several single-institutional reports have confirmed the

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Fig. 9. Biochemical relapse-free survival (bRFS) by IMRT/CRT. IMRT, intensity-modulated radiation therapy; CRT, 3-D conformal radiation therapy.

feasibility of delivering high doses to the target at the same time reducing the volume of normal tissues radiated to higher doses. Zelefsky et al. (41) recently reported their experience in 772 patients with clinically localized prostate cancer. A total of 698 patients (90%) were treated to 81 Gy, and 74 patients (10%) were treated to 86.4 Gy. The 3-yr actuarial relapse-free survival rates for favorable, intermediate, and unfavorable risk groups were 92, 86, and 81%, respectively. At the Cleveland Clinic, 278 patients have been treated with IMRT at 2.5 Gy per fraction to 70 Gy with a minimum follow-up of 2 yr. The 3-yr bNED rate is 91% for all patients. The 3-yr bNED outcomes for three-dimensional CRT and IMRT were 81% vs 91% (p = 0.0012) (Fig. 9). The overall survival outcomes for all 1267 patients treated at the Cleveland Clinic from 1986 to 2001 are given in Figs. 10–12. OUTCOMES WITH PARTICLE BEAM THERAPY In a phase III randomized trial (33) comparing external beam photon irradiation (70 Gy) with external beam neutron irradiation (20.40 nGy) for patients with high-grade T2 or T3–4, N0–1, M0 adenocarcinomas of the prostate, the 5-yr actuarial clinical local-regional failure rate for patients treated with neutrons was 11% vs 32% for photons (p < 0.01). The “histologic” local-regional tumor failure rates were 13% for neutrons vs 32% for photons (p = 0.01); patients had planned post-treatment prostate biopsies at 2 yr post therapy. The bNED rates were 83% of neutron-treated patients and 55% of photon-treated patients at 5 yr (p < 0.001). No overall or disease-speciﬁc survival differences were noted. Severe late complications of treatment were higher for the neutron-treated patients (11% vs 3%). In another study (32), patients were randomized to receive either conventional photon radiation or neutron/photon mixed beam. Ten-year results for clinically assessed

Fig. 10. Overall survival for external beam patients: 1986–2001 (n = 1267).

Fig. 11. Overall survival (OS) by clinical T stage.

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Fig. 12. Overall survival (OS) by biopsy gleason score (bGS).

local control were 70% for the mixed-beam group vs 58% for the photon group (p = 0.03). Ten-year actuarial survival was 46% for the mixed-beam group vs 29% for the photon group (p = 0.04). Five (14%) photon and seven (13%) mixed-beam patients had severe toxicities. Because of the poorly penetrating properties of the neutron beams, skin and subcutaneous reactions were more severe in the mixed beam group. Conventional dose RT (67.2 Gy) vs 75.6 CGE using a conformal perineal proton boost was evaluated in a randomized trial (7) for patients with stage T3–4 prostate cancer. No signiﬁcant differences in overall survival, disease-free survival, or local control between the two arms were found. The local control for patients with bGS 8–10 at 8 yr for the 75.6-CGE arm was 84%, and it was 19% for the 67.2-Gy arm (p = 0.0014). Grade 1 and 2 rectal bleeding (32 vs 12%, p = 0.002) and urethral stricture (19 vs 8%, p = 0.07) were higher in the 75.6-CGE arm.

Outcomes: Quality of Life The philosophy behind CRT is the delivery of increased doses to achieve better disease control outcomes and at the same time reduce toxicity and thereby improve the therapeutic ratio. Tables 4 and 5 list the RTOG acute and late morbidity scoring criteria. ACUTE TOXICITY A randomized trial (42) comparing conventional RT with CRT without dose escalation has reported reduced toxicities with CRT, implying an improved therapeutic ratio. Pollack et al. (43) reported equivalent acute bowel and bladder toxicity in a randomized dose escalation study comparing conventional RT with CRT. Zelefsky et al. (44) reported equivalent acute grade 2 or higher urinary toxicity in patients treated to 81 Gy with IMRT and three-dimensional CRT (37% vs 44% respectively). The proportion of

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Fig. 13. Comparison of conventional and conformal treatment plans on one patient being considered for external beam radiation therapy. The prostate gland was prescribed a dose 7400 cGy. The top images show isodose distributions at the central axis of the beams. The middle row shows the dosevolume histograms for the target (prostate) and normal tissues (bladder and rectum). The bottom row compares the volumes of bladder and rectum receiving signiﬁcant doses with the methods of radiation delivery.

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Fig. 14. Comparison of 3D conformal radiation therapy and intensity-modulated radiation therapy (IMRT).

Table 4 Acute Toxicity Criteria of the Radiation Therapy Oncology Groupa Grade 1

Grade 2

GI

Grade 3

Grade 4

Increased frequency Diarrhea requiring Diarrhea requiring or change in quality parasympatholytic parenteral support/ of bowel habits drugs (e.g., Lomotil)/ severe mucous or not requiring mucous discharge blood discharge medication/ rectal not necessitating necessitating sanitary discomfort not sanitary pads/rectal pads/abdominal requiring analgesics or abdominal pain distention (ﬂat requiring analgesics plate radiograph demonstrates distended bowel loops) GU Frequency of Frequency of urination Frequency with urgency Hematuria urination or or nocturia that is and nocturia hourly requiring nocturia twice less frequent than or more frequently/ transfusion/ pretreatment habit/ every hour; dysuria, dysuria, pelvic pain, acute bladder dysuria, urgency urgency, bladder or bladder spasm obstruction not requiring spasm requiring requiring regular, not secondary medication local anesthetic frequent narcotic/gross to clot passage, (e.g., Pyridum) hematuria with/without ulceration, clot passage or necrosis a

Grade 5, death directly related to radiation effects.

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Table 5 Late Toxicity Criteria of the Radiation Therapy Oncology Groupa Grade 1

Grade 2

Grade 3

Grade 4

GI

Mild diarrhea; mild Moderate diarrhea Obstruction or Necrosis/ cramping; bowel and colic; bowel bleeding, requiring perforation movement ≤ 5 movement > 5 times surgery ﬁstula times daily; slight daily; excessive rectal discharge rectal mucus or or bleeding intermittent bleeding GU Slight epithelial Moderate frequency; Severe frequency and Necrosis/contracted atrophy; minor generalized dysuria; severe bladder (capacity telangiectasia telangiectasia; generalized <100 cc); severe (microscopic intermittent telangiectasia (often hemorrhagic hematuria) macroscopic with petechiae); cystitis hematuria frequent hematuria; reduction in bladder capacity (<150 cc) a

Grade 5, death directly related to radiation effects.

patients experiencing grade 0 acute rectal toxicity was higher in the IMRT group (54% vs 39%; p = 0.05). CHRONIC TOXICITY Pollack et al. (2) reported increased grade 2 or higher toxicities rates at 6 yr for the 78-Gy arm vs the 70-Gy arm (26% vs 12%, respectively; p = 0.001). Grade 2 or higher bladder complications were the same, at 10%. Dearnaley et al. (45) reported toxicity results of a randomized study comparing conformal and conventional radiotherapy delivering 64 Gy. Signiﬁcantly fewer men developed ≥grade 2 rectal toxicity in the conformal group (5% vs 15%, p = 0.01). There were no differences between the groups with respect to bladder toxicity. Zelefsky et al. (44) reported equivalent chronic urinary toxicity in patients treated to 81 Gy with IMRT and three-dimensional CRT (9% vs 7% respectively). Grade 2 late rectal toxicity was seen in 0.5% of IMRT patients vs 13% of patients receiving threedimensional CRT (p = 0.0001). Results from the Cleveland Clinic show excellent short-term tolerance of IMRT (46). The actuarial rectal bleeding rates at 24 mo for three-dimensional CRT and IMRT were 13 and 9%, respectively (p = 0.87). Volume of rectum receiving ≥70 Gy (with a cutoff at 15 cc) was a signiﬁcant predictor of rectal bleeding in patients receiving IMRT. The actuarial rectal bleeding rate at 18 mo for rectal volumes receiving ≥70 Gy at ≤15 cc was 2%, and at >15 cc it was 54% (p < 0.001). Pollack et al. (2) reported a 46% incidence of grade ≥2 rectal toxicity when >25% of rectal volume received ≥70 Gy vs 16% when <25% of the rectal volume received ≥70 Gy (p = 0.001). Dose-volume histograms (DVHs) are commonly utilized to evaluate treatment plans, since a volume effect exists in the probability of developing late side effects, as shown above (2,46,47). The difﬁculty with assessing DVHs results from the variability in the extent of outlining of the rectal volumes for assessment. Absolute rectal volume

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receiving full prescription dose may be an alternative assessment tool. Results from the Cleveland Clinic (48) have shown that on multivariate analysis, absolute volume of the rectum receiving full doses was the only signiﬁcant factor (p = 0.011) to predict for late rectal bleeding. Potency preservation is another important quality of life outcome in this population. Among patients who were potent before RT, 100, 83 and 63% preserved their potency at 1, 2, and 3 yr after three-dimensional CRT in a study reported by Wilder et al. (49). Sildenaﬁl improved potency in 43% of those who had become impotent. In a report from the University of Chicago, 96, 75, 59, and 53% preserved potency at 1, 20, 40, and 60 mo after RT (50). Factors identiﬁed as signiﬁcant predictors of post-RT impotence included pre-RT partial impotence, diabetes, coronary artery disease, and antiandrogen therapy. A trend toward better potency preservation was noted for CRT vs conventional RT.

FUTURE DIRECTIONS Tomotherapy, literally “slice therapy,” is a proposal for the delivery of radiation therapy with intensity-modulated strips of radiation. This employs a linear accelerator mounted on a ring gantry like a CT scanner. The patient would move through the bore of the gantry simultaneously with gantry rotation. The intensity modulation would be performed by temporally modulated multiple independent leaves that open and close across the slit opening. This method is expected to result in the delivery of highly conformal radiation. The ring gantry would make it convenient to mount a narrow multisegmented megavoltage detector system for beam veriﬁcation. Such a treatment unit could become a powerful tool for treatment planning, conformal treatment, and veriﬁcation using tomographic images. Clinical application of this system in delivering RT for prostate cancer is evolving. RT for prostate cancer has been until now delivered to the whole gland. Functional and biologic imaging innovations will drive localization of high-dose regions to the sites of intraprostatic dominant lesions. Further follow-up and clinical experience are needed to assess deﬁnitively the role of particle beam therapy. Increased availability of these modalities in the future should make it possible to evaluate their role in the management of prostate cancer.

SUMMARY External beam radiation therapy is an excellent option in the management of prostate cancer along with prostatectomy and brachytherapy. Advances in the technology have made external beam radiation therapy less toxic and more effective. Since prostatectomy, brachytherapy, and external beam RT provide equivalent outcomes in early-stage prostate cancer, treatment decisions will be based ultimately on quality of life considerations. As early detection of prostate cancer increases worldwide because of PSA screening, the goal of enhancing the quality of life of the treated patient will be paramount, since aggressive treatments are offered to asymptomatic patients who are likely to live long enough to experience any late toxicity.

REFERENCES 1. Fiveash JB, Hanks G, Roach M, et al. 3D conformal radiation therapy (3DCRT) for high-grade prostate cancer: a multi-institutional review. Int J Radiat Oncol Biol Phys 2000;47:335–342. 2. Pollack A, Zagars GK, Starkschall G, et al. Prostate cancer radiation dose response: results of the M.D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002;53:1097–1105.

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3. Kupelian PA, Mohan DS, Lyons J, et al. Higher than standard radiation doses (≥72 Gy) with or without androgen deprivation in the treatment of localized prostate cancer. Int J Radiat Oncol Biol Phys 2000;46:567–574. 4. Zelefsky MJ, Leibel SA, Gaudin PB, et al. Dose escalation with three dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys 1998;41:491–500. 5. Valicenti R, Lu J, Pilepich M, et al. Survival advantage from higher-dose radiation therapy for clinically localized prostate cancer treated on the Radiation Therapy Oncology Group trials. J Clin Oncol 2000;18:2740–2746. 6. Hanks GE, Hanlon AL, Pinover WH, et al. Survival advantage for prostate cancer patients treated with high-dose three-dimensional conformal radiotherapy. Cancer J Sci Am 1999;5:152–158. 7. Shipley WU, Verhey LJ, Munzenrider JE, et al. Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional does irradiation using photons alone. Int J Radiat Oncol Biol Phys 1995;32:3–12. 8. Mizowaki T, Cohen GN, Fung AY, et al. Towards integrating functional imaging in the treatment of prostate cancer with radiation: the registration of the MR spectroscopy imaging to ultrasound/CT images and its implementation in treatment planning. Int J Radiat Oncol Biol Phys 2002;54:1558–1564. 9. Sannazzari GL, Ragona R, Ruo Redda MG, et al. CT-MRI image fusion for delineation of volumes in three-dimensional conformal radiation therapy in the treatment of localized prostate cancer. Br J Radiol 2002;75:603–607. 10. Krempien RC, Schubert K, Zierhut D, et al. Open low-ﬁeld magnetic resonance imaging in radiation therapy treatment planning. Int J Radiat Oncol Biol Phys 2002;53:1350–1360. 11. Kitamura K, Shirato H, Seppenwoolde Y, et al. Three-dimensional intrafractional movement of prostate measured during real-time tumor-tracking radiotherapy in supine and prone treatment positions. Int J Radiat Oncol Biol Phys 2002;53:1117–1123. 12. Lattanzi J, McNeeley S, Donnelly S, et al. Ultrasound-based stereotactic guidance in prostate cancer— quantiﬁcation of organ motion and set-up errors in external beam radiation therapy. Comput Aided Surg 2000;5:289–295. 13. Langen KM, Jones DT. Organ motion and its management. Int J Radiat Oncol Biol Phys 2001;50:265–278. 14. Beard CJ, Kijewski P, Bussiere M, et al. Analysis of prostate and seminal vesicle motion: implications for treatment planning. Int J Radiat Oncol Biol Phys 1996;34:451–458. 15. Crook JM, Raymond Y, Salhani D, et al. Prostate motion during standard radiotherapy as assessed by ﬁducial markers. Radiother Oncol 1995;37:35–42. 16. Melian E, Mageras GS, Fuks Z, et al. Variation in prostate position quantitation and implications for three-dimensional conformal treatment planning. Int J Radiat Oncol Biol Phys 1997;38:73–81. 17. Roeske JC, Forman JD, Mesina CF, et al. Evaluation of changes in the size and location of the prostate, seminal vesicles, bladder, and rectum during a course of external beam radiation therapy. Int J Radiat Oncol Biol Phys 1995;33:1321–1329. 18. Rudat V, Schraube P, Oetzel D, et al. Combined error of patient positioning variability and prostate motion uncertainty in 3D conformal radiotherapy of localized prostate cancer. Int J Radiat Oncol Biol Phys 1996;35:1027–1034. 19. Vigneault E, Pouliot J, Laverdiere J, Roy J, Dorion M. Electronic portal imaging device detection of radioopaque markers for the evaluation of prostate position during megavoltage irradiation: a clinical study. Int J Radiat Oncol Biol Phys 1997;37:205–212. 20. Lattanzi J, McNeeley S, Hanlon A, et al. Ultrasound-based stereotactic guidance of precision conformal external beam radiation therapy in clinically localized prostate cancer. Urology 2000;55:73–78. 21. Kuriyama K, Onishi H, Sano N, et al. A new irradiation unit constructed of self-moving gantry-CT and linac. Int J Radiat Oncol Biol Phys 2003;55:428–435. 22. Hua C, Lovelock DM, Mageras GS, et al. Development of a semi-automatic alignment tool for accelerated localization of the prostate. Int J Radiat Oncol Biol Phys 2003;55:811–824. 23. Ruchala KJ, Olivera GH, Kapatoes JM. Limited-data image registration for radiotherapy positioning and veriﬁcation. Int J Radiat Oncol Biol Phys 2002;54:592–605. 24. Mackie TR, Balog J, Ruchala K, et al. Tomotherapy. Semin Radiat Oncol 1999;9:108–117. 25. Kupelian PA, Katcher J, Levin HS, Klein EA. Stage T1–2 prostate cancer: a multivariate analysis of factors affecting biochemical and clinical failures after radical prostatectomy. Int J Radiat Oncol Biol Phys 1997;37:1043–1052. 26. Sohayda C, Kupelian PA, Levin HS, Klein EA. Extent of extracapsular extension in localized prostate cancer. Urology 2000;55:382–386.

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27. Katcher J, Kupelian PA, Zippe C, Klein EA, Sohn JW. Indications for excluding the seminal vesicles when treating clinically localized prostatic adenocarcinoma with radiotherapy alone. Int J Radiat Oncol Biol Phys 1997;37:871–876. 28. Asbell SO, Krall JM, Pilepich MV, et al. Elective pelvic irradiation in stage A2, B carcinoma of the prostate: analysis of RTOG 77-06. Int J Radiat Oncol Biol Phys 1988;15:1307–1316. 29. Roach M, DeSilvio M, Lawton C, et al. Neoadjuvant hormonal therapy (NHT) with whole-pelvic (WP) radiotherapy (RT) improves progression-free survival (PFS): RTOG (Radiation Therapy Oncology Group) 9413, a phase III randomized trial. J Urol 2002;10:1904–1911, Abs. #500164. 30. Rossi CJ Jr, Slater JD, Reyes-Molyneux N, et al. Particle beam radiation therapy in prostate cancer: is there an advantage? Semin Radiat Oncol 1998;8:115–123. 31. Forman JD, Duclos M, Sharma R, et al. Conformal mixed neutron and photon irradiation in localized and locally advanced prostate cancer: preliminary estimates of the therapeutic ratio. Int J Radiat Oncol Biol Phys 1996;35:259–266. 32. Laramore GE, Krall JM, Thomas FJ, et al. Fast neutron radiotherapy for locally advanced prostate cancer. Final report of Radiation Therapy Oncology Group randomized clinical trial. Am J Clin Oncol 1993;16:164–167. 33. Russell KJ, Caplan RJ, Laramore GE. Photon versus fast neutron external beam radiotherapy in the treatment of locally advanced prostate cancer: results of a randomized prospective trial. Int J Radiat Oncol Biol Phys 1994;28:47–54. 34. American Society for Therapeutic Radiology and Oncology Consensus Panel. Consensus statement: guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 1997;37:1035–1041. 35. Zagars GK, Pollack A, von Eschenbach AC. Prognostic factors for clinically localized prostate cancer. Analysis of 938 patients irradiated in the prostate speciﬁc antigen era. Cancer 1997;79:1370–1380. 36. Zietman AL, Coen JJ, Dallow KC, et al. The treatment of prostate cancer by conventional radiation therapy: an analysis of long-term outcome. Int J Radiat Oncol Biol Phys 1995;32:287–292. 37. Kupelian PA, Buchsbaum JC, Reddy CA. Radiation dose response in patients with favorable localized prostate cancer (stage T1–T2, biopsy Gleason ≤ 6, and pretreatment prostate-speciﬁc antigen ≤10). Int J Radiat Oncol Biol Phys 2001;50:621–625. 38. Hanks GE, Martz KL, Diamond JJ. The effect of dose on local control of prostate cancer. Int J Radiat Oncol Biol Phys 1988;15:1299–1305. 39. Leibel SA, Hanks GE, Kramer S. Patterns of care outcome studies: results of the national practice in adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 1984;10:401–409. 40. Perez CA, Michalski JM, Purdy JA, et al. Three-dimensional conformal therapy or standard irradiation in localized carcinoma of prostate: preliminary results of nonrandomized comparison. Int J Radiat Oncol Biol Phys 2000;47:629–637. 41. Zelefsky MJ, Fuks Z, Hunt M, et al. High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients. Int J Radiat Oncol Biol Phys 2002;53:1111–1116. 42. Koper PC, Stroom JC, van Putten WL, et al. Acute morbidity reduction using 3DCRT for prostate carcinoma: a randomized study. Int J Radiat Oncol Biol Phys 1999;43:727–734. 43. Pollack A, Zagars GK, Starkschall G, et al. Conventional vs conformal radiotherapy for prostate cancer: preliminary results of dosimetry and acute toxicity. Int J Radiat Oncol Biol Phys 1996;34:555–564. 44. Zelefsky MJ, Fuks Z, Hunt M, et al. Clinical experience with intensity modulated radiation therapy (IMRT) in prostate cancer. Radiother Oncol 2000;55:241–249. 45. Dearnaley DP, Khoo VS, Norman AR, et al. Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomized trial. Lancet 1999;353:267–272. 46. Kupelian PA, Reddy CA, Klein EA. Short-course intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: preliminary results on late toxicity and quality of life. Int J Radiat Oncol Biol Phys 2001;51:988–993. 47. Schultheiss TE, Hanks GE, Hunt MA, et al. Incidence of and factors related to late complications in conformal and conventional radiation treatment of cancer of the prostate. Int J Radiat Oncol Biol Phys 1995;32:643–649. 48. Kupelian PA, Reddy CA, Carlson TP, et al. Dose/volume relationship of late rectal bleeding after external beam radiotherapy for localized prostate cancer: Absolute or relative rectal volume? Cancer 2002;8:62–66. 49. Wilder RB, Chou RH, Ryu JK, et al. Potency preservation after three-dimensional conformal radiotherapy for prostate cancer: preliminary results. Am J Clin Oncol 2000;23:330–333. 50. Mantz CA, Song P, Farhangi E, et al. Potency probability following conformal megavoltage radiotherapy using conventional doses for localized prostate cancer. Int J Radiat Oncol Biol Phys 1997;37:551–557.

16

Brachytherapy Kenneth W. Angermeier and Jay P. Ciezki

INTRODUCTION The concept of using radioactive isotopes for placement internally, i.e., brachytherapy, “in the practice of medicine for internal examinations or for destroying germs, microbes, bacteria, and the like” has been documented as early as 1903 in the United States Patent and Trademark Ofﬁce (1). Various iterations in the techniques have emerged during the last century for treating prostate cancer with brachytherapy. The current transrectal ultrasound (TRUS)-guided techniques were ﬁrst described in the mid-1980s (2). Since then, the technique has gained enough currency to be paired off against radical retropubic prostatectomy in a National Cancer Institute-sponsored protocol. This chapter reviews the more recent trends in implantation technique and also discusses patient selection, side effects, and efﬁcacy.

PATIENT SELECTION The criteria for selecting the optimal patients for prostate brachytherapy have become more clear over time. Obviously the patient should be a candidate for deﬁnitive therapy for his prostate cancer based on age and medical status. Pathologic studies have shown that in patients with clinical stage T1–2 adenocarcinoma of the prostate, prostate-speciﬁc antigen (PSA) < 10 ng/mL and Gleason score ≤ 6, the radial extent of extracapsular extension when present is usually ≤ 4 mm (3). Prostate brachytherapy with a peripheral margin of 3–5 mm would encompass all known tumor in the vast majority of patients in this group (4), and they are therefore considered to be optimal candidates. This information is corroborated by clinical studies documenting excellent biochemical relapse-free survival for patients in this “low-risk” category treated with brachytherapy alone (5–10). Unfortunately, the use of brachytherapy in patients with intermediate (PSA > 10 ng/mL or Gleason score > 6) or high (PSA > 10 ng/mL and Gleason score > 6) risk disease is less clear. A combination of external beam radiotherapy and brachytherapy has been used frequently in these situations, which in theory increases the periprostatic margin while providing a high radiation dose to the bulk of disease within the

From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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prostate gland (11). However, there have been no randomized studies comparing this approach with monotherapy using external beam radiation or brachytherapy. Recent studies have shown the ability to achieve an extended prostatic margin using brachytherapy alone (12), and results comparable to the combined technique in patients with intermediate- and high-risk disease have been reported (13,14). Further studies will be needed to better elucidate the exact role of brachytherapy in these higher risk patient groups. In order to minimize postoperative side effects, several factors may be taken into consideration when evaluating a patient for brachytherapy. The issue of pubic arch interference has become virtually nonexistent with the advent of intraoperative planning, which allows image acquisition and seed implantation in an exaggerated lithotomy position under anesthesia. It was initially suggested that the preoperative American Urological Association symptom score or prostate volume could predict patients who were at risk for postoperative urinary morbidity or urinary retention (15). In our series, only prostate length was a signiﬁcant predictor on multivariate analysis of the need for intermittent self-catheterization after 125I brachytherapy (16). We have seen no need for a prostate volume “cutoff” beyond which a patient is not a candidate for brachytherapy, as long as adequate ultrasound imaging can be obtained. If a patient has undergone a previous transurethral resection of the prostate, brachytherapy can be done with minimal to no additional morbidity as long as the preoperative ultrasound demonstrates that there is adequate prostatic parenchyma surrounding the prostatic defect to support an implant (17). A relative contraindication to prostate brachytherapy is a history of previous pelvic radiotherapy.

PROCEDURE Setup and Image Acquisition Early in our experience, we adopted an approach allowing us to use a preplanned modiﬁed peripheral loading technique carried out during one intraoperative session (18). This procedure is usually done under general anesthesia owing to the patient positioning required. Boot-type stirrups are used to place the patient carefully into an exaggerated lithotomy position, taking care to ensure that there are no unusual pressure points along the lower extremities. The genitalia are taped superiorly to expose the perineum. The patient is given a cleansing enema prior to the procedure; however, we also place a Malecot catheter at this time and irrigate the rectum with normal saline to ensure that it is free of debris that may interfere with imaging. The perineum is shaved and prepped with Betadine solution. The ultrasound probe is inserted into the rectum and then placed within the stepping device, which is attached to the operating table (Fig. 1). The ultrasound frequency is adjusted to optimize the images as needed. The position of the ultrasound probe is then maneuvered to optimize the implant procedure. The vertical D line should be centered on the prostate gland as well as the urethra more distally, and the inferior border of the prostate should approximate the horizontal “1” line at the midgland. The probe often needs to be lowered somewhat to allow free mobility proximally and distally for adequate imaging of the base of the gland in the longitudinal plane. This maneuver will also often eliminate the lateral “dog ears” of the prostate that may be present on transverse imaging owing to upward pressure of the probe on the central gland. After establishing adequate imaging in both the transverse and longitudinal planes, transverse images of the prostate from the base to the apex at 0.5-cm intervals are

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Fig. 1. Example of a patient placed in exaggerated dorsal lithotomy position with the transrectal ultrasound probe and template in place.

captured onto the computer. The border of each image is circumscribed using the cursor, and treatment planning is then turned over to the radiation oncologist and physicist.

Planning A key aspect of treatment is creating a treatment plan that is executable. The use of computerized anatomic reconstructions to assist brachytherapy treatment planning permits the creation of excellent plans—in cyberspace. The essential element is translating the plan into reality. In other words, a plan must be chosen, from the myriad of plans available, that can be executed in the patient. The setup and positioning as described above are important ﬁrst steps. A major innovation in the planning of prostate brachytherapy is the performance of the planning session immediately preceding the implantation. Many practitioners perform the planning session separately from the implantation (2). Our practice has been to incorporate the planning session into the same anesthesia session as the implant. Intuitively this results in no movement of the patient between the time the plan is performed and the time the sources are inserted. Practically, there are several advantages. First, the patient may be placed in an exaggerated dorsal lithotomy position during the planning session. This is nearly impossible when the planning session is done separately in an ofﬁce-based setting since the patient may have difﬁculty maintaining this position for the duration of the planning session. Second, when the planning occurs in the exaggerated dorsal lithotomy position, the implantation can also occur in the same position, resulting in a nearly complete

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elimination of the interference of the pubic bone with the insertion of the sources. The exaggerated dorsal lithotomy causes the pubic bone to rotate anteriorly and permits a greater area of the perineum to serve for the insertion of the sources, which in turn allows greater freedom with planning since even laterally placed sources may be inserted. Without this freedom, the plan must often be modiﬁed to ﬁt the physical limitation of the patient’s position. Speciﬁcally, wide glands are difﬁcult to implant, and they must be excluded from eligibility for the procedure. Third, the dosimetric results are superior. The improved accuracy that one may theorize as resulting from no patient movement between planning and insertion is measurable (18). There are many recommendations for planning permanent prostate brachytherapy. They vary in both recommended dose and anatomic parameter constraints. For the purposes of this discussion, the American Brachytherapy Society’s guidelines will be followed (11). The basic tenets of their recommendations are that the prostate should receive a minimum dose of approx 144 Gy over the life of the implant if 125I is used and approx 115 Gy if 103Pd is used. The target (the prostate gland) is usually planned with an approx 0.5-cm radial margin (laterally and superiorly) at both the apex and base but no margin in the center of the gland or at any point in the posterior aspect of the gland. To minimize urethral toxicity, the central prostatic dose should not exceed 150% of the target dose. To achieve this, the larger glands will require the removal of sources from positions from within the gland. The larger the gland, the more removal (or unloading) will occur to meet the central prostatic dose criterion. In addition, it is recommended that the individual source activity be approx 0.40 U. Use of these dose and activity guidelines yields an average number of sources per implant of 100.

Loading The placement of the sources into the prostate is accomplished in two basic ways: preloaded needles and applicator “guns.” They both accomplish the goal of placing sources into the gland. The needles will place a row of sources at once, whereas the applicators will place sources individually within a needle track. Both techniques permit the use of individual loose sources. The use of preloaded needles is the only technique that enables the operator to place stranded sources. Stranded sources are simply sources linked to each other with absorbable suture material (Fig. 2). The advantage to their use is the reduced incidence of source migration after placement. The disadvantage is that they are not very useful for placement around the urethra and rectum because if they are misplaced in the lumen of the urethra, the cystoscopic removal of one source in the train will result in all sources in the strand being removed. Similarly, an aberrantly placed source in the rectum will more easily fall out on it own when not stranded as opposed to a stranded source, which may remain in place longer, resulting in potential ﬁstula formation. Loose sources are still recommended for placement around the urethra even if the peripheral sources are stranded (Fig. 3).

Implantation Since both the preloaded needle and applicator techniques rely on needle placement, the placement of the needles will be the focus of this section. In addition, although alternate imaging modalities are available (i.e. MRI, CT, etc.) the TRUS-guided technique will be used for demonstrative purposes. The placement of the needles should rely on visualization of the needle’s position on ultrasound, not depth measurements relative to the perineal skin surface. It is best to

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Fig. 2. Stranded source product seen in the manufacturer’s carrier prior to insertion into a needle.

Fig. 3. An overhead view of the needle holder just after the loading of the needles and prior to the implantation of the sources. The orientation is such that the rectum is at the inferior aspect of the array. The needles with the blue hubs are loaded with loose sources, and those with white hubs are loaded with stranded sources. With this sequencing, the urethra and rectum are spared the placement of stranded sources in their immediate surrounds.

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Fig. 4. A sagittal transrectal ultrasound image of the prostate during implantation. A needle is seen being placed at the posterior aspect of the gland adjacent to the rectum. Notice that the needle is angled downward to follow the contour of the rectal wall.

start the placement of the needles in the axial coordinate furthest from the ultrasound probe so as to minimize image distortion on subsequent needle placements. The x, y, and z coordinates should be considered when placing each needle. The x and y coordinates are imaged on the axial plane of the prostate. As a general rule, each needle should be placed in the planned position. An exception may be made if a stranded source is being used. It may be useful to err the placement of the needle medially to “snag” the prostate’s capsule. Doing this allows most of the strand to be placed external to the gland but keeps it tethered to the prostate, minimizing source migration. Another exception should be made in the needles placed adjacent to the rectum. The contour of the rectum is such that the apex of the gland is further anterior from the ultrasound probe than the base and middle of the gland. To follow this contour (Fig. 4), it is useful to insert the needle planned for this position 0.5 cm anterior to the planned coordinate (e.g., at 1.5 rather than 1.0). The z coordinate is imaged with each needle placement. Unless otherwise planned, each needle tip should be placed just up to the bladder wall. This includes median lobes. There should be sources placed in the median lobe of the prostate if it is present. Failure to place the needle at the proper depth (z coordinate) may result in sources placed in tissue inferior to the apex of the gland. This is particularly a problem when the needle is close to the probe. As mentioned earlier, the apex of the gland is more anterior than the rest of the gland. If sources are misplaced inferiorly in this position, they will dwell in the rectal wall. Proper placement of these sources results in no sources outside of the gland (Fig. 5).

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Fig. 5. The same sagittal transrectal ultrasound image of the prostate as in Fig. 4. Here the needle seen in Fig. 4 has been withdrawn, leaving the sources in the gland but not in the rectal wall (in particular, the rectal wall at the apex of the gland, where the needle tip may still be seen).

Cystoscopy Early in our experience, cystoscopy was performed at the end of every prostate brachytherapy procedure to conﬁrm that there were no sources within the prostatic urethra or urinary bladder. If present, the seeds were removed with irrigation or grasping forceps. With experience, we have found that the presence of such seeds is uncommon. Currently we rely on the ultrasound imaging to help us determine whether this is necessary. If there is no blood at the urethral meatus and there were no suspicious punctures during the procedure as determined by ultrasound, cystoscopy is not performed. If we do elect to perform cystoscopy, we use a ﬂexible cystoscope, as this has demonstrated a lower incidence of postoperative hematuria and irritative voiding symptoms in our hands compared with rigid cystoscopy.

Postoperative Care Brachytherapy is performed on an outpatient basis. All patients are instructed as to how to perform intermittent catheterization, although 90% will not have to do so (16). Prescriptions are given for a 1-wk course of ciproﬂoxacin and an α-blocker (if the patient is not already taking one). In addition, patients are cautioned to avoid having pregnant women and children (< 18 yr of age) in their lap for more than 20 min/h for the ﬁrst 2 mo.

SIDE EFFECTS The side effects of brachytherapy may be divided into the acute and the long term. The acute side effects are typically related to radiation-induced irritation of the

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Fig. 6. A graphic representation of the mean American Urological Association (AUA) score in the ﬁrst 8 wk following an implant for 122 patients on a clinical trial evaluating tansulosin as a prophylactic treatment for postimplant urinary morbidity. Regardless of treatment, the AUA score peaks around wk 3.

prostate, urethra, and bladder. Almost all patients experience these symptoms. Typical duration is 2–3 mo, with peak symptoms being experienced at the 2–3 wk mark after implantation (Fig. 6). The use of α-blockers often relieves these symptoms signiﬁcantly. A minority (approx 10%) will experience temporary urinary retention requiring catheterization (16). Long-term side effects are generally limited to impotence and unusual severe rectal reactions such as ﬁstula formation. The rate of impotence following prostate brachytherapy is usually reported as approx 25% (19). Often, the impotence is overcome with medical management. Late rectal problems, although uncommon (1–3% incidence), can be devastating. They are most common when brachytherapy is combined with external beam radiotherapy. Rectal ﬁstula repair may result in permanent colostomy because the ﬁstula frequently occurs at the apex of the gland and may communicate with the urethra below the dentate line. Such a location precludes the maintenance of anal continence.

EFFICACY As a general rule, the efﬁcacy of prostate brachytherapy is comparable to competing therapies for low- and intermediate-risk patients (20). Similar data have been generated from the Cleveland Clinic Foundation. The PSA outcome for brachytherapy and external beam radiotherapy patients is assessed according to the American Society of Therapeutic Radiology and Oncology consensus deﬁnition: three consecutive PSA rises above a nadir with each rise documented at least 2 mo apart (21). With this deﬁnition, low-risk patients have a biochemical relapse-free survival of approx 91%, and intermediate-risk patients have bRFS of approx 84% (Figs. 7 and 8). The use of implantation alone or in combination with external beam radiation is being investigated.

Fig. 7. Kaplan-Meier biochemical relapse-free (bRFS) survival curves of low-risk patients treated at the Cleveland Clinic Foundation with implantation (PI), external beam radiation (RT), and radical retropubic prostatectomy (RP). The efﬁcacy is identical.

Fig. 8. Kaplan-Meier biochemical relapse-free survival (bRFS) curves of intermediate-risk patients treated at the Cleveland Clinic Foundation with implantation (PI), external beam radiation (RT), and radical retropubic prostatectomy (RP). The efﬁcacy is identical.

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Fig. 9. Kaplan-Meier biochemical relapse-free (bRFS) survival curves of patients treated with implantation as the sole method of radiotherapy segregated into two groups: those who exhibited a PSA bounce and those who did not. The difference in survival was signiﬁcant (p = 0.037).

An idiosyncratic aspect of the PSA after prostate brachytherapy is its tendency, in approx 25% of patients, to rise without an associated oncologic event. This is often called the PSA bounce. Its cause is unknown, but it may be associated with improved outcome. Data from the Cleveland Clinic Foundation suggest that patients with a bounce do better than those without (Fig. 9). Should a PSA rise be noted, it should be followed until and if it exceeds the initial pretreatment PSA value. If the PSA exceeds the initial PSA value, a workup should be initiated with therapy as indicated.

REFERENCES 1. Kunz GF. Luminous Composition. United States Patent Ofﬁce. United States, 1905. 2. Blasko JC, Ragde H, Schumacher D. Transperineal percutaneous iodine-125 implantation for prostatic carcinoma using transrectal ultrasound and template guidance. Endocuriether Hypertherm Oncol 1987;3:131. 3. Sohayda C, Kupelian PA, Levin HS, Klein EA. Extent of extracapsular extension in localized prostate cancer. Urology 2000;55:382–386. 4. Davis BJ, Pisansky TM, Wilson TM, et al. The radial distance of extraprostatic extension of prostate carcinoma. Cancer 1999;85:2630–2637. 5. D’Amico AV, Whittington R, Malkowicz B, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969–974. 6. Merrick GS, Butler WM, Galbreath RW, Lief JH. Five-year biochemical outcome following permanent interstitial brachytherapy for clinical T1–T3 prostate cancer. Int J Radiat Oncol Biol Phys 2001;51:41–48.

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7. Kwok Y, DiBiase SJ, Amin PP, Naslund M, Sklar G, Jacobs SC. Risk group stratiﬁcation in patients undergoing permanent I-125 prostate brachytherapy as monotherapy. Int J Radiat Oncol Biol Phys 2002;53:588–594. 8. Grimm PD, Blasko JC, Sylvester JE, Meier RM, Cavanagh W. 10-Year biochemical (prostate-speciﬁc antigen) control of prostate cancer with (125)I brachytherapy. Int J Radiat Oncol Biol Phys 2001;51:31–40. 9. Potters L, Cha C, Oshinsky G, Venkatramen E, Zelefsky M, Leibel S. Risk proﬁles to predict PSA relapse-free survival for patients undergoing permanent prostate brachytherapy. Cancer J Sci Am 1999;5:301–306. 10. Zelefsky MJ, Hollister T, Raben A, Matthews S, Wallner KE. Five-year biochemical outcome and toxicity with transperineal CT-planned permanent I-125 prostate implantation for patients with localized prostate cancer. Int J Radiat Oncol Biol Phys 2000;47:1261–1266. 11. Nag S, Beyer D, Friedland J, Grimm P, Nath R. American brachytherapy society (ABS) recommendations for transperineal placement brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999;44:789–799. 12. Butzbach D, Waterman FM, Dicker AP. Can extraprostatic extension be treated by pro vstate brachytherapy? An analysis based on postimplant dosimetry. Int J Radiat Oncol Biol Phys 2001;51:1196–1199. 13. Blasko JC, Grimm PD, Sylvester JE, Badiozamani KR, Hoak D, Cavanagh W. Palladium-103 brachytherapy for prostate carcinoma. Int J Radiat Oncol Biol Phys 2000;46:839–850. 14. Potters L, Fearn P, Kattan MW. External radiotherapy and permanent prostate brachytherapy in patients with localized prostate cancer. Brachytherapy 2002;1:36–41. 15. Terk MD, Stock RG, Stone NN. Identiﬁcation of patients at increased risk for prolonged urinary retention following radioactive seed implantation of the prostate. J Urol 1998:1379–1382. 16. Elshaikh MA, Angermeier K, Ulchaker JC, et al. Effect of anatomic, procedural, and dosimetric variables on urinary retention after permanent iodine-125 prostate brachytherapy. Urology 2003;61:152–155. 17. Wallner K, Lee H, Wasserman S, Dattoli M. Low risk of urinary incontinence following prostate brachytherapy in patients with a prior transurethral prostate resection. Int J Radiat Oncol Biol Phys 1997;37:565–569. 18. Wilkinson DA, Lee EJ, Ciezki JP, et al. Dosimetric comparison of pre-planned and OR-planned prostate seed brachytherapy. Int J Radiat Oncol Biol Phys 2000;48:1241–1244. 19. Robinson JW, Moritz S, Fung T. Meta-analysis of rates of erectile function after treatment of localized prostate carcinoma. Int J Radiat Oncol Biol Phys 2002;54:1063–1068. 20. Vicini FA, Martinez A, Hanks G, et al. An interinstitutional and interspecialty comparison of treatment outcome data for patients with prostate carcinoma based on predeﬁned prognostic categories and minimum follow-up. Cancer 2002;95:2041–2043. 21. Cox J, Grognon D, Kaplan R, Parsons J, Schellhammer P. Consensus statement: guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 1997;37:1035–1041.

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Androgen Deprivation and Radiation Therapy for Localized Prostate Cancer Patrick A. Kupelian and Tom Carlson

INTRODUCTION The combination of hormonal therapy (HT) with radiation therapy (RT) to treat localized prostate cancer, particularly locally advanced prostate cancers, has substantially increased in recent years. The optimal use of HT, which is constantly expanding, is still to be determined. Fortunately, multiple prospective studies performed since the 1980s have shed some light on many questions related to the use of HT in combination with RT. This chapter reviews the data and the ﬁndings from these prospective studies, although relevant retrospective data are also discussed.

STUDIES Retrospective Studies Many retrospective studies have been published in recent years reporting on the experience of the addition of HT to RT in localized prostate cancer, typically in relatively advanced localized prostate cancers. It is noteworthy that none of these retrospective series has clearly shown an advantage with respect to overall survival. Two representative studies will be discussed. Two large retrospective series were recently reported demonstrating the effect of the combination of short-term HT (6 mo or less) and RT for localized prostate cancer. The ﬁrst series was based on a total of 974 patients treated with external beam RT at the Cleveland Clinic Foundation for localized prostate cancer between 1986 and 1999 (1). The median total radiation dose was 70.2 Gy (range 60.0–78.0). Patients receiving <72 Gy constituted 58% of all cases, and patients receiving ≤72 Gy constituted 42% of all cases. Androgen deprivation therapy (HT) for 6 mo or less was delivered in the neoadjuvant or adjuvant setting in 247 cases (25% of the total). The median follow-up time was 43 mo (range 6–161 mo). Three risk groups were deﬁned on the basis of clinical T stage, pretreatment prostate-speciﬁc antigen (PSA; iPSA), and biopsy Gleason score From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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(bGS): low (T1–T2, iPSA ≤ 10, and bGS ≤ 6), intermediate (T1–T2 and either iPSA between 10.1 and 20.0 or bGS 7), and high (any T3, any PSA > 20.0, any bGS ≥ 8, or both iPSA 10.1–20.0 and bGS 7). The endpoint was biochemical relapse-free survival (bRFS), with relapse deﬁned by the American Society of Therapeutic Radiation and Oncology (ASTRO) 1996 consensus statement (2). In low-risk patients, the 5-yr bRFS rates were 81% vs 94% (no HT vs HT; p = 0.51). In intermediate-risk patients, the 5-yr bRFS rates were 56% vs 98% (no HT vs HT; p < 0.001). In high-risk patients, the 5-yr bRFS rates were 30% vs 85% (no HT vs HT; p < 0.001). On multivariate analysis including iPSA levels and bGS, HT remained an independent predictor of biochemical failure in intermediate- and high-risk patients. The second series, reported by D’Amico et al. (3), was based on a total of 1586 patients with stage T1–T2 prostate cancers treated with RT between 1989 and 1999. The median total radiation dose was 70.4 Gy (range 70.0–72.4). HT for 6 mo was delivered in 276 cases (17% of the total). Three risk groups were deﬁned as follows: low (T1C–T2A, iPSA ≤ 10, and bGS ≤ 6), intermediate (T2B, or iPSA between 10.1 and 20.0, or bGS 7), and high (T2C, or PSA > 20.0, or bGS ≥ 8). The median follow-up time was 49 mo (range 6–118 mo). In low-risk patients, the 5-yr bRFS rates were 84% vs 92% (no HT vs HT; p = 0.08). In intermediate-risk patients, the 5-yr bRFS rates were 62% vs 86% (no HT vs HT; p < 0.001). In high-risk patients, the 5-yr bRFS rates were 43% vs 67% (no HT vs HT; p = 0.009). It is remarkable how similar the outcomes were in both series with and without the use of short-term HT in similar risk groups. The better outcomes in intermediate- and high-risk patients receiving androgen deprivation in the Cleveland Clinic series might be explained by the fact that the median radiation doses were 78.0 Gy in both intermediate- and high-risk groups receiving HT, vs around 70 Gy in the series reported by D’Amico et al. (3). The intermediate- and high-risk groups would be the subgroups in which the largest beneﬁt from dose escalation would be seen. It is also important to note that overall survival was not the endpoint in either study.

Randomized Studies DES STUDY This study, performed in the 1960s, was limited to stage T3 and T4 cancers. Only the results of a subset of these patients treated at the M.D. Anderson Cancer Center (MDACC) were reported (4). The randomization was RT alone (n = 40) vs RT immediately followed by permanent androgen deprivation with 5 mg of diethylstilbestrol (DES) daily (n = 38). The median follow-up was 14.5 yr. The 5-yr disease-free survival was improved in patients receiving DES (71%) vs patients treated with RT alone (49%). However, the 5-yr overall survival was comparable between the two groups: 73% for RT and HT vs 68% for RT alone. This lack of difference in overall survival was presumed to be secondary to the excessive number of cardiovascular deaths from the high DES doses. MRC TRIAL This three-arm randomized trial reported by Fellows et al. (4a) compared the combination RT and permanent HT with permanent HT alone with RT alone. Patients with locally advanced prostate cancer were included. The overall survival rates were very low in all arms, compared with what is expected in modern series of locally advanced

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prostate cancer patients. This probably reﬂects a signiﬁcant understaging of patients. Overall, patients receiving HT alone had survival rates comparable to those of patients receiving the combination HT and RT. This is the only trial including an HT-only arm, and it has been used to support the claim that in locally advanced prostate cancer, RT does not improve outcomes compared with permanent HT. However, it is difﬁcult to extrapolate the outcomes from this series to modern patients. Most importantly, the radiation techniques and doses were not uniform, rendering the assessment of local RT difﬁcult at best. UMEA TRIAL This randomized trial performed in Sweden (4b) studied outcomes in patients with locally advanced, mostly lymph node-positive, prostate cancers. The randomization was between RT alone vs RT and permanent HT. Patients receiving HT in addition to RT had signiﬁcantly improved overall survival compared with patients receiving RT alone: the 10-yr overall survival rates were 62% for RT and HT vs 39% for RT alone. The largest improvement was seen in patients with node-positive disease. The trial showed early beneﬁt from HT, and the trial was closed prior to complete accrual. RTOG 85-31 Pilepich at al. (5) reported the results of this phase III Radiation Therapy Oncology Group (RTOG) trial (85–31) evaluating the potential beneﬁt of androgen suppression following standard RT in 945 evaluable patients with unfavorable-prognosis carcinoma of the prostate: T3 (>25 cm2), or pelvic/para-aortic adenopathy, or postprostatectomy with either seminal vesicle involvement or capsular penetration with positive surgical margins. The randomization was between adjuvant goserelin started during the last week of RT and continued indeﬁnitely or until signs of progression vs RT alone followed by goserelin at the time of progression. The radiation ﬁelds covered the entire pelvis. With evidence of common iliac nodal chain involvement, the periaortic nodes were included to L2–3. With evidence of para-aortic involvement, the para-aortic ﬁeld was raised to T11. The initial ﬁeld received 44–50 Gy, and the prostate target volume received a boost of 20–25 Gy. The initial report, with a median follow-up of 4.5 yr, revealed a higher 5-yr disease-free survival in patients receiving adjuvant HT (53%) vs patients treated with RT alone (20%). However, the 5-yr overall survival was comparable between the two groups: 75% for RT and HT vs 71% for RT alone. Lawton et al. (6) recently published an update of RTOG 85-31, with a median follow-up of 5.6 yr. It is remarkable that although all endpoints studied were signiﬁcantly improved with the addition of HT, neither overall survival nor cause-speciﬁc survival were improved in the entire cohort. Only in the subset of nonprostatectomy patients with a bGS of 8–10 were improvements in cause-speciﬁc and overall survival observed with the addition of permanent HT (Table 1). EORTC 22863 This European phase III study included T3/T4 disease, in addition to patients with poorly differentiated tumors (7,8). A total of 208 evaluable patients were randomized to radiation alone vs 207 patients randomized to RT and HT (goserelin) for 3 yr starting with the radiation. Cyproterone acetate was given during the ﬁrst month of HT. The radiation included standard ﬁelds. The median radiation dose was 70 Gy. With a median follow-up of 45 mo, Bolla et al. (7) reported a statistically signiﬁcant survival improvement in patients receiving HT. The 5-yr overall survival in patients receiving

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Kupelian and Carlson Table 1 Results From the RTOG 85-31 Trial Estimated 8-yr rates (%) RT + adjuvant RT + goserelin goserelin at relapse

Local failure Distant metastases NED survival bNED PSA < 1.5 ng/mL Overall survival all cases Overall survival bGS 8–10, no prostatectomy Cause-speciﬁc survival, all cases Cause-speciﬁc survival bGS 8–10, no prostatectomy

23 27 36 32 49 45 16 76

37 37 25 8 47 35 21 63

p value <0.0001 <0.0001 <0.0001 <0.0001 0.36 0.036 0.23 0.02

Abbreviations: bGS, biopsy Gleason score; bNED, biochemical no evidence of disease; PSA, prostatespeciﬁc antigen.

adjuvant HT was 79% vs 62% for patients treated with RT alone (p < 0.05). A more recent update, with a median follow-up of 61 mo, conﬁrmed the sustained improvement in all endpoints with the addition of 3 yr of adjuvant HT. The 5-yr local control in patients receiving adjuvant HT was 79% vs 97% for patients treated with RT alone (p < 0.001). The 5-yr disease-free survival in patients receiving adjuvant HT was 75% vs 40% for patients treated with RT alone (p < 0.001). The 5-yr overall survival in patients receiving adjuvant HT was 78% vs 62% for patients treated with RT alone (p < 0.001). RTOG 86-10 This phase III study was designed to assess the addition of short-term neoadjuvant and concomitant androgen deprivation to deﬁnitive RT in locally advanced carcinoma of the prostate (9). Inclusion criteria included bulky T2–T4 tumors (>25 cm2) based on digital rectal examination, or node-positive patients with disease below the level of the common iliac lymph nodes. A total of 456 evaluable patients were randomized between neoadjuvant goserelin and ﬂutamide starting 2 mo before initiation of RT and continuing through the RT course vs RT alone. RT ﬁelds included the pelvis lymph nodes. If pelvic lymph node involvement was identiﬁed, the superior border was extended to the L2–3 interspace. The lateral margins were 1 cm lateral to the maximum width of the bony pelvis. This initial ﬁeld received 45 Gy. A boost target volume including the prostate and sufﬁciently wide margins to encompass all the tumor extensions into the surrounding tissues received an additional 20–25 Gy. With a median follow-up of 4.5 yr, Pilepich et al. (9) reported an improvement in the 5-yr disease-free survival rates with the addition of HT: 36% for the combination vs 15% for RT alone. The 5-yr overall survival rates were comparable. Table 2 summarizes the results from a more recent update (9). The same trends were demonstrated to persist, with the 8-yr overall survival rates for the entire cohort being similar between patients treated with the addition of HT (53%) and RT alone (44%). However, the analysis revealed a statistically signiﬁcant difference in 8-yr overall survival rates in the subgroup of patients with centrally reviewed bGS 2–6: the 5-yr overall survival rates with the addition of HT were 70% for the combination vs 52% for RT

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345 Table 2 Results From the RTOG 86-10 Trial 8-yr data (%) RT + hormones RT alone

Local failure Distant metastases Survival Cause-speciﬁc survival

30 34 53 23

42 45 44 31

Gleason 2–6 central review (%) p value

RT + hormones

RT alone

p value

0.016 0.04 0.1 0.05

21 13 70 2

46 34 52 17

0.005 0.006 0.015 0.0002

alone (p = 0.015). It is noteworthy that the centrally reviewed bGS was not the one used for stratiﬁcation. RTOG 92-02 Reported by Hanks et al. (10), this is the only randomized trial that address the question of the length of adjuvant HT. A total of 1554 patients were randomized between short-term HT (neoadjuvant goserelin and ﬂutamide starting 2 mo before initiation of RT and continuing through the RT) and long-term HT (neoadjuvant goserelin and ﬂutamide starting 2 mo before initiation of RT and continuing through the RT, followed by an additional 24 mo of goserelin). The inclusion criteria were locally advanced prostate cancer patients with clinical stage T2C–T4 and a serum PSA level < 150 ng/mL. The median PSA level of the entire cohort was 20 ng/mL. The initial pelvic ﬁeld received a minimum total dose of 45 Gy, followed by a 20–25-Gy boost to the prostate. With a median follow-up of 48 mo, the local failure at 5 yr for patients receiving long-term HT was 7% vs 13% for patients receiving short-term HT (not signiﬁcant). The prostate cancer death rate at 5 yr for patients receiving long-term HT was 4% vs 7% for patients receiving short-term HT (not signiﬁcant). The 5-yr disease-speciﬁc survival for patients receiving long-term HT was 46% vs 21% for patients receiving shortterm HT (p = 0.001). The 5-yr overall survival for patients receiving long-term HT was 79% vs 78% for patients receiving short-term HT (not signiﬁcant). However, in the subgroup of 300 patients with bGS 8–10, there was an overall survival advantage with long-term HT: the 5-yr overall survival for patients receiving long-term HT was 80% vs 69% for patients receiving short-term HT (p = 0.02). RTOG 94-13 This four-arm randomized trial addressed two issues in the treatment of locally advanced prostate cancers; the beneﬁt from pelvic nodal irradiation and the sequencing of short-term androgen deprivation (11). Randomization was between neoadjuvant HT (2 mo before and 2 mo during RT) and adjuvant HT (4 mo immediately after the completion of RT). The second randomization was whole-pelvis vs prostate-only RT. Patients considered to have a >15% chance of pelvic lymph node metastasis were eligible. A total of 1323 patients were evaluable. The median PSA level was 23 ng/mL, 67% had T2C–T4 disease, and 72% had bGS 7 or above. Standard radiation therapy ﬁelds and doses were utilized. With a median follow-up of 59 mo, biochemical relapsefree survival rates were signiﬁcantly better in the patients receiving neoadjuvant HT

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and pelvic RT. The 5-yr bRFS rate was 61% for the neoadjuvant HT and pelvic RT arm vs 45% for the neoadjuvant HT and prostate-only arm, 47% for the adjuvant HT and prostate-only arm, and 49% for the adjuvant HT and pelvic RT arm (p = 0.005). No overall survival differences could be seen in this report.

THE EFFECT OF HT ON OUTCOME ENDPOINTS Over the past 10–12 years, the use of serum PSA levels as tumor markers for detecting recurrences has dramatically changed the way outcomes are assessed. Rising PSA levels after radiation therapy, i.e., biochemical failure, indicate disease recurrence. After prostatectomy, PSA levels are expected to be undetectable; after radiotherapy, PSA levels are typically expected to remain low and stable. Fluctuations in a low range are typically seen. To ensure uniformity of reported results, the 1996 ASTRO consensus conference determined the deﬁnition of biochemical failure as three consecutive rising PSA levels after a nadir. However, this was speciﬁcally deﬁned for patients treated with external beam RT alone. Androgen deprivation will affect PSA production, and the interpretation of serum PSA levels is rendered difﬁcult. Currently, there are no widely accepted guidelines for interpreting serum PSA levels after radiation and either short-term or long-term HT. If HT is continued permanently after radiation, PSA levels will be permanently suppressed as long as the disease is androgen-dependent. This renders PSA levels unreliable for determining disease recurrence. Once the disease is androgen-independent, there would be an observed PSA rise while the patient is receiving HT. Reports on patients receiving permanent HT often compare bRFS rates with biochemical failure deﬁned as the rise of PSA levels while the patient is on HT. This renders the comparison with outcomes in patients treated with RT alone practically useless. For patients on long-term or permanent HT, more traditional endpoints such disease-speciﬁc survival or overall survival should be the endpoints of choice. If patients receive short-term HT or whenever HT is discontinued, it is expected that PSA levels will have a ﬁrst rise. Such a rise might or might not satisfy the deﬁnition of biochemical failure by ASTRO criteria. Regardless, if PSA levels ultimately stabilized or decreased, the ﬁrst rise would have been an indication of a return to testosterone production rather than disease recurrence. Such rises make comparisons with treatment regimens not containing HT difﬁcult. In this context, a second rise, i.e., a deﬁnite rise in PSA levels after the initial rise associated with return of testosterone production, would be a more appropriate endpoint. However, reports rarely include a “second rise” as the outcome endpoint. As with long-term or permanent HT, the ultimate outcome endpoints should be disease-speciﬁc survival or overall survival. In this context, overall survival has to be the most signiﬁcant evaluation endpoint. The association between initial biochemical failure and death is adequate only if the follow-up of patients studied is long. Even disease-speciﬁc survival can be difﬁcult to assess owing to the wellrecognized problems of evaluating local and distal recurrences with prostate cancer. In addition, primary clinical events are relatively few in the PSA era, when salvage therapy is often instituted at the time of the ﬁrst biochemical failure.

Interaction of Radiation and Androgen Deprivation The actual mechanism of interaction between HT and RT in prostate cancer cell kill is still poorly understood. It is still unclear whether the effect is additive or synergistic

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(12,13). However, the observed clinical beneﬁts from adding HT to RT could be simply explained by slowing of tumor growth rather than actual cell kill. From the clinical studies, it is difﬁcult to assess whether the beneﬁts seen with combination therapy are the result of actual synergy resulting in excess cancer cell death, or just the result of slowing tumor growth. For example, in the RTOG 86-10 trial, in which the combination was given before and during the radiation, one could assume that the beneﬁt observed would be owing to synergy. However, the effects of androgen deprivation, especially slowing the growth of cells, can be seen for long periods after androgen levels are restored. In the RTOG 94-13 trial, the duration of hormonal therapy was kept constant, with the HT sequence and RT coverage differing in the four arms. This trial would suggest that synergy is the mechanism of action since all patients received the same duration of HT. However, somehow this effect was limited to micrometastatic disease in the irradiated lymphatics, since only the patients who had their lymphatics irradiated and received neoadjuvant/concomitant HT had better outcomes. In trials such as RTOG 92-02 or the European Organization for Research and Treatment of Cancer (EORTC) trial, in which HT was maintained for extended periods, the mechanism of action is difﬁcult to assess. However, RTOG 92-02 would suggest that, at least in patients with high-grade cancers, in addition to additive or synergistic effects of radiation and HT on cancer cells in irradiated areas (the initial part of the treatment was identical in the two arms), there might be an effect on micrometastatic deposits. This leads to the more important question: is the beneﬁt of HT from a synergistic or additive effect on cells in the irradiated prostate and periprostatic tissues, or a systemic effect? Even in locally advanced cancers, is the beneﬁt from HT an increased cell kill within the irradiated areas, or a slowing down or perhaps sterilization of micrometastatic deposits? If the expected effect is only local, then the local therapy (in this case external radiation) is the modality that should be optimized. In an era in which signiﬁcant advances in the delivery of radiation (such as conformal techniques including intensitymodulated radiotherapy) allow the delivery of signiﬁcantly higher doses to the prostate and periprostatic tissues, the currently available prospective trials do not help in understanding the additional beneﬁt of androgen deprivation, since all trials used standard radiation ﬁelds and radiation doses. Especially in the context of relatively advanced cancers, there is clear evidence that such doses are inadequate for tumor control (14–17). HT could be only compensating for suboptimal local therapy, mainly by slowing down cancer cells inadequately controlled in irradiated areas. However, if the expected beneﬁt from the combination is a systemic one, then HT should be used for relatively long periods only in patients with a signiﬁcant risk of having metastatic disease, and only after local therapy is optimized. It is noteworthy that a clear overall survival beneﬁt was observed only in patients with the most advanced cancers receiving long-term hormonal therapy, such as in the EORTC trial (a majority of T3–T4 and high-grade cancers), and the subgroups within RTOG 85-31 and RTOG 92-02 with high Gleason scores. However, even in these subgroups, it is not clear how much of the beneﬁt was from slowing down inadequately controlled treated local disease vs slowing down of metastatic disease, since all these trials used modest radiation doses.

PATIENT SELECTION The only subgroup that does not seem to beneﬁt from HT is that of patients with early-stage, low-risk prostate cancers (stage T1–T2A, bGS ≤ 6, and iPSA ≤ 10). There

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are no prospective or retrospective data suggesting any improvement in any outcome in this subset. However, trials such as the Early Prostate Cancer Trial (described below) might ultimately shed some light on any possible role of HT in this subgroup. For the remaining patient subgroups, there are either prospective or retrospective studies supporting a possible role for HT in combination with RT. When combined with standard RT, the beneﬁt from androgen deprivation has been most signiﬁcant in patients with T3–T4 tumors, or with bGS 8–10. This patient group constitutes a minority (10–15%) of patients diagnosed today with prostate cancer. Stage T3–T4 cancers are uncommon. Patients who present with early clinical stages and high Gleason scores are most commonly the group of patients that ﬁt this high-risk category. The outcomes in this particular group of patients are not as dire as previously thought. In a recent study speciﬁcally looking at the small subset of patients with high Gleason scores (≥8) but early clinical stages and low PSA levels at the time of therapy, the bRFS rates after combined HT and high dose RT were relatively favorable (18). Patients presenting with low clinical stage (T1 or T2), low iPSA levels (≤10 ng/ML), and a high GS (≥8) treated at the Cleveland Clinic Foundation were studied. A total of 104 such cases were identiﬁed; 54 were treated with RT vs 50 with prostatectomy, and 52 had were androgen deprived for ≤6 mo. The median follow-up of this group was 40 mo. Figure 1A shows the bRFS rates of all 104 cases. The 5-yr bRFS rate was 64% for all 104 cases. For the 52 cases who were treated with ≤6 mo of HT, the 5-yr bRFS rate was 78% (Fig. 1B). It is possible that patients diagnosed nowadays with bGS ≥ 8 have relatively smaller disease bulk compared with patients enrolled in the late 1980s and early 1990s in trials such as EORTC 22863, RTOG 85-31, and even RTOG 92-02. There has been a clear stage migration in the PSA era, probably owing to earlier diagnosis secondary to widespread screening and patient awareness about prostate cancer. An analysis from the Cleveland Clinic showed that year of therapy is an independent predictor of outcome in patients treated with either prostatectomy or RT (19,20). This makes the extrapolation of outcome results in patients diagnosed and treated 10 or 15 years ago to modern patients somewhat difﬁcult, specially long-term survival outcomes, even when stratiﬁed by clinical stage, pretreatment iPSA, and bGS. The situation is also confounded by the lack of pretreatment PSA information on patients from some of the earlier trials. Obviously, the disease biology itself has not changed; however, the extent and bulk of disease has probably changed, even independently from rectal examination ﬁndings, PSA levels, and Gleason scores. In patients with clinically palpable locally extensive disease, bGS 8–10, long-term adjuvant therapy is probably warranted. This could be also extrapolated to patients with high pretreatment PSA levels, although clear randomized data are lacking with respect to the use of PSA as a prognosticator in this context. The margin of beneﬁt from HT in modern patients with clinically palpable locally extensive disease, with bGS 8–10, might not be as large as expected from the previously quoted studies, owing to the more effective local therapies delivered today. However, secondary to the high likelihood of micrometastatic disease in such patients, long-term adjuvant HT should be delivered. Considering the signiﬁcant toxicity from long-term (or permanent) androgen deprivation, prospective data are needed to assess the extent of the beneﬁt with long-term HT when high (optimal) doses are delivered to the prostate in patients with high-risk disease. In the large majority of the patients with prostate cancer presenting for treatment with radiation, there are no clear data from randomized trials for indications of HT. For

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Fig. 1. Biochemical relapse-free survival (bRFS) in 104 cases treated at the Cleveland Clinic Foundation with either RT or prostatectomy with clinical stage T1 or T2, pretreatment PSA ≤ 10 ng/mL, and biopsy Gleason score ≥ 8. (A) All cases. (B) Split by the use of HT. All 52 cases receiving HT received only up to 6 mo of HT (18). Symbols represent censored events. AD, androgen deprivation.

patients with low Gleason scores, the only evidence for any beneﬁt for HT is the subgroup analysis from RTOG 86-10. It is important to note that patients from RTOG 86–10 still had signiﬁcantly advanced cancers, even with bGS ≤ 6. These patients would be considered intermediate risk, if not high risk, by today’s standards. If real, this beneﬁt from short-term HT in intermediate-risk patients is consistent with the ﬁndings from the two retrospective analyses presented above from the Cleveland Clinic

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and the Dana Farber Cancer Institute. Similar to what has been established with highrisk cancers (T3–T4 and/or bGS ≥ 8), prospective data are needed to assess the extent of the beneﬁt of any HT when modern RT techniques and doses are delivered to the prostate in patients with intermediate-risk disease (T2B–T2C, bGS 7, iPSA > 10).

ANDROGEN DEPRIVATION METHODS Most randomized trials have been performed with short-term hormonal therapy delivered with combined androgen blockade; long-term androgen deprivation was done with luteinizing hormone-releasing hormone (LHRH) agonists alone. With short-term hormonal therapy, it is difﬁcult to assess the added beneﬁt from adding antiandrogens for the 4–6 month duration. With LHRH agonists delivered over extended periods, the toxicity of HT has to be weighed carefully against the potential beneﬁt. In patients with locally advanced bulky cancer, with Gleason score ≥ 8, the beneﬁt has been clearly demonstrated. However, for patients with less advanced cancers, regardless of age, the addition of HT, particularly long-term HT, can have a signiﬁcant impact on quality of life. The option of using antiandrogens alone has been attractive owing to a lesser effect on libido and bone density. However, deﬁnite evidence that the combination of antiandrogens with radiation is as effective as complete androgen blockade or LHRH agonists alone is still lacking. The most compelling study so far with respect to the use of antiandrogens with radiation is the Early Prostate Cancer study. The report by See et al. (21) was a pooled analysis of three separate trials. The trials tested the use of bicalutamide, 150 mg daily, as immediate therapy adjuvant to standard care of patients with localized or locally advanced prostate cancer. The ﬁrst trial conducted in North America included 3292 patients, stage T1B–T3 N0–X, M0, randomized after either prostatectomy or deﬁnitive radiotherapy to 2 yr of adjuvant bicalutamide or placebo. The second trial (conducted in Europe, South Africa, Israel, Mexico, and Australia) included 3603 patients, T1B–T4, any N, M0, managed with either prostatectomy, RT or watchful waiting, and randomized to 5 yr of bicalutamide or placebo. The third trial, conducted in Scandinavia, included 1218 patients, T1B–T4, any N, M0, managed either with prostatectomy, RT, or watchful waiting, randomized bicalutamide or placebo, and continued till progression. The primary endpoint was clinical progression (e.g., bony events). Overall, there was a statistically significant reduction in objective progression at 5 yr in all cases from 13 to 9%. However, such a reduction was not observed in the subset from the North American trial, which did not include a watchful waiting arm. Overall, at the time of analysis, only 5% of patients had died; therefore the assessment of the effect of adjuvant bicalutamide on survival was difficult owing to the paucity of events. It is noteworthy that around 70% of patients experienced either gynecomastia and/or breast tenderness. This resulted in the discontinuation of the drug in 17% of cases from the North American trial. However, there was minimal effect on libido and sexual function. In addition, no change in bone mineral density could be observed. The results from this trial will significantly alter the management of localized prostate cancer in the future by making adjuvant androgen deprivation a routine addition to standard care in nearly all cases, including after definitive RT. However, further follow-up will be needed to evaluate the full impact from adjuvant bicalutamide in patients with localized prostate cancer, particularly patients diagnosed and treated in North America.

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ANDROGEN DEPRIVATION DURATION The necessary duration of androgen deprivation when combined with RT for localized prostate cancer is perhaps the most prominent issue that needs to be addressed today. There are several confounding factors in the assessment of the ideal duration of hormonal therapy, the most important of which might be that the duration of androgen deprivation is different from the time during which LHRH agonists and/or antiandrogens are actually administered. It is a well-known phenomenon that testosterone levels will be suppressed for extended periods after androgen blockade is discontinued. None of the studies studying the required duration of hormonal therapy reliably correlate outcomes with testosterone levels. A more thorough examination of outcomes with actual testosterone levels is required, particularly in randomized trials. Another issue is the impact of prolonged androgen deprivation and its effect on follow-up PSA levels. This renders either second PSA relapse, or clinical progression (e.g., bony events), or ultimately overall survival the relevant endpoints in studying HT duration. Most recent studies, particularly retrospective series, have routinely included ﬁrst biochemical relapse as a study endpoint. This will invariably favor the outcomes in patients receiving HT. The duration of HT has to be related to the probability of residual prostate cancer cells after the initial local RT. The probability of residual cancer cells is related either to inadequate local therapy (geographic misses, inadequate radiation doses, excessive cancer volume, radioresistance) or to pre-existing micrometastases. Patients enrolled on RTOG 85-31 treated with radiotherapy, patients on EORTC 22863, and patients on RTOG 86-10, 92-02, and even 94-13 had significantly advanced local disease. Judging from the proportion of positive prostate biopsies in the patients treated with different dose levels with conformal radiotherapy at Memorial Sloan Kettering Cancer Center, a substantial proportion of patients treated on the above-mentioned trials would have residual local disease (16). It is possible that even in the event that a subset of such patients did not have any microscopic metastatic disease at the time of initial therapy, secondary metastases could have occurred from uncontrolled primaries. In this context, adjuvant androgen deprivation would have an effect in slowing tumor cells both locally and distantly. In either case, only long-term (permanent) HT would perform that function. Since extensive follow-up is needed to assess survival in patients with localized prostate cancer, it is likely that differences in overall survival are currently observed with long-term HT mainly in the subset of patients having the most likelihood of failing (the largest number of events), i.e., in patients with substantial local disease (clinical stage T3 or T4), or high bGS (8–10). In this subset of patients, it is likely that long-term HT would be needed even if local therapy was optimal. RTOG 92-02 is the only trial that speciﬁcally addresses the question of length of hormonal therapy. Two years of adjuvant therapy resulted in increased survival only in patients with bGS ≥ 8. Whether HT should be continued for 2 yr (as in RTOG 92-02), 3 yr (as in EORTC 28663), 5 yr (as in the Early Prostate Cancer trial), or indeﬁnitely until progression (as in RTOG 85-31) is unclear. However, if the aim is to affect micrometastatic disease, permanent HT would be needed. Short-term HT would, at best, result in increasing local cell kill, or, at worst, temporarily slowing down cancer cells. Evidence against short-term hormonal therapy having any lasting effect on distant disease is the lack of improvement in outcome seen in all randomized trials using

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neoadjuvant HT prior to prostatectomy. However, HT in combination with radical prostatectomy was typically limited to only 3 mo (22–24). Prospective trials investigating longer periods of HT prior to prostatectomy will provide a better assessment of the effect of length of HT (25). Short-term neoadjuvant and concomitant hormonal therapy would be useful mainly to improve local control. This could also have an effect on the irradiated regional lymphatics, as suggested by the results of RTOG 94-13: only patients who received concomitant HT and radiation to the lymphatics had a superior outcome. If the effect from hormonal therapy was purely on micrometastatic disease, no difference should have been observed in any of the four arms. If the effect from HT was purely on cancer cells in the prostate gland, then the improvement should have been seen in both patients treated to prostate-only ﬁelds and patients treated with pelvic ﬁelds. The added beneﬁt of short-term HT on controlling local disease might be needed in patients with localized disease falling in the intermediate-risk category, particularly in patients treated with modest doses of radiation, such as in the series reported by D’Amico et al. (3). The beneﬁt from HT is decreased with the use of higher than standard radiation doses, such as suggested in the Cleveland Clinic series (1) (and see below). However, there are no randomized data supporting the use of short-term HT in patients with intermediate-risk localized prostate cancer. The Early Prostate Cancer Trial might ultimately answer questions about the need for long-term adjuvant hormonal therapy in patients with intermediate- and low-risk prostate cancer (21). A concern with the HT and RT combination in this context is the potential desensitization of prostate cancer cells by an initial course of HT, and then a decreased response rate at the time of salvage HT. The most compelling evidence against such a phenomenon is the study reported by Shipley et al. (26). Patients treated on the RTOG 86-10 protocol were studied for their response to salvage HT. There was no evidence of worse outcome after the institution of salvage HT in patients treated with an initial course of short-term HT vs patients treated with RT alone. If this is the case, then it would be reasonable to limit the initial course of HT and avoid the toxicity with long-term HT. For patients who fail, salvage therapy would still be effective. The argument against any long-term HT in any patient subgroup is the toxicity from prolonged androgen deprivation. Although most manifestations of androgen deprivation are manageable, they can be of signiﬁcant impact on an individual patient’s quality of life. Patients going on long-term androgen deprivation should be counseled adequately on what to expect and how to manage the potential toxicity of prolonged therapy.

ANDROGEN DEPRIVATION AND RADIATION: SEQUENCING The issue of the sequence of radiation and HT has different aspects. Biologically, it is counterintuitive to use HT during RT, mainly because cells should not be put in a dormant state during active RT. However, clinically, a detrimental effect in administering HT prior to RT has not been observed. Long-term HT was started at the completion of radiation in the RTOG 85-31 trial. In contrast, long-term adjuvant HT was started at the beginning of radiation in the EORTC trial. That particular study was the most inﬂuential in demonstrating a survival advantage to the HT and RT combination. Shrinkage of the prostate gland is most signiﬁcant during the ﬁrst 2–3 mo after initiation of HT. In more recent times, with the use of conformal radiation ﬁelds and higher than standard radiation doses, there is concern

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that starting the HT with the radiation might result in signiﬁcant changes in the conﬁguration of the target and normal structures, possibly resulting in misadministration of the radiation, with unexpected doses in target and normal structures. It is probably best to avoid having a target chaging shape during the course of radiation. For short-term HT, the RTOG 94-13 trial is the most important in determining the ideal sequence (11). The results of this trial indicate that using neoadjuvant HT results in superior outcomes. However, the beneﬁt from HT delivered neoadjuvantly was seen only in the arm that also included pelvic radiotherapy. For patients receiving prostateonly radiotherapy, the sequence of HT did not matter. A possible explanation is that, in patients treated to the prostate only, neoadjuvant HT actually results in superior outcomes compared with adjuvant HT. This might not have been observed owing to the artifact of having hormonal therapy lasting at a later time in the course of follow-up in patients receiving adjuvant HT, artiﬁcially improving the observed outcomes in the adjuvant HT group.

RADIATION DOSE In the past 10–15 yr, the techniques for delivering external RT have allowed signiﬁcantly higher doses to be delivered to target areas within the pelvis (14,17,27–31). With the advent of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy, radiation doses exceeding 70 Gy are routinely used. There is substantial evidence that dose escalation results in signiﬁcantly better bRFS rates and possibly higher overall survival rates (32,33). This strongly indicates that, particularly in patients presenting with tumors that have advanced features, standard radiation doses are not adequate to control local disease. All prospective trials using HT have included RT techniques delivering standard doses. It will be important to assess the beneﬁt from additional HT, either short or long term, when local therapy is adequate. Results from randomized studes are needed assessing high radiation doses alone vs high radiation doses and HT. From retrospective series, there is a suggestion that the beneﬁt from the addition of short-term HT decreases with increasing radiation doses, suggesting mainly a local effect: as higher radiation doses sterilize a higher proportion of the local cancer, there is less need for HT to control residual local disease. Figure 2 shows the bRFS rates in a cohort of 823 patients with high-risk prostate cancer treated at the Cleveland Clinic in the PSA era (1987–2000). In this cohort, high risk was deﬁned as any T3, any iPSA > 10, or bGS ≥ 7. All patients had at least three follow-up PSA levels assessed. RT doses exceeding 72 Gy were delivered in 131 cases, and 360 cases received short-term HT (≤ 6 mo). The median follow-up of the entire cohort was 59 mo. The median follow-up was 89 mo for patients receiving <72 Gy and no HT, 65 mo for patients receiving <72 Gy and HT, 54 mo for patients receiving ≥72 Gy and no HT, and 43 mo for patients receiving ≥72 Gy and HT. As seen in Fig. 1, the larger difference with the use of HT is in patients receiving <72 Gy. Although it is difﬁcult to assess the impact of each factor (RT dose and HT) because of the shorter follow-up in patients receiving HT and the higher radiation doses, these data suggest that androgen deprivation, particularly short-term HT, should not be a substitute for adequate local therapy. Consequently, one should approach carefully assumptions that HT can compensate for a compromise in radiation doses delivered. If there is any beneﬁt to the addition of HT to RT, it should be performed in combination with adequate local therapy.

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Fig. 2. Biochemical relapse-free survival rates in 823 high-risk (any T3, any pretreatment PSA > 10 ng/mL, or biopsy Gleason score ≥ 7) prostate cancer patients treated at the Cleveland Clinic in the PSA era (1987–2000). The subgroups are by radiation dose (<72 Gy vs ≥72 Gy), and use of shortterm androgen deprivation (AD). Symbols represent censored events. Time is in years.

CONCLUSIONS The role of HT in the overall management of patients with localized prostate cancer has expanded dramatically over the past 10 years. Outcome results from multiple prospective series suggest that the only clear indication for the use of combined androgen deprivation and RT is in the long-term use of HT after RT for patients with stage T3–T4 cancers and/or bGS ≥ 8. There is no demonstrated beneﬁt for HT, either short or long term, in patients with early-stage prostate cancers (stage T2A or less, pretreatment PSA ≤ 10 ng/mL, and Gleason score ≤ 6). The role of androgen deprivation in patients with intermediate-risk disease is still controversial.

REFERENCES 1. Davies-Johns T, Reddy C, Kupelian P. Localized prostate cancer treated with radiotherapy: who beneﬁts from hormonal therapy? Int J Radiat Oncol Biol Phys 2000;48:170. 2. Consensus statement: guidelines for PSA following radiation therapy. American Society for Therapeutic Radiology and Oncology Consensus Panel. Int J Radiat Oncol Biol Phys 1997;37:1035–1041. 3. D’Amico AV, Schultz D, Loffredo M, et al. Biochemical outcome following external beam radiation therapy with or without androgen suppression therapy for clinically localized prostate cancer. JAMA 2000;284:1280–1283. 4. Zagars GK, Johnson DE, von Eschenbach AC, et al. Adjuvant estrogen following radiation therapy for stage C adenocarcinoma of the prostate: long-term results of a prospective randomized study. Int J Radiat Oncol Biol Phys 1988;14:1085–1091. 4a. Fellows GJ, Clark PB, Beynon LL, et al. Treatment of advanced localised prostatic cancer by orchiectomy, radiotherapy, or combined treatment. A Medical Research Council Study. Urological Cancer Working Party–Subgroup on Prostatic Cancer. Br J Urol 1992;70:304–309. 4b. Grantors T, Modig H, Damber JE, Tomic K. Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: a prospective randomized study. J Urol 1998;159:2030–2034. 5. Pilepich MV, Caplan R, Byhardt RW, et al. Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with deﬁnitive radiotherapy: report of Radiation Therapy Oncology Group Protocol 85-31. J Clin Oncol 1997;15:1013–1021.

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6. Lawton CA, Winter K, Murray K, et al. Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential beneﬁt of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001;49:937–946. 7. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002;360:103–106. 8. Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997;337:295–300. 9. Pilepich MV, Winter K, John MJ, et al. Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to deﬁnitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001;50:1243–1252. 10. Hanks GE, Lu JD, Machtay M, et al. RTOG protocol 92-02: a phase III trial of the use of long term total androgen supression following neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2000;48:112. 11. Roach M 3rd, DeSilvio M, Lawton C, et al. Phase III trial comparing whole-pelvic versus prostateonly radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol 2003;21:1904–1911. 12. Joon DL, Hasegawa M, Sikes C, et al. Supraadditive apoptotic response of R3327-G rat prostate tumors to androgen ablation and radiation. Int J Radiat Oncol Biol Phys 1997;38:1071–1077. 13. Zietman AL, Prince EA, Nakfoor BM, et al. Androgen deprivation and radiation therapy: sequencing studies using the Shionogi in vivo tumor system. Int J Radiat Oncol Biol Phys 1997;38:1067–1070. 14. Pollack A, Zagars GK, Starkschall G, et al. Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002;53:1097–1105. 15. Hanks GE, Hanlon AL, Pinover WH, et al. Dose selection for prostate cancer patients based on dose comparison and dose response studies. Int J Radiat Oncol Biol Phys 2000;46:823–832. 16. Zelefsky MJ, Leibel SA, Gaudin PB, et al. Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys 1998;41:491–500. 17. Lyons JA, Kupelian PA, Mohan DS, et al. Importance of high radiation doses (72 Gy or greater) in the treatment of stage T1–T3 adenocarcinoma of the prostate. Urology 2000;55:85–90. 18. Kupelian PA, Buchsbaum JC, Elshaikh M, et al. Factors affecting recurrence rates after prostatectomy or radiotherapy in localized prostate carcinoma patients with biopsy Gleason score 8 or above. Cancer 2002;95:2302–2307. 19. Buchsbaum J, Elshaikh M, Kupelian P, et al. Improvement in relapse-free survival throughout the PSA era in patients with localized prostate cancer treated with deﬁnitive radiotherapy: year of treatment is an independent predictor of outcome. Int J Radiat Oncol Biol Phys 2001;51;169:169. 20. Jhaveri FM, Klein EA, Kupelian PA, et al. Declining rates of extracapsular extension after radical prostatectomy: evidence for continued stage migration. J Clin Oncol 1999;17:3167–3172. 21. See WA, Wirth MP, McLeod DG, et al. Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: ﬁrst analysis of the early prostate cancer program. J Urol 2002;168:429–435. 22. Soloway MS, Pareek K, Shariﬁ R, et al. Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results. J Urol 2002;167:112–116. 23. Soloway MS, Shariﬁ R, Wajsman Z, et al. Randomized prospective study comparing radical prostatectomy alone versus radical prostatectomy preceded by androgen blockade in clinical stage B2 (T2bNxM0) prostate cancer. The Lupron Depot Neoadjuvant Prostate Cancer Study Group. J Urol 1995;154:424–428. 24. Klotz LH, Goldenberg SL, Jewett M, et al. CUOG randomized trial of neoadjuvant androgen ablation before radical prostatectomy: 36-month post-treatment PSA results. Canadian Urologic Oncology Group. Urology 1999;53:757–763. 25. Gleave ME, Goldenberg SL, Chin JL, et al. Randomized comparative study of 3 versus 8-month neoadjuvant hormonal therapy before radical prostatectomy: biochemical and pathological effects. J Urol 2001;166:500–506; discussion 506–507. 26. Shipley WU, Lu JD, Pilepich MV, et al. Effect of a short course of neoadjuvant hormonal therapy on the response to subsequent androgen suppression in prostate cancer patients with relapse after radiotherapy: a secondary analysis of the randomized protocol RTOG 86-10. Int J Radiat Oncol Biol Phys 2002;54:1302–1310. 27. Martinez AA, Yan D, Lockman D, et al. Improvement in dose escalation using the process of adaptive radiotherapy combined with three-dimensional conformal or intensity-modulated beams for prostate cancer. Int J Radiat Oncol Biol Phys 2001;50:1226–1234.

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28. Zelefsky MJ, Fuks Z, Hunt M, et al. High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients. Int J Radiat Oncol Biol Phys 2002;53:1111–1116. 29. Kupelian PA, Buchsbaum JC, Reddy CA, et al. Radiation dose response in patients with favorable localized prostate cancer (stage T1–T2, biopsy Gleason < or = 6, and pretreatment prostate-speciﬁc antigen < or = 10). Int J Radiat Oncol Biol Phys 2001;50:621–625. 30. Kupelian PA, Willoughby TR. Short-course, intensity-modulated radiotherapy for localized prostate cancer. Cancer J 2001;7:421–426. 31. Kupelian PA, Mohan DS, Lyons J, et al. Higher than standard radiation doses (72 Gy or greater) with or without androgen deprivation in the treatment of localized prostate cancer. Int J Radiat Oncol Biol Phys 2000;46:567–574. 32. Kupelian PA. Improvement in overall survival for patients with localized prostate cancer with higher than standard radiation doses: preliminary results. J Urol 1999;161:386. 33. Hanks GE, Hanlon AL, Pinover WH, et al. Survival advantage for prostate cancer patients treated with high-dose three-dimensional conformal radiotherapy. Cancer J Sci Am 1999;5:152–158.

18

Prostate Brachytherapy The Role of Supplemental External Beam Radiotherapy

Gregory S. Merrick and Wayne M. Butler

INTRODUCTION Over the past 15 yr, permanent prostate brachytherapy has been increasingly utilized as deﬁnitive treatment for potentially curable prostate cancer, with most series reporting biochemical and quality of life (QOL) outcomes that compare favorably with radical prostatectomy (RP) and external beam radiation therapy (XRT) (1–4). These favorable biochemical proﬁles are in part a result of dose escalation and the ability to treat the periprostatic region aggressively with extracapsular seed placement and/or supplemental XRT (5–14). Early in the development of prostate brachytherapy protocols, the concept of combination brachytherapy and supplemental XRT was adopted for patients who possessed a high probability of extracapsular extension (i.e., pretreatment prostatespecific antigen [PSA] > 10 ng/mL, a biopsy Gleason score ≥ 7, and/or bilobar palpable disease) (15–19). Although the biochemical control rates with this treatment philosophy have been favorable, two areas of clinical investigation have questioned the need for supplemental XRT. First, results with monotherapeutic brachytherapy, even in patients with higher PSA and Gleason scores, have been remarkably good in selected studies (20–23). Second, detailed pathology studies have revealed that the radial extent of extraprostatic cancer extension in patients undergoing RP is almost always limited to ≤5 mm regardless of the pretreatment PSA level and Gleason score (24,25).

RATIONALE FOR SUPPLEMENTAL XRT The rationale for supplemental XRT in conjunction with permanent prostate brachytherapy includes the enhancement of periprostatic doses, intraprostatic dose escalation, and/or dose modiﬁcation of a technically inadequate implant (Table 1).

From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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Merrick and Butler Table 1 Rationale for Supplemental External Beam Radiation Therapy Enhance periprostatic dose Escalate intraprostatic dose Rectify a technically inadequate implant

Fig. 1. Schematic of a transverse prostate with 2-mm radial extraprostatic capsular extension (EPE) of the tumor. To encompass 99% of likely EPE with the prescription dose, the 100% isodose line should extend 5 mm beyond the capsule.

Extraprostatic Extension Patients with extraprostatic capsular extension (EPE) but negative pelvic lymph nodes remain potentially curable provided that the extracapsular tumor can be eradicated. Even in patients with clinically organ-conﬁned prostate cancer and a PSA ≤10 ng/mL, approx 50% manifest extracapsular disease at the time of RP (26). Thus, the primary rationale for supplemental XRT is to increase the dose and radial extent of periprostatic radiation for sterilization of EPE (Fig. 1). Merrick and colleagues have previously reported that implant prescription doses of radiation can consistently be delivered to both the prostate and periprostatic region with the utilization of extracapsular seed placement (5–7,27,28). At the periphery of the implant target volume, the radiation dose decreases by up to 20 Gy/mm (29). Consequentially, if extracapsular brachytherapy margins are not utilized, supplemental XRT is essential to ensure adequate periprostatic radiation doses. The limitation of most pathology studies regarding EPE is that they address the incidence but not the radial distance from the prostatic capsule. Recent studies of the radial extent of EPE have fueled discussion regarding its clinical signiﬁcance and the rationale for supplemental XRT (24,25). The mean extent of EPE in RP specimens has been reported to be 0.5 mm in the Mayo Clinic series and 1.1 mm at the Cleveland Clinic, with maximum extraprostatic extension of 4.4 and 10.0 mm, respectively (24,25). Both studies concluded that brachytherapy margins of 5 mm with or without supplemental XRT should encompass all sites of extracapsular disease in approx 99% of cases

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(7,24,25) (Fig. 1). It is likely that cancer eradication in high Gleason score patients and/or patients with a high risk of EPE requires the addition of supplemental XRT or, if a monotherapeutic approach is utilized, generous periprostatic margins with the placement of multiple periprostatic seeds to irradiate the prostate, the extracapsular region, and the base of the seminal vesicles with postimplant dosimetric analyses to conﬁrm adequate radiation doses (7,30). High Gleason score, perineural invasion (PNI), and extensive tumor in the biopsy specimen have been correlated with a higher likelihood of EPE. Brachytherapy’s ability (with or without supplemental XRT) to irradiate the prostate aggressively with generous margins may make these adverse prognosticators less important compared with RP and XRT. The Partin tables have eloquently presented the relationship between higher Gleason scores and greater risks of extracapsular extension, seminal vesicle invasion, and pelvic lymph node involvement (26). In RP series, the prognostic value of PNI in predicting biochemical outcome is controversial. Although multiple RP studies have reported PNI to be of prognostic value (31–35), other studies have reported PNI to be of no prognostic value (36,37). Most recently, O’Malley and colleagues (38) reported a nonsigniﬁcant trend for decreased biochemical disease-free survival in surgical patients with PNI. For three-dimensional conformal XRT (3D-CRT) patients with a pretreatment PSA < 20 ng/mL, Bonin et al. (39) reported that PNI was predictive of biochemical failure. In contrast, following brachytherapy, PNI does not appear to affect biochemical outcomes adversely (4,11,40). Using supplemental XRT and/or generous periprostatic margins with multiple extracapsular seeds, Merrick and colleagues (11) reported no overall difference in biochemical outcome when stratiﬁed by PNI. Similar analyses revealed no statistically signiﬁcant difference in biochemical outcome for patients in any risk group (low, intermediate, or high), treatment approach (monotherapeutic brachytherapy or combined with supplemental XRT), neoadjuvant hormonal status, or several combined categories (11). D’Amico and colleagues (41–43) reported that the percent positive prostate biopsies was statistically signiﬁcant in predicting biochemical outcome following RP or 3DCRT. Other studies have reported that the percent positive needle biopsy cores is a strong predictor of pathologic stage (44–46) and an independent predictor of positive surgical margins (47,48). Merrick et al. (12) evaluated hormone-naïve low-, intermediate-, and high-risk brachytherapy patients stratiﬁed by the percent positive biopsies. Although the percent positive biopsies strongly correlated with risk group, when each group was stratiﬁed into the percent positive biopsy categories of <34%, 34–50%, and >50%, there was no statistical difference in biochemical outcome for any of the biopsy subgroups, although a trend for decreased disease-free survival was reported (12). These favorable brachytherapy results were attributed to a treatment philosophy that aggressively irradiated the extracapsular regions including the base of seminal vesicles with either supplemental XRT and/or extracapsular seeds. An aggressive locoregional approach that includes supplemental XRT and/or the utilization of generous preplanned periprostatic margins with the subsequent delivery of therapeutic doses to the prostate gland, extracapsular region, and base of seminal vesicles may improve biochemical outcome in patients with adverse pathologic features but a low risk of pelvic lymph node involvement (5–7). Consistent with pathologic evaluation of RP specimens showing that nearly all cases of EPE are limited to within 5 mm of the prostatic capsule, brachytherapy with or without supplemental XRT should be able to sterilize EPE (5–7,24,25).

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Dose Escalation The second rationale for adding supplemental XRT is to increase the intraprostatic and extraprostatic dose distributions. Unfortunately, the precise intraprostatic and extraprostatic cancercidal doses, either with brachytherapy alone or combined with supplemental XRT, are unclear because the cancercidal doses for gross and microscopic disease are unknown. Although tempting in its simplicity, the addition of brachytherapy and XRT doses is not radiobiologically legitimate. Orton and Webber (49) estimated dose translations between radiation modalities; however, such estimates are plagued by absence of confirmation of the validity of the radiobiologic parameters used in such calculations. Simpler estimates, expressed as percent of full monotherapy doses, suggest that the biologic effect of combined modality therapy may be higher than monotherapeutic brachytherapy or definitive doses of XRT. If one assumes that the Pd-103 monotherapeutic dose is 125 Gy and the monotherapeutic XRT dose is 80 Gy, a boost dose of 90 Gy represents 72% of the monotherapeutic brachytherapy dose; 45 Gy of supplemental XRT represents 56% of the definitive beam dose. When combined, the brachytherapy boost and supplemental XRT doses total 128% of a monotherapeutic prescription.

Inadequate Implants There are two causes for technically inadequate implants—poor technique (including inadequate brachytherapy treatment plans and/or poor intraoperative technique) and/or implant-related edema. When compared with other seed-loading philosophies, our modiﬁed uniform/peripheral approach results in the most homogeneic dose distribution throughout the target volume (prostate gland and extracapsular region), is least dependent on seed migration, and is relatively independent of brachytherapy-related edema (28,50,51). Although implant-related edema occurs in all cases (52,53), the use of treatment margins minimizes the effect of edema (54,55). Regardless, on d 0 computed tomography (CT)-based dosimetry, some segments of the prostate gland may have a less than desired treatment margin (7,50,51,56–58). Fortunately, the d 0 CTdetermined periprostatic margin represents a minimal value that increases with time (56). Adding supplemental XRT adds several millimeters to the periprostatic margin, thus decreasing the clinical impact of a technically inadequate implant and/or treatment-related edema. In contrast, implants with d 0 CT-determined treatment margins of 5 mm or greater may not beneﬁt from the addition of supplemental XRT (7,58).

THE INTERRELATIONSHIP BETWEEN BRACHYTHERAPY TREATMENT PLANNING AND THE NEED FOR SUPPLEMENTAL XRT Favorable brachytherapy results have been obtained with a variety of planning and intraoperative techniques. It is universally accepted that an adequate implant should encompass the prostate, but there is no consensus as to what represents the optimal target volume. Although multiple seed-loading philosophies have been utilized, an American Brachytherapy Society (ABS) survey reported that 75% of brachytherapists used modiﬁed peripheral loading, and 25% used modiﬁed uniform approaches (59). Only 61% of brachytherapists utilized periprostatic margins, with 5 mm being most common, and only 63% implanted seeds in the periprostatic region (59). The beneﬁcial effect of supplemental XRT may be to some extent dependent on the deﬁnition of the target volume (i.e., margins vs no margins).

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Table 2 Mean Dosimetric Margins From the Prostate Capsule to Selected Isodose Lines 100% isodose

90% isodose

125I

125I

103Pd

Margin (mm ± SD) 6.8 ± 1.6 6.3 ± 1.9 Isotope p-value 0.056 Mean isodose margin 6.5 ± 1.8 (mm ± SD)

103Pd

8.1 ± 1.6 7.5 ± 1.7 0.015 7.8 ± 1.6

75% isodose 125I

103Pd

10.1 ± 1.7 9.1 ± 1.7 <0.001 9.6 ± 1.8

Data from ref. 7.

In our preplanned approach, the planning target volume (PTV; the prostate gland with a periprostatic margin) is determined by a 3–8-mm enlargement of each ultrasound slice, with a resultant PTV approx 1.8 times the ultrasound volume (5–7,50,51). The rationale for this additional margin is based on pathologic measures of the probability of microscopic extracapsular extension (24–26) and estimates that seed placement uncertainty is approx 5 mm longitudinally and 3 mm in transverse directions (60). Our approach places up to 40% of seeds in periprostatic regions with a long-term ﬁxity (or persistence) of >98% for Pd-103 Theraseed (Theragenics, Norcross, GA) or I-125 RapidStrand (Amersham Health, Princeton, NJ) (28,50,51). Investigators at Thomas Jefferson University have also reported the ability to treat the periprostatic region aggressively (61). The determination to use 3–8-mm margins was in part based on recent studies reporting that it is rare for EPE to extend more than a few millimeters from the prostate capsule (24,25). Both of these studies suggested that a periprostatic brachytherapy margin of 5 mm should encompass 99% of all specimens. One caveat to what appears to be adequate periprostatic margins via these two RP pathology studies is that all margins were evaluated by hematoxylin and eosin (H&E) staining, but H&E may not adequately deﬁne the radial EPE extent. The determination of molecular margins after RP has brought into question the validity of extracapsular extension and surgical margin assessment by standard H&E staining (62,63). Even if H&E techniques do not adequately assess true margins and the radial extent of disease in the periprostatic region, Davis and colleagues (64) have reported a ratio of extraprostatic to intraprostatic cancer of 0.4%. Thus, doses signiﬁcantly less than prescription would be likely to control such low volume disease. Via d 0 CT-based dosimetry, mean postimplant treatment margins for the 100, 90, and 75% isodose lines were 6.5, 7.8, and 9.6 mm, respectively (7) (Table 2). The 100% isodose margin exceeded 5 mm around the lateral and anterior periphery with the notable exception of the area near the bladder neck (7). Posterior margins for the 100% isodose line were usually < 5 mm for Pd-103 but normally > 5 mm for I-125. These dosimetric margins have not resulted in any increased urinary, rectal, or sexual toxicity compared with brachytherapy techniques that do not utilize generous periprostatic margins (3). Treatment margins can vary markedly between patients, even those with comparable dosimetric parameters (i.e., V100—the percent of the prostate volume receiving 100% of the prescribed minimum peripheral dose; and D90—the minimum dose received by 90% of the prostate gland). Day 0 dosimetric results from an ongoing prospective randomized trial have shown that brachytherapy treatment margins outperform other dosimetric

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Fig. 2. Left, midgland slice of the CT-determined seed distribution and prostate volume. Right, the corresponding isodose plot illustrating the margins determined for the 100, 90, and 75% isodose lines relative to the shaded prostate. Tick marks along the crossed axes are at 10-mm increments in both sets of images.

parameters (V100 and D90) in predicting the 3-yr PSA response after prostate brachytherapy (65) (Fig. 2). If implants are designed and executed with generous periprostatic margins, the determination of postimplant CT prostate volumes does not signiﬁcantly inﬂuence the traditionally assessed dosimetric parameters, i.e., V100, D90, V150, and V200 (the percent prostate volume receiving 150 and 200% of the prescribed minimum peripheral dose) (27). In addition, brachytherapy plans consisting of prostate with margin minimize any dosimetric difference between the 2 isotopes (5,6). Biochemical disease-free survival has been correlated with the radiation dose delivered to 90% of the target volume (D90) (30). Since the radiation therapy dose decreases by up to 20 Gy/mm at the periphery of the target volume (29), the utilization of treatment planning margins further increases the conﬁdence that a therapeutic radiation dose will be consistently delivered to the periprostatic region. Yu et al. (66) reported that the use of extraprostatic seeds signiﬁcantly increases the volume of extraprostatic tissue treated compared with implant philosophies that exclusively utilize intraprostatic seeds. This phenomenon may partially explain the fact that in programs routinely implanting the prostate gland with a periprostatic margin, the addition of supplemental XRT may not improve outcome for low-, intermediate-, or even selected high-risk patients (20). When stratiﬁed in terms of preimplant PSA, the 5-yr biochemical no evidence of disease (NED) survival rates for a monotherapeutic approach and an approach that includes supplemental XRT with the brachytherapy dose calculated to the prostatic capsule without margin are virtually superimposable (20,67). Because the vast majority of prostate cancer is intraprostatic (64), it is reasonable to assume that the control of extraprostatic cancer should be at least as good as the intraprostatic component if the radiation doses delivered to the intra- and extraprostatic sites are comparable.

BIOCHEMICAL OUTCOMES Low Risk In contemporary series, brachytherapy as a monotherapeutic approach for patients with low-risk features (Gleason score ≤ 6, PSA ≤ 10 ng/mL, and clinical stage T1c-T2b

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2002 AJCC) has resulted in high rates of biochemical control without further improvement following the addition of supplemental XRT. With 5- to 10-yr follow-up, biochemical disease-free (bNED) survival rates of 87–96% have been reported (8,20,67–75). Grimm and colleagues (74) reported the presence of a learning curve by demonstrating signiﬁcant differences in progression-free survival in low-risk patients stratiﬁed into 1986–1987 vs 1988–1990 cohorts. This ﬁnding probably explains the poorer results of the earlier Seattle series in which patients who received supplemental XRT in conjunction with brachytherapy (“spackle” effect) had improved bNED survival despite poorer prognosticators (76,77). Ragde et al. (77) reported a 60% 10-yr bNED survival rate (PSA ≤ 0.5 ng/mL) for the ﬁrst 95 monotherapy patients implanted in the Seattle series without a plateau on the disease-free survival curve. Twenty-one percent (20/95) of these monotherapy patients presented with a pretreatment PSA >10 ng/mL. The absence of a plateau is probably a result of suboptimal radiation coverage owing to inexperience. In the early Seattle series, supplemental XRT apparently “spackled” dose deﬁciencies in the implant volume. This is partially supported by the fact that subsequent studies of low-risk patients in Seattle undergoing monotherapeutic brachytherapy had markedly superior outcomes (73,74). When stratiﬁed in terms of pretreatment PSA, biochemical disease-free survival curves for monotherapeutic brachytherapy with treatment margins and an approach that utilizes supplemental XRT without treatment margins are virtually superimposable (20,67,78).

Intermediate Risk For patients with intermediate-risk disease (Gleason score ≥ 7 or PSA ≥ 10 ng/mL or clinical stage ≥ T2b 2002 AJCC), Blasko and colleagues (20) reported a 9-yr freedom from biochemical progression rate of 82% with a plateau on the curve for a Pd-103 monotherapeutic approach. The addition of supplemental XRT to brachytherapy did not improve the 5-yr biochemical outcome for intermediate-risk patients (84% vs 85%) (79). For hormone-naïve intermediate-risk and Gleason score 7 patients managed with supplemental XRT and brachytherapy, Merrick and colleagues (80,82) reported 6-yr actuarial bNED survival rates of 97% and 90%, respectively, with a median post-treatment PSA < 0.1 ng/mL. Approximately 20% of these intermediate-risk and Gleason score 7 patients underwent monotherapeutic brachytherapy without a detrimental effect on biochemical outcome. When these data are taken together, no biochemical advantage has been reported for the addition of supplemental XRT in hormone-naïve intermediate-risk patients implanted with generous periprostatic margins (20,79–82).

High Risk For high-risk patients two or three of the following risk factors: Gleason score ≥ 7, PSA ≥ 10 ng/mL, and/or clinical stage ≥ T2b, 2002 AJCC), Dattoli and colleagues (10,13) reported a 79% 10-yr bNED survival rate (PSA ≤ 0.2 ng/mL) for patients receiving supplemental XRT followed by a Pd-103 boost with the suggestion of a plateau on the biochemical freedom from failure curves within 3 yr of implantation. For hormone-naïve high-risk patients receiving brachytherapy and supplemental XRT, Merrick and colleagues (9,81) reported an 80% 6-yr freedom from biochemical failure rate with a median post-treatment PSA of < 0.1 ng/mL. In addition, an 84% 7-yr biochemical disease-free survival rate (PSA ≤ 0.4 ng/mL) has been reported for Gleason score 8 and 9 prostate cancer patients (median pretreatment PSA 7.7 ng/mL) who underwent Pd-103 brachytherapy and supplemental XRT (83). Twenty-eight percent of

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those patients received short-term (≤ 6 mo) hormonal therapy, and the other 72% were hormone-naïve. Two studies have reported favorable results for high-risk patients undergoing monotherapeutic brachytherapy. Blasko and colleagues (20) reported a 65% 9-yr freedom from biochemical progression rate for Pd-103 monotherapy patients with a pretreatment PSA > 20 ng/mL. Lee et al. (23) stratiﬁed high-risk brachytherapy patients undergoing brachytherapy without supplemental XRT into “low-dose” (d 30 D90 < 140 Gy for I-125 and < 100 Gy for Pd-103) vs “high-dose” implants, with an 80% 5-yr freedom from biochemical failure rate in the high-dose arm (23).

Conﬂicting Results Almost all studies of intermediate- and high-risk brachytherapy patients receiving supplemental XRT have reported favorable biochemical outcomes. However, the biochemical outcome data are fraught with conﬂicting outcomes for intermediate- and high-risk patients undergoing monotherapeutic brachytherapy. Brachman and colleagues (84) reported 5-yr bNED survival rates of 53% for pretreatment PSA levels of 10–20 ng/mL and 28% for Gleason score 7 following monotherapeutic brachytherapy. Following Pd-103 monotherapy, D’Amico and colleagues (85) reported 35% and projected 0% 5-yr rates of biochemical NED survival for intermediate- and high-risk patients. In addition, Kwok et al. (86) reported 5-yr freedom from biochemical progression rates of 63% and 24% for intermediate- and high-risk patients undergoing I125 monotherapeutic brachytherapy. Most importantly, in none of these three monotherapeutic studies were extraprostatic seeds utilized nor were postimplant dosimetric outcomes reported. It is likely that cancer eradication in intermediate- and high-risk brachytherapy patients, especially those undergoing a monotherapeutic approach, requires meticulous technique, generous periprostatic margins, the placement of multiple periprostatic seeds, and postimplant dosimetric conﬁrmation of adequate radiation dose distributions (7,50,51,61). In the absence of any of these criteria, the utilization of supplemental XRT may be mandatory for the securement of durable biochemical outcomes (Fig. 3).

CLINICAL TRIALS To investigate what may be the most appropriate dose of supplemental XRT in Pd103 patients implanted with 5-mm periprostatic margins, the University of Washington and the Schifﬂer Cancer Center are conducting a large prospective randomized study comparing different dose regimens. In this study, patients are randomized to either 44 Gy of supplemental XRT followed by a conventional Pd-103 boost (90 Gy) or 20 Gy of supplemental XRT followed by a dose-escalated Pd-103 boost (115 Gy) (Fig. 4). The rationale for this trial is that brachytherapy treatment margins may obviate the need for higher dose supplemental XRT. Endpoints of the study include biochemical outcome and quality of life parameters including urinary, bowel, and sexual function. Biochemical results are expected in 2004. If this study shows no difference in biochemical outcome between the treatment arms, low-dose supplemental XRT will be compared with a monotherapeutic approach. Additional questions regarding supplemental XRT that deserve consideration of prospective study include sequencing, time gaps, isotope choice, and beam ﬁeld sizes. To date, these issues have been approached empirically with no basis in comparative trials.

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⊗

Fig. 3. Biochemical no evidence of disease (bNED) survival in hormone-naïve, high-risk patients treated with brachytherapy. After each author, the notation M or ∅ M means the presence or absence of signiﬁcant dosimetric treatment margin, and B or ∅ B means the presence or absence of supplemental external beam radiation therapy. Data are from Blasko et al. (20), D’Amico et al. (84), Dattoli et al. (4), and Merrick et al. (11). ⊗

Fig. 4. Outline of the University of Washington (Seattle) and Schifﬂer Cancer Center (Wheeling) randomized trial for prostate cancer patients with higher risk features. PSA, prostate-speciﬁc antigen.

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MORBIDITY Urinary Although supplemental XRT is utilized in a large percentage of brachytherapy patients, its impact on long-term urinary function has not been completely elucidated. Recently, a long-term urinary function study using the patient-administered urinary domain of the Expanded Prostate Cancer Index Composite (EPIC) revealed that supplemental XRT adversely affected the urinary function and incontinence domains but did not alter the irritation/obstruction or bother scores (87). In addition, in an ongoing prospective randomized trial, supplemental XRT has been reported to increase the risk of late hematuria (88). To date, supplemental XRT has not been implicated in any additional deleterious urinary effects including catheter dependency, the need for postimplant surgical intervention, urethral strictures, or prolonged International Prostate Symptom Score (I-PSS) elevation.

Rectal Problems In three studies the use of supplemental XRT has been shown to result in minimal but detectable long-term bowel dysfunction; two additional studies do not support such an association (89–93). These equivocal results indicate that modern brachytherapy techniques provide sufﬁcient dosimetric sparing of the rectum, with subsequent severe rectal complications a rarity. For patients receiving high-dose 3D-CRT, Jackson et al. (94) reported an independent association with larger percent volumes exposed to intermediate doses (approx 46 Gy) and the development of rectal bleeding. They hypothesized that a “large surrounding region of intermediate dose may interfere with the ability to repair the effects of a central high dose region.” This may explain the deleterious effect of supplemental XRT in some brachytherapy series.

Erectile Dysfunction The addition of supplemental XRT increases the incidence of brachytherapy-induced erectile dysfunction (ED) (95–100). Using the patient-administered International Index of Erectile Function-5 (IIEF-5), Merrick and colleagues (95,96) reported that the addition of supplemental XRT decreased the 6-yr actuarial rate of potency preservation from 52% to 26% (Fig. 5). Radiation dose to the proximal penis has been implicated in the development of radiation-induced ED (97,98,101). It is conceivable that higher doses of radiation are delivered to the proximal penis with the combination of brachytherapy and supplemental XRT compared with brachytherapy alone. Fortunately, most cases of brachytherapy-induced ED respond favorably to sildenaﬁl citrate (102).

COST The avoidance of hospitalization and prolonged XRT with brachytherapy was assumed to offer substantial cost savings in the treatment of prostate cancer; however, cost investigators have typically concluded that brachytherapy is more expensive than prostatectomy (103–106). However, the elimination/limitation of supplemental XRT would signiﬁcantly reduce the cost of brachytherapy (4). As illustrated in Fig. 6, traditional supplemental XRT (45 Gy over 5 wk) with a brachytherapy boost costs approx twice that of monotherapeutic brachytherapy and is at least 50% greater than Medicare fees for dose-escalated XRT (80 Gy) and radical prostatectomy (4). Most importantly,

Fig. 5. Rate of potency preservation stratiﬁed between monotherapy implant patients (censored patients marked with Is) and combined modality external beam plus implant patients (censored patients marked with Xs). The difference between long-term potency preservation in the two cohorts is statistically signiﬁcant.

Fig. 6. Approximate physician and hospital charges for radical prostatectomy (surgery), external beam radiation therapy (XRT), permanent seed brachytherapy (implant), and combined external beam plus brachytherapy. (Adapted from ref. 4.)

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the ultimate cost of any medical/surgical procedure is dictated not by up-front costs, but rather by complications and failures (107). Thus, if brachytherapy for intermediate- and high-risk patients is executed without generous periprostatic margins, the use of supplemental XRT (although more expensive initially) would remain cost-effective.

CONCLUSIONS Generous periprostatic margins (accomplished via either extracapsular seed placement or supplemental XRT) are of great utility in patients with any risk of extracapsular extension and a low risk of pelvic lymph node involvement/distant metastases. For patients with intermediate- and high-risk disease undergoing brachytherapy, the addition of supplemental XRT remains the standard of care. However, generous brachytherapy treatment margins may obviate the need for combined modality therapy for low-, intermediate- and selected high-risk patients. If generous treatment margins are not used in patients with intermediate- and high-risk disease, supplemental XRT may be mandatory to secure durable biochemical outcomes. Monotherapeutic brachytherapy volume dose escalation has been safely obtained with acceptable rates of urinary, bowel, and sexual function. Although long-term morbidity following brachytherapy has been acceptable, some data suggest that morbidity is greater with supplemental XRT. Continued reﬁnements in implant technique and patient selection, along with continued maturation of the biochemical and quality of life outcomes data will hopefully result in further reﬁnement of the role of supplemental XRT in brachytherapy.

REFERENCES 1. Merrick GS, Wallner KE, Butler WM. Permanent interstitial brachytherapy in the management of carcinoma of the prostate gland. J Urol 2003;5:1643–1652. 2. Merrick GS, Butler WM, Lief JH, et al. Permanent prostate brachytherapy: do prostatectomy and external beam measure up? J Brachyther Int 2001;17:189–204. 3. Merrick GS, Wallner KE, Butler WM. Minimizing prostate brachytherapy-related morbidity. Urology 2003;62:786–792. 4. Wallner KE, Blasko JC, Dattoli MJ, eds. SmartMedicine: Prostate Brachytherapy Made Complicated, 2nd ed. SmartMedicine Press, Seattle, 2001. 5. Merrick GS, Butler WM, Dorsey AT, et al. Potential role of various dosimetric quality indicators in prostate brachytherapy. Int J Radiat Oncol Biol Phys 1999;44:717–724. 6. Merrick GS, Butler WM, Dorsey AT, et al. The effect of prostate size and isotope selection on dosimetric quality following permanent seed implantation. Tech Urol 2001;7:233–240. 7. Merrick GS, Butler WM, Wallner KE, et al. Extracapsular radiation dose distribution following permanent prostate brachytherapy. Am J Clin Oncol 2003;26:E178–E189. 8. Merrick GS, Butler WM, Lief JH, et al. Five-year biochemical outcome after prostate brachytherapy for hormone-naïve men ≤ 62 years of age. Int J Radiat Oncol Biol Phys 2001;50:1253–1257. 9. Merrick GS, Butler WM, Lief JH, et al. Biochemical outcome for hormone naïve patients with high risk prostate cancer managed with permanent interstitial brachytherapy and supplemental external beam radiation. Cancer J Sci Am 2002;8:322–327. 10. Dattoli M, Wallner K, True L, et al. Prognostic role of serum prostatic acid phosphatase for 103Pdbased radiation for prostatic carcinoma. Int J Radiat Oncol Biol Phys 1999;45:853–856. 11. Merrick GS, Butler WM, Galbreath RW, et al. Perineural invasion is not predictive of biochemical outcome following prostate brachytherapy. Cancer J Sci Am 2001;7:404–412. 12. Merrick GS, Butler WM, Galbreath RW, et al. The relationship between percent positive biopsies and biochemical outcome following permanent interstitial brachytherapy for clinically organ-conﬁned carcinoma of the prostate gland. Int J Radiat Oncol Biol Phys 2002;52:664–673. 13. Dattoli M, Wallner K, True L, et al. Long-term outcomes after treatment with external beam radiation therapy and palladium 103 for patients with higher risk prostate carcinoma. Cancer 2003;97:979–983.

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14. Dattoli M, Wallner K, Sorace R, et al. 103Pd brachytherapy and external beam irradiation for clinically localized high-risk prostatic carcinoma. Int J Radiat Oncol Biol Phys 1996;35:875–879. 15. Blasko JC, Grimm PD, Ragde H. Brachytherapy and organ preservation in the management of carcinoma of the prostate. Semin Radiat Oncol 1993;3:240–249. 16. Blasko JC, Mate T, Sylvester JE, et al. Brachytherapy for carcinoma of the prostate: techniques, patient selection, and clinical outcomes. Semin Radiat Oncol 2002;12:81–94. 17. Syed AM, Puthawala A, Austin P, et al. Temporary iridium-192 implant in the management of carcinoma of the prostate. Cancer 1992;69:2515–2524. 18. Mate TP, Gottesman JE, Hatton J, et al. High dosed-rate after-loading iridium-192 prostate brachytherapy: feasibility report. Int J Radiat Oncol Biol Phys 1998;41:525–533. 19. Martinez A, Gonzalez J, Spencer W, et al. Conformal high dose rate brachytherapy improves biochemical control and cause speciﬁc survival in patients with prostate cancer and poor prognostic factors. J Urol 2003;169:974–980. 20. Blasko JC, Grimm PD, Sylvester JE, et al. Palladium-103 brachytherapy for prostate carcinoma. Int J Radiat Oncol Biol Phys 2000;46:839–850. 21. Sharkey J, Chovnick SD, Behar RJ, et al. Minimally invasive treatment for localized adenocarcinoma of the prostate: review of 1048 patients treated with ultrasound-guided palladium-103 brachytherapy. J Endourol 2000;14:343–350. 22. Sharkey J, Chovnick SD, Behar RJ, et al. Outpatient ultrasound-guided palladium 103 brachytherapy for localized adenocarcinoma of the prostate: a preliminary report of 434 patients. Urology 1998;51:796–803. 23. Lee LN, Stock RG, Stone NN. Role of hormonal therapy in the management of intermediate- to highrisk prostate cancer treated with permanent radioactive seed implantation. Int J Radiat Oncol Biol Phys 2002;52:444–452. 24. Davis BJ, Pisansky TM, Wilson TM, et al. The radial distance of extraprostatic extension of prostate carcinoma: implications for prostate brachytherapy. Cancer 1999;85:2630–2637. 25. Sohayda C, Kupelian PA, Levin HS, et al. Extent of extracapsular extension in localized prostate cancer. Urology 2000;55:382–386. 26. Partin AW, Mangold LA, Lamm DA, et al. Contemporary update of prostate cancer staging nomograms (Partin tables) for the new millenium. Urology 2001;58:843–848. 27. Merrick GS, Butler WM, Dorsey AT, et al. The dependence of prostate postimplant dosimetric quality on CT volume determination. Int J Radiat Oncol Biol Phys 1999;44:1111–1117. 28. Merrick GS, Butler WM, Dorsey AT, et al. Seed ﬁxity in the prostate/periprostatic region following brachytherapy. Int J Radiat Oncol Biol Phys 2000;46:215–220. 29. Dawson JE, Wu T, Roy T, et al. Dose effects of seed placement deviations from preplanned positions in ultrasound guided prostate implants. Radiother Oncol 1994;32:268–270. 30. Stock RG, Stone NN, Tabert A, et al. A dose-response study for I-125 prostate implants. Int J Radiat Oncol Biol Phys 1998;41:101–108. 31. Stone NN, Stock RG, Parikh D, et al. Perineural invasion and seminal vesicle involvement predict lymph node metastasis in men with localized carcinoma of the prostate. J Urol 1998;160:1722–1726. 32. Vargas SO, Jiroutek M, Welch WR, et al. Perineural invasion in prostate needle biopsy specimens. Am J Clin Pathol 1999;111:223–228. 33. De la Taille A, Rubin MA, Bagiella E, et al. Can perineural invasion on prostate needle biopsy predict prostate speciﬁc antigen recurrence after radical prostatectomy? J Urol 1999;162:103–106. 34. Rubin MA, Bassily N, Sanda M, et al. Relationship and significance of greatest percentage of tumor and perineural invasion on needle biopsy in prostatic adenocarcinoma. Am J Surg Pathol 2000;24:183–189. 35. Endrizzy J, Seay T. The relationship between early biochemical failure and perineural invasion in pathological T2 prostate cancer. BJU Int 2000;85:696–698. 36. Egan AJ, Bostwick DG. Prediction of extraprostatic extension of prostate cancer based on needle biopsy ﬁndings: perineural invasion lacks signiﬁcance on multivariate analysis. Am J Surg Pathol 1997;21:1496–1500. 37. Epstein JI. The role of perineural invasion and other biopsy characteristics as prognostic markers for localized prostate cancer. Semin Urol Oncol 1998;16:124–128. 38. O’Malley KJ, Pound CR, Walsh PC, et al. Inﬂuence of biopsy perineural invasion on long-term biochemical disease-free survival after radical prostatectomy. Urology 2002;59:85–90. 39. Bonin SR, Hanlon AL, Lee WR, et al. Evidence of increased failure in the treatment of prostate carcinoma patients who have perineural invasion treated with three-dimensional conformal radiation therapy. Cancer 1997;79:75–80.

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40. Grann A, Gaudin PB, Raben A, et al. Pathologic features from prostate needle biopsy and prognosis after I-125 brachytherapy. Radiat Oncol Invest 1998;6:170–174. 41. D’Amico AV, Whittington R, Malkowica SB, et al. Clinical utility of the percentage of positive prostate biopsies in deﬁning biochemical outcome after radical prostatectomy for patients with clinically localized prostate cancer. J Clin Oncol 2000;18:1164–1172. 42. D’Amico AV, Whittington R, Malkowica SB, et al. Clinical utility of percent-positive prostate biopsies in deﬁning biochemical outcome after radical prostatectomy or external beam radiation therapy for patients with clinically localized prostate cancer. Mol Urol 2000;4:171–175. 43. D’Amico AV, Schultz D, Silver B, et al. The clinical utility of the percent of positive prostate biopsies in deﬁning biochemical outcome following external-beam radiation therapy for patients with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2001;49:679–684. 44. Sebo TJ, Bock BJ, Cheville JC, et al. The percent of cores positive for cancer in prostate needle biopsy specimens is strongly predictive of tumor stage and volume at radical prostatectomy. J Urol 2000;163:174–178. 45. Wills ML, Sauvageot J, Partin AW, et al. Ability of sextant biopsies to predict radical prostatectomy stage. Urology 1998;51:759–764. 46. Grossfeld GD, Chang JJ, Broering JM, et al. Under staging and under grading in a contemporary series of patients undergoing radical prostatectomy: results from the cancer of the prostate strategic urologic research endeavor database. J Urol 2001;165:851–856. 47. Tigrani VS, Bhargava V, Shinohara K, et al. Number of positive systemic sextant biopsies predicts surgical margin status at radical prostatectomy. Urology 1999;54:689–693. 48. Gao X, Mohideen N, Glanigan RC, et al. The extent of biopsy involvement as an independent predictor of extraprostatic extension and surgical margin status in low risk prostate cancer: implications for treatment selection. J Urol 2000;164:1982–1986. 49. Orton CG, Webber BM. Time-dose factor (TDF) analysis of dose rate effects in permanent implant dosimetry. Int J Radiat Oncol Biol Phys 1997;2:55–60. 50. Butler WM, Merrick GS, Lief JH, et al. Comparison of seed loading approaches in prostate brachytherapy. Med Phys 2000;27:381–392. 51. Merrick GS, Butler WM. Modiﬁed uniform seed loading for prostate brachytherapy: rationale, design, and evaluation. Tech Urol 2000;6:78–84. 52. Badiozamani K, Wallner K, Sutlief S, et al. Anticipating prostatic volume changes due to prostate brachytherapy. Radiat Oncol Invest 1999;7:360–364. 53. Merrick GS, Butler WM, Dorsey AT, et al. Inﬂuence of prophylactic dexamethasone on edema following prostate brachytherapy. Tech Urol 2000;6:117–122. 54. Waterman FM, Dicker AP. Impact of postimplant edema on V100 and D90 in prostate brachytherapy: can implant quality be predicted on day? Int J Radiat Oncol Biol Phys 2002;53:610–621. 55. Butler WM, Merrick GS, Dorsey AT, et al. Isotope choice and the effect of edema on prostate brachytherapy dosimetry. Med Phys 2000;27:1067–1075. 56. Corriveau J, Wallner K, Merrick G, et al. Effect of post-implant edema on treatment margin measurements after prostate brachytherapy. Int J Radiat Oncol Phys 2004; in press.. 57. Mueller A, Wallner K, Merrick G, et al. Modiﬁcation of prostate implants based on postimplant treatment margin assessment. Med Phys 2002;29:2782–2787. 58. Han B, Wallner K, Aggarwal S, et al. Treatment margins for prostate brachytherapy. Semin Urol Oncol 2000;18:137–141. 59. Prete JJ, Prestidge BR, Bice WS, et al. A survey of physics and dosimetry practice of permanent prostate brachytherapy in the United States. Int J Radiat Oncol Biol Phys 1998;40:1001–1005. 60. Roberson PL, Narayana V, McShan DL, et al. Source placement error for permanent implant of the prostate. Med Phys 1997;24:251–257. 61. Butzbach D, Waterman FM, Dicker AP. Can extraprostatic extension be treated by prostate brachytherapy? An analysis based on postimplant dosimetry. Int J Radiat Oncol Biol Phys 2001;51:1196–1199. 62. Theodorescu D, Frierson Jr HF, Sikes RA. Molecular determination of surgical margins using fossa biopsies at radical prostatectomy. J Urol 1999;161:1442–1448. 63. Straub B, Muller M, Goessl C, et al. Reverse transcriptase-polymerase chain reaction for prostatespeciﬁc antigen in the molecular staging of pelvic surgical margins after radical prostatectomy. Urology 2001;57:1006–1011. 64. Davis BJ, Haddock MG, Wilson TM, et al. Treatment of extraprostatic cancer in clinically organ-conﬁned prostate cancer by permanent interstitial brachytherapy: is extraprostatic seed placement necessary? Tech Urol 2000;6:70–77.

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65. Wallner K, Merrick G, Butler W. Treatment margins predict three-year PSA response after Pd-103 prostate brachytherapy. Brachytherapy 2004; in press. 66. Yu Y, Waterman FM, Suntharalingam N, et al. Limitations of the minimum peripheral dose as a parameter for dose speciﬁcation in permanent I-125 prostate implants. Int J Radiat Oncol Biol Phys 1996;34:717–725. 67. Critz FA, Williams WH, Levinson AK, et al. Simultaneous irradiation for prostate cancer: intermediate results with modern techniques. J Urol 2000;164:738–743. 68. Blasko JC, Wallner K, Grimm PD, et al. Prostate speciﬁc antigen based disease control following ultrasound guided 125iodine implantation for stage T1/T2 prostate carcinoma. J Urol 1995;154:1096–1099. 69. Merrick GS, Butler WM, Galbreath RW, et al. 5-year biochemical outcome following permanent interstitial brachytherapy for clinical T1–T3 prostate cancer. Int J Radiat Oncol Biol Phys 2001;51:41–48. 70. Potters L, Cha C, Oshinsky G, et al. Risk proﬁles to predict PSA relapse-free survival for patients undergoing permanent prostate brachytherapy. Cancer J Sci Am 1999;5:301–306. 71. Zelefsky MJ, Hollister T, Raben A, et al. Five-year biochemical outcome and toxicity with transperineal CT-planned permanent I-125 prostate implantation for patients with localized prostate cancer. Int J Radiat Oncol Biol Phys 2000;47:1261–1266. 72. Zelefsky MJ, Wallner KE, Ling CC, et al. Comparison of the 5-year outcome and morbidity of threedimensional conformal radiotherapy versus transperineal permanent iodine-125 implantation for early-stage prostatic cancer. J Clin Oncol 1999;17:517–522. 73. Ragde H, Blasko JC, Grimm PD, et al. Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer 1997;80:442–453. 74. Grimm PD, Blasko JC, Sylvester JE, et al. 10-year biochemical (prostate-speciﬁc antigen) control of prostate cancer with 125I brachytherapy. Int J Radiat Oncol Biol Phys 2001;51:31–40. 75. Sharkey J, Chovnik SD, Behar RJ, et al. Outpatient ultrasound-guided palladium 103 brachytherapy for localized adenocarcinoma of the prostate: a preliminary report of 434 patients. Urology 1998;51:796–803. 76. Ragde H, Korb L, Elgamal A, et al. Modern prostate brachytherapy. Cancer 2000;89:135–141. 77. Ragde H, Elgamal AA, Snow PB, et al. Ten-year disease free survival after transperineal sonographyguided iodine-125 brachytherapy with or without 45-gray external beam irradiation in the treatment of patients with clinically localized, low to high Gleason’s grade, prostate carcinoma. Cancer 1998;83:989–1001. 78. Critz FA, Levinson AK, Williams WH, et al. Simultaneous radiotherapy for prostate cancer: 125I prostate implant followed by external beam radiation. Cancer J Sci Am 1998;4:359–363. 79. Blasko JC, Grimm PD, Sylvester JE, et al. The role of external beam radiotherapy with I-125/Pd-103 brachytherapy for prostate carcinoma. Radiother Oncol 2000;57:273–278. 80. Merrick GS, Butler WM, Lief JH, et al. Biochemical outcome for hormone-naïve intermediate-risk prostate cancer managed with permanent interstitial brachytherapy and supplemental external beam radiation. Brachytherapy 2002;1:95–101. 81. Merrick GS, Butler WM, Galbreath RW, et al. Does hormonal manipulation in conjunction with permanent interstitial brachytherapy, with or without supplemental external beam irradiation, improve the biochemical outcome for men with intermediate or high-risk prostate cancer? BJU Int 2003;91:23–29. 82. Merrick GS, Butler WM, Galbreath RW, et al. Biochemical outcome for hormone-naïve patients with Gleason score 3+4 versus 4+3 prostate cancer undergoing permanent prostate brachytherapy. Urology 2002;60:98–103. 83. Merrick GS, Butler WM, Wallner KE, et al. Biochemical outcome following a primary brachytherapy approach for Gleason score 8 and 9 prostate cancer with a pretreatment PSA < 20 ng/mL. Am J Clin Oncol 2004; in press. 84. Brachman DG, Thomas T, Hilbe J, et al. Failure-free survival following brachytherapy alone or external beam irradiation alone for T1–2 prostate tumors in 2222 patients: results from a single practice. Int J Radiat Oncol Biol Phys 2000;48:111–117. 85. D’Amico AV, Whittington R, Malkowicz B, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969–974. 86. Kwok Y, DiBiase SJ, Amin PP, et al. Risk group stratiﬁcation in patients undergoing permanent 125I prostate brachytherapy as monotherapy. Int J Radiat Oncol Biol Phys 2002;53:588–594. 87. Merrick GS, Butler WM, Wallner KE, et al. Long-term urinary quality of life following permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2003;2:454–461.

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88. Barker J, Wallner K, Merrick G. Hematuria after prostate brachytherapy. Urology 2003;61:408–411. 89. Merrick GS, Butler WM, Dorsey AT, et al. Rectal function following prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000;48:667–674. 90. Kang SK, Chou RH, Dodge RK, et al. Gastrointestinal toxicity of transperineal interstitial prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002;53:99–103. 91. Merrick GS, Butler WM, Wallner KE, et al. Late rectal function following prostate brachytherapy. J Radiat Oncol Biol Phys 2003;1:42–48. 92. Gelblum DY, Potters L. Rectal complications associated with transperineal interstitial brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2000;48:119–124. 93. Merrick GS, Butler WM, Wallner KE, et al. Rectal function following brachytherapy: results of two prospective randomized trials. Int J Radiat Oncol Biol Phys 2003;57(2 Suppl):S230. 94. Jackson A, Skwarchuk MW, Zelefsky MJ, et al. Late rectal bleeding after conformal radiotherapy of prostate cancer (II): Volume effects and dose-volume histograms. Int J Radiat Oncol Biol Phys 2001;49:685–698. 95. Merrick GS, Butler WM, Galbreath RW, et al. Erectile function after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002;52:893–902. 96. Merrick GS, Wallner KE, Butler WM. Management of sexual dysfunction after prostate brachytherapy. Oncology 2003;17:52–62. 97. Merrick GS, Wallner K, Butler WM, et al. A comparison of radiation dose to the bulb of the penis in men with and without prostate brachytherapy-induced erectile dysfunction. Int J Radiat Oncol Biol Phys 2001;50:597–604. 98. Merrick GS, Butler WM, Wallner KE, et al. The importance of radiation doses to the penile bulb vs crura in the development of postbrachytherapy erectile dysfunction. Int J Radiat Oncol Biol Phys 2002;54:1055–1062. 99. Talcott JA, Clark JA, Stark PC, et al. Long-term treatment related complications of brachytherapy for early prostate cancer: a survey of patients previously treated. J Urol 2001;166:494–499. 100. Potters L, Torre T, Fearn PA, et al. Potency after permanent prostate brachytherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2001;50:1235–1242. 101. Fisch BM, Pickett B, Weinberg V, et al. Dose of radiation received by the bulb of the penis correlates with risk of impotence after three-dimensional conformal radiotherapy for prostate cancer. Urology 2001;57:955–959. 102. Merrick GS, Butler WM, Lief JH, et al. Efﬁcacy of sildenaﬁl citrate in prostate brachytherapy patients with erectile dysfunction. Urology 1999;53:1112–1116. 103. Wagner TT, Young D, Bahnson RR. Charge and length of hospital stay analysis of radical retropubic prostatectomy and transperineal prostate brachytherapy. J Urol 1999;161:1216–1218. 104. Ciezki JP, Klein EA, Angermeier KW, et al. Cost comparison of radical prostatectomy and transperineal brachytherapy for localized prostate cancer. Urology 2000;55:68–72. 105. Brandeis J, Pashos CL, Henning JM, et al. A nationwide charge comparison of the principal treatments for early stage prostate carcinoma. Cancer 2000;89:1792–1799. 106. Kohan AD, Armenakas NA, Fracchia JA. The perioperative charge equivalence of interstitial brachytherapy and radical prostatectomy with 1-year follow-up. J Urol 2000;163:511–514. 107. Wallner K. How to cut medical costs and cure cancer. SmartMedicine Press, Seattle, 2000.

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Health-Related Quality of Life Issues John T. Wei and David Miller

INTRODUCTION The physician’s primary responsibility in caring for a prostate cancer patient is to address the patient’s concerns regarding treatment and prognosis. Fortunately, the prognosis for prostate cancer, particularly for localized disease, is often favorable. Given that most patients will have survival measured in years, prostate cancer can reasonably be characterized as a “chronic” disease of aging (1). As with most chronic diseases, health-related quality of life (HRQOL) becomes a primary concern for the patient, and an appreciation of HRQOL outcomes plays a role in treatment decision making. The use of HRQOL as an endpoint for treatment has been increasingly emphasized in urologic and oncologic clinical trials as a means to differentiate between various therapies and to track disease progression (2–6). This chapter introduces state of the art concepts underlying the assessment of HRQOL, gives guidelines for selecting HRQOL instruments, and summarizes the contemporary literature related to prostate cancer HRQOL.

WHAT IS HEALTH-RELATED QUALITY OF LIFE? The utilization of rigorous HRQOL methods to evaluate prostate cancer outcomes is a relatively recent development (7–10). The term “quality of life” in the urologic literature has been used as a catch phrase to include studies of urinary symptoms and health function; however, more appropriately, HRQOL should represent the functional effects and impairment that an illness or its therapies have on a patient as perceived by that patient. This deﬁnition is particularly appropriate given that it is usually the therapies for prostate cancer that negatively impact patient quality of life, rather than manifestations of the disease. Increasingly, HRQOL endpoints are being included in clinical trials and studies. In many cases, funding agencies for large prostate cancer clinical research efforts require assessment of HRQOL, and a growing number of measures have been developed and validated to meet these demands (11–14). Research over the past decade has laid the foundation for HRQOL assessments in prostate cancer, and the From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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Fig. 1. Conceptualization of HRQOL for men with prostate cancer. Symptoms related to prostate cancer or its therapies will affect health functions (e.g., urinary function or sexual function). These perturbations then lead to impairment of normal activities that will have an impact on a patient’s overall HRQOL.

HRQOL literature on prostate cancer has grown exponentially. Consequently, clinicians and scientists alike need to become familiar with this discipline. In the broadest sense, assessment of HRQOL should include measures of generic HRQOL, cancer-speciﬁc aspects of quality of life, and prostate-speciﬁc quality of life (9,15). The common goal of HRQOL assessment is to measure changes or differences in physical, functional, psychological, and social health. A frequent application of HRQOL assessments is the evaluation of new programs or interventions (16). Although the measurement of HRQOL is relevant to most clinical research, ﬁndings should be considered in the context of a broader research paradigm that includes clinical outcomes such as biologic and physiologic measures (17). As described by Wilson and Cleary (17), health assessments should be considered on a continuum of biologic and physiologic factors that arise from the diagnosis and treatment of prostate cancer (Fig. 1). Speciﬁcally, symptoms resulting from prostate cancer, or associated treatment, may affect physiologic functions (e.g., urinary function or sexual function) that then lead to impairment of normal activities. In turn, these individual and collective processes will impact on a patient’s overall HRQOL. Hence, simultaneous assessment of symptoms, functions, and impairment will enhance the validity of HRQOL evaluations. Furthermore, various personal, motivational, and psychosocial factors may affect elements of this continuum. For example, postprostatectomy urinary incontinence is quite distressing to most men; however, the use of adaptive behaviors such as a small continence pad may decrease the level of impair-

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ment associated with this symptom. As the goal of health care in general is to improve patient outcomes, clinical research studies, by their design, should attempt to identify the causal links within this continuum; such reliable assessments of HRQOL are necessary to complement traditional clinical endpoints such as cancer control and survival. Measurement of HRQOL is complex and should not be undertaken lightly. The most common approach taken by researchers is to administer validated survey instruments (a.k.a. questionnaires or tools) that contain items (a.k.a. individual questions) that have been formulated to capture a speciﬁc aspect of a patient’s quality of life. However, it is important to recognize that HRQOL assessments are methodologically complex and require careful consideration of a number of factors, including the proper framework for assessing HRQOL, choice of survey instruments, mode of administration, and interpretation of ﬁndings.

RELIABILITY AND VALIDITY Whenever possible, HRQOL instruments should have demonstrable validity and reliability in order to ensure meaningful interpretation of the ﬁndings (18). In survey work, reliability is an estimate of the consistency in the measurements. In other words, reliability is a measure of the likelihood that an instrument will yield the same result on repeated trials without any signiﬁcant changes in the clinical condition. Validity is the concept that an instrument will measure the attributes that it was designed to measure. The validity of a measure is more difﬁcult to assess than the reliability, particularly in the absence of an external criterion or gold standard. There are several forms of validity (face, content, convergent, criterion, concurrent, and construct) and reliability (testretest, internal consistency, interobserver, and intraobserver). In the ideal sense, all survey instruments will have demonstrated all aspects of validity and reliability; however, this is seldom accomplished without years of instrument application and continued research. Practically speaking, a “valid” instrument is one that has demonstrated robust properties in several forms of validity and reliability but not necessarily all (18). When reading the literature, one must be cognizant of the many HRQOL studies that are based on homegrown questionnaires lacking reliability and validity (19). The practice of applying a subset of items from a previously validated instrument is fundamentally ﬂawed, as the items may not perform reliably when taken out of context. Currently, all properly designed clinical protocols should strive to utilize only validated instruments. Alternatively, there may be a reasonable plan to conduct the necessary psychometric testing of the instruments.

CONCEPTUAL FRAMEWORK HRQOL for men with prostate cancer is comprised of three components or levels: (1) generic health function; (2) cancer-speciﬁc HRQOL; and (3) prostate cancer-speciﬁc HRQOL (Fig. 2). The relative contribution of each of these components to the overall HRQOL will depend on the acuity of disease, current treatment, and disease status. Currently, several validated HRQOL instruments are appropriate for assessing each of these components. Generic measures of HRQOL are typically broad in scope and applicability. Several psychosocial domains are usually included, such as general health perceptions, satisfaction with health, social function, psychological function, physical function, and impairment. Several generic HRQOL instruments have been

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Fig. 2. Three components (levels) of HRQOL for men with prostate cancer. The relative contribution of each of these components to the overall HRQOL will depend on the acuity of disease, current therapy, and disease status.

described in the prostate cancer literature (Table 1). Of these, by far the most common is the Medical Outcomes Study Short Form 36 (SF 36) (7). To date, a number of investigators have demonstrated that generic HRQOL is impaired early on in the treatment course for prostate cancer. In an analysis from the prospective Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database, 449 men newly diagnosed (within 6 mo) with prostate cancer were compared with 1898 men who had previously been diagnosed (6 mo or more) (20–22). Newly diagnosed men were found to have uniformly lower health status in all but one (general health perceptions) of the SF 36 domains. This ﬁnding highlights the frequently substantial negative impact of a cancer diagnosis on global health function. However, health function can and does recover over time (23). In a separate study using the SF-36, Litwin et al. (3) found that only the emotional role functioning domain was signiﬁcantly different between men who were treated and those who were followed expectantly. Several other instruments have also been used to assess generic HRQOL. In a study of Medicare beneﬁciaries, investigators used the RAND Mental Health Index (MHI-5) and General Health Index (GHI), to demonstrate that patients with the greatest degree of urinary incontinence have signiﬁcantly lower scores on both the MHI-5 and the GHI (24). Similarly, Braslis and colleagues (25) administered the Proﬁle of Moods States (POMS) questionnaire to a group of patients prior to radical prostatectomy (RP) and to a second group of patients who were at least 12 mo post prostatectomy. Although this was not a prospective cohort study, their ﬁndings suggest that preoperative patients have higher

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Table 1 Validated Instruments for Assessment of Prostate Cancer HRQOL Instrument Generic HRQOL instruments Medical Outcomes Study (MOS) Short Form 36 (SF 36) Proﬁle of Moods States (POMS) Mental Health Index (MHI-5) General Health Index (GHI) Cancer-speciﬁc HRQOL instruments Functional Assessment of Cancer Therapy (FACT-G) European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) CAncer Rehabilitation Evaluation System (CARES) Prostate cancer-speciﬁc HRQOL instruments Prostate Cancer Index (PCI) Expanded Prostate Cancer Index: Composite (EPIC) Functional Assessment of Cancer Therapy Prostate Module (FACT-P) Prostate Cancer Outcomes Study Questionnaire (PCOS) PC-QOL

Author Ware et al. (7) Lim et al. (86) Fowler et al. (24) Fowler et al. (24) Cella et al. (87) Da Silva et al. (88) Schag et al. (30) Litwin et al. (31) Wei et al. (32) Esper et al. (29) Stanford et al. (47) Giesler et al. (33)

levels of “tension” compared with patients who were evaluated 12 mo after surgery. More recently, Bacon and colleagues (26) have examined the association between treatment-related symptoms with generic HRQOL. In this study, men diagnosed with localized prostate cancer from the Health Professionals Follow-Up Study were administered the SF 36 as well as the Prostate Cancer Index (PCI). Adjusted regression analyses demonstrated that sexual, urinary, and bowel functions explained 26, 25, and 29% of the variance for the physical summary scale of the SF 36, respectively. These treatmentrelated functional outcomes were associated with the mental summary scale to a lesser extent (26). Taken together, these data would suggest that prostate cancer and its therapies have limited, and generally short-term, effects on generic HRQOL. Cancer-speciﬁc measures address symptoms, functional limitations, and concerns common to all malignancies (Table 1). These tools often quantify emotional distress related to the cancer diagnosis, pain, and physical impairment. In 1980, the European Organization for Research and Treatment of Cancer (EORTC) created a study group on quality of life (27). Their product, the Quality of Life Questionnaire Core instrument (QLQ-C30), consisted of nine multi-item scales and a total of 30 items. The QLQ-C30 has been administered in numerous cancer-related clinical trials worldwide. Indeed, along with the SF 36, the QLQ-C30 is one of the most commonly administered HRQOL instruments used in prostate cancer studies. For example, the QLQ-C30 was used in a quality of life study including six Veterans Administration medical centers (28). The study found that men with progressive disease generally had lower emotional functioning and physical functioning scores compared with men who were newly diagnosed. In addition, cancer-speciﬁc HRQOL has been shown to be sensitive to disease status. Esper and coworkers (29) used the Functional Assessment of Cancer Therapy questionnaire (FACT-G) in a comparative study of early and advanced prostate cancer.

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Men with advanced cancer who had a rising prostate-speciﬁc antigen (PSA) had poorer cancer-speciﬁc HRQOL scores, compared with men with decreasing PSA levels. Treatment for localized cancer was also found to be associated with greater impairment as measured by the physical and psychosocial domains of the CAncer Rehabilitation and Evaluation System (CARES) (3). In general, prostate cancer therapy and disease progression are likely to be associated with changes in cancer-speciﬁc HRQOL (30). A growing number of prostate cancer-speciﬁc HRQOL instruments have now been developed (Table 1). However, symptoms and the impact of symptoms for men with prostate cancer may differ dramatically from those of other cancer patients. The slowly progressive nature of prostate cancer has resulted in a diverse population of men with regards to HRQOL. Many patients with early, localized disease detected primarily by screening have minimal to no symptoms attributable to their disease, whereas others with advanced prostate cancer experience signiﬁcant negative effects on their mental and physical quality of life. The PCI, developed by Litwin and colleagues (31), is a 20item disease-specific questionnaire consisting of six scales (urinary function and bother, sexual function and bother, and bowel function and bother). The PCI has demonstrated reliability and validity in various settings; consequently, it has been widely used in clinical studies. Building on the framework of PCI, the Expanded Prostate Cancer Index Composite (EPIC), a 50-item validated HRQOL instrument, was developed to assess in addition irritative urinary, bowel, and hormonal symptoms, which have not been adequately measured on prior scales (32). Like the PCI, the EPIC has established robust psychometric properties. Foreign language versions have been developed or are being validated for both tools. A shorter 26-item version of EPIC is also available. More recently, Kattan and colleagues (33) developed a survey instrument for localized prostate cancer HRQOL that has 10 domains, the PC-QoL. This 52item instrument was validated in a group of prostate cancer patients initially diagnosed through prostate cancer screening. Unique to this tool is a domain to assess patient concerns over effectiveness of their therapy.

SELECTING AN HRQOL INSTRUMENT Contemporary prostate cancer researchers are confronted with a diverse array of HRQOL instruments. The selection of instrument(s) for a particular study should be individualized and based on several criteria. First, one should select a tool that has undergone a rigorous validation process. Speciﬁc attention must be paid to assessing published data that support the validity and reliability of the instrument. The fact that a HRQOL tool has been reported in a clinical paper does not necessarily confer validity or reliability. An additional goal should be to select an instrument that has been previously administered in a similar clinical setting. The investigator must also decide whether to measure generic, cancer-specific, or prostate cancer-specific HRQOL. Although it would be easy to simply measure HRQOL at all three levels, lengthy surveys often result in respondent fatigue. As a rule, longer survey instruments have a greater likelihood of incomplete items or nonresponse. When considering an instrument, it is best to actually review the items in the questionnaire(s) for face and content validity. Do the items reﬂect the information that is relevant to your study? This need not be a perfect match, but consideration should be given as to whether there is going to be an evaluation of localized or advanced prostate cancer, as some instruments have been developed for a particular stage of disease.

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Another reason to review items carefully when selecting a survey instrument is to evaluate the potential sensitivity of the instrument for detecting differences. For example, if an investigator is interested in measuring differences in urinary incontinence but administers a survey instrument that assesses urinary urgency and obstructive and incontinence symptoms together, then the differences in the summary score may not be owing solely to urinary incontinence. The options available to this investigator are as follows: (1) to select another, more speciﬁc survey instrument that assesses urinary incontinence or (2) to perform a secondary analysis of the speciﬁc urinary incontinence items to determine whether or not they were responsible for the observed differences. After reviewing the instrument, the investigator must determine how to score and interpret the survey data. In some cases, there will be a ﬁnancial cost to administer the instrument, or even copyright restrictions. However, most HRQOL developers simply ask that you reference their work appropriately. One must also consider the mode of data collection (e.g., patient self-completion, telephone interview, face to face interview, and so on). Most survey instruments are validated only as written tools, but several, including EPIC, are undergoing alternate form reliability testing to determine whether other modes of data collection can be done in a reliable manner. Finally, if there are absolutely no pre-existing instruments, then one should work with an experienced quality of life researcher to develop a new instrument. The task of developing a new instrument with its requisite psychometric evaluation is time-consuming and costly but is well worth the effort if it results in a valuable contribution to the survey armamentarium. Data collection in most health survey studies involves patient self-report. A number of studies have now demonstrated that a patient’s self-reported symptoms are likely to differ from his physician’s assessment (34). The typical mode of survey administration is via a mailed document, although the use of telephone interviews often results in greater survey completion. Few instruments have demonstrated reliability for telephone-based data collection, and the use of a telephone interview in many cases would require that the investigator assess the reliability of the instrument prior to implementation. An alternative to patient self-report is the assessment of HRQOL by proxy. Knight and colleagues (35) compared the responses of patients with advanced prostate cancer and the responses of their spouses, using three validated surveys. In general, there was reasonable correlation between the patients and their spouses on HRQOL scores for the physical and functional domains; however, the social and emotional domains yielded divergent responses, suggesting that assessment of these domains requires direct patient input (35). Similarly, others have found proxy rating by spouses to be reliable for the physical domains and overall HRQOL, but not for sexual function and satisfaction (36). The timing of HRQOL assessments along the prostate cancer treatment continuum is critical. Whereas prostate cancer typically has a slow, progressive natural history, most therapies will acutely alter HRQOL and health status. As a result, some effects are short lived, whereas others persist even among long-term prostate cancer survivors (37). In a longitudinal cohort study, Litwin and coworkers (23) evaluated the rate of HRQOL recovery in men following RP. Using the PCI, they found that bowel function was the first symptom to return to baseline level (mean 4.8 mo), sexual function was the last (mean 11.3 mo), and urinary function was intermediate (mean 7.7 mo) (23). Therefore, survey time point(s) should be based on the specific question being asked (e.g., early vs long-term recovery of function after RP) (38). As a corollary, the investigator should statistically adjust for the duration of follow-up after

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therapy if data are collected over a range of follow-up time points, to account for potential confounding effects. Socioeconomic factors (e.g., patient age, race, education, income, insurance status, and marital status) should always be assessed concomitantly with HRQOL. In addition to disease factors, these indicators of socioeconomic status have been found to be associated with HRQOL assessments. Speciﬁc to prostate cancer, Lubeck and colleagues (39) have examined the question of racial disparity in prostate cancer HRQOL using the CAPSURE dataset. They observed that Black men generally had lower pretreatment HRQOL scores as measured by the MOS SF 36 and the PCI. Moreover, posttreatment recovery in a number of health domains was prolonged for Black patients compared with White patients. Other social factors including lower income and health insurance status were associated with lower post-treatment HRQOL in a study by Penson et al. (40). Eton and colleagues (41) also explored the role of psychosocial factors on HRQOL among men who had recently completed therapy for prostate cancer. Investigators observed in this study that a higher level of spousal support was associated with better urinary and mental functioning in patients. In the same study, the researchers evaluated demographic factors and found that African-American men were more likely to report poorer urinary and sexual function following therapy, after adjustment for age. In total, variable distributions of these socioeconomic factors are likely to have a tangible impact on HRQOL and should be considered in the analysis and interpretation of all HRQOL ﬁndings.

HRQOL IN LOCALIZED PROSTATE CANCER Impact of Radical Prostatectomy Data from the Surveillance, Epidemiology, and End Results (SEER) study and the American College of Surgeons consistently report surgery as the most commonly employed therapy for localized prostate cancer (42,43). Wei and colleagues (44) examined HRQOL using the EPIC instrument in a cross-sectional study of men following RP and compared their data with data for an age-matched control group. General and cancer-speciﬁc HRQOL scores did not differ; however, urinary incontinence and sexual domain scores were lower (poorer health state) in the RP group. In a longitudinal study of radical prostatectomy outcomes, Litwin et al. (23) prospectively conﬁrmed that the recovery of urinary function relative to baseline function occurred in 56% of patients at 12 mo after surgery, with little additional recovery observed beyond 18 mo. Sexual function returned to baseline in a third of patients by 12 mo, but improvements were noted beyond 24 mo of follow-up as well (45). More recently, a randomized, controlled trial from Sweden compared self-reported quality of life outcomes among men treated with RP vs those managed expectantly. Using a nonvalidated questionnaire, the investigators demonstrated a signiﬁcantly higher prevalence of distressful erectile dysfunction and urinary leakage among surgical patients vs those assigned to watchful waiting. However, measures of general HRQOL, including physical and psychological well-being and subjective quality of life, were similar between the two groups (45). Nerve-sparing surgery is a common practice among urologists to improve functional outcomes after prostatectomy (46). This approach has been shown to decrease the time to recovery for both erectile function and urinary continence after RP (47–49). This ﬁnding is supported by a prospective observational study that examined the impact of nerve sparing on sexual function (50). In this study, the authors deﬁned potency as

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erection sufﬁcient for intercourse, and a signiﬁcant beneﬁt was noted for the bilateral nerve-sparing technique (21% vs 0%). An effect of unilateral nerve sparing was not found at 12 mo following surgery; however, the study was severely underpowered, with an evaluable cohort size of only 49 subjects. When nerve sparing cannot be performed for fear of compromising cancer control, sural nerve grafting has the theoretical ability to permit regeneration of the peripheral nerves necessary for erectile function (51,52). In a study of 28 men who had undergone bilateral neurovascular bundle resection, 26% of subjects had spontaneous return of erections sufﬁcient for sexual intercourse at nearly 2 yr of follow-up. Another 26% reported partial erections using a visual analog scale. Although this technique appears promising, further investigation using validated HRQOL instruments will be necessary before widespread application (53,54). Recently, laparoscopic and robotic surgical techniques have emerged, with the promise of improving postoperative function (55,56). Use of these techniques has been driven primarily by consumerism, as there have been a paucity of validated HRQOL data to demonstrate any beneﬁt. A preliminary study reported spontaneous erections in 45% of men who had preoperative erections, but a validated instrument was not used in this study (57). The same group examined urinary continence at 1, 3, 6, and 12 mo postoperatively. As expected, urinary control improved over the course of the ﬁrst year, and daytime control, deﬁned as needing no pads and reporting no leakage at all, was observed in 56.8% of patients at 12-mo follow-up (58). These data suggest that recovery of urinary and sexual function is feasible with these new laparoscopic approaches; however, comparative HRQOL studies between laparoscopic or standard open RP techniques using validated instruments will be necessary to justify the increased expense that accompanies the use of this new technology. By and large, these data are immature, and further experience with longer follow-up will be necessary for sural nerve graft and laparoscopic techniques to determine adequately the marginal beneﬁt of these techniques over the standard nerve-sparing techniques.

Impact of External Beam Radiation Therapy External beam radiation therapy (EBRT) is the second most commonly employed modality in the treatment of localized prostate cancer. Over the years, treatment techniques for EBRT have continued to evolve toward higher therapeutic doses, while minimizing toxicity (59,60). A randomized trial comparing conformal with conventional EBRT demonstrated a lower incidence of proctitis and rectal bleeding in the conformal group with 2 yr of follow-up (61). Persistence of bladder and bowel symptoms was also evident with longer follow-up in one cross-sectional study of conformal EBRT (62). Additional radiation to the entire pelvis was also found to decrease HRQOL in this study. Moreover, the manifestation of toxicities for EBRT patients may occur in a delayed fashion, and the use of neoadjuvant and adjuvant androgen deprivation therapies is common (63). Hence, one must be mindful of the treatment technique and duration of follow-up in HRQOL studies of patients undergoing EBRT. In a randomized trial of 108 men with localized stage prostate cancer, EBRT was found to have signiﬁcantly poorer outcomes for generic HRQOL (social functioning and limitations in daily activities) compared with expectant management as measured by the QLQ-C30 and the QUFW94 instruments (64,65). The median dose received in this study was only 64.8 Gy, and the subjects received either conventional or conformal techniques. With a median follow-up of >30 mo, urinary incontinence, hematuria, stool frequency, stool soilage, and other bowel symptoms were also found to be signiﬁcantly

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higher in men receiving EBRT compared with expectant management. More immediate effects of EBRT on urinary, sexual, and bowel function and cancer level HRQOL have been well documented (65–68). Caffo and coworkers (69) described the primary side effects of radiation therapy to be urinary and sexual impairment. More globally, physical and psychological functions were found to remain relatively high. Using the Prostate Cancer Outcomes Study (PCOS) instrument, Hamilton and colleagues (68) reported signiﬁcant declines in disease-speciﬁc domains in 497 men with clinically localized disease treated with external beam radiation monotherapy. At 24 mo of follow-up, 7.4% of men reported having frequent bowel movements on a daily basis, 14% reported pain on at least some days, and 8.9% described bowel function as being a moderate to big problem. Urinary function was affected to a much lesser degree, with severe urinary incontinence as an uncommon occurrence. Signiﬁcant declines in sexual function are an important concern following EBRT, as the neurovascular bundles are immediately adjacent to the posterior-lateral limits of the prostate gland. In order to treat the peripheral zone completely, where the prostate cancer is likely to be, EBRT must, by deﬁnition, also include the neurovascular bundles in the radiated ﬁeld. This is supported by HRQOL ﬁndings of decreased frequency of sexual activity, decreased penile rigidity, and decreased ability to maintain an erection following EBRT. Moreover, 40% of men complained of a moderate to big problem with sexual function at 24 mo compared with 26% at baseline. An age effect of EBRT on sexual functioning after such treatment was also demonstrated. This ﬁnding may be particularly relevant, as the average age of men undergoing EBRT tends to be signiﬁcantly greater than that of men undergoing other active therapies. Overall, significant advances in EBRT techniques have improved HRQOL outcomes. Signiﬁcant effects on disease-speciﬁc HRQOL are apparent after EBRT, even with long-term follow-up; however, effects on generic and cancer-speciﬁc domains occur to a lesser degree.

Impact of Brachytherapy Brachytherapy, which is often presented as a less invasive alternative to RP and EBRT, has become a recognized standard treatment option for men with low-risk prostate cancer. Recently, HRQOL studies for contemporary brachytherapy techniques have been reported. Early assessment of HRQOL following implantation suggests modest changes in FACT P scores at 1 mo that returned to baseline by 6 mo (70). Lower urinary tract symptoms as measured by the American Urological Association Symptom Index (AUASI) persisted for up to 6 mo before returning to baseline. In many centers, it is not uncommon to treat higher risk patients with a combination of brachytherapy and EBRT. Prospective assessments of functional outcomes in these patients would suggest a decline in generic HRQOL 1 mo after treatment as measured by SF 36; however, HRQOL scores generally returned to baseline by 12 mo (71). Toxicities using the physician-assessed Radiation Therapy Oncology Group (RTOG) criteria were also measured over the same period. Importantly, the investigators determined that these RTOG criteria were insensitive to signiﬁcant HRQOL changes owing to therapy (71). A cross-sectional study of 105 men receiving either brachytherapy or brachytherapy combined with EBRT, using an unvalidated tool, found signiﬁcant bowel complaints to be greater in those who received combination therapy at an average of 5 yr following therapy (72). Bowel complications, including diarrhea and rectal bleeding, were less common than urinary and sexual effects but were found in 9 and 11%, respectively. Patient self-reported urinary incontinence deﬁned as “some urine

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leakage” was observed in 45% of men, and only 27% reported having adequate erections for intercourse. Again, these effects were more frequently reported by those who received EBRT (72). Men treated with brachytherapy and neoadjuvant androgen deprivation therapy (ADT) also demonstrated worse sexual HRQOL than those receiving brachytherapy monotherapy (73).

Impact of Watchful Waiting Relatively few studies have examined HRQOL in men undergoing watchful waiting. The PCOS is a population-based study that examines HRQOL in a subset of men diagnosed in 1994 and 1995 (74). As one might expect, men undergoing watchful waiting tended to be older and more frail, with >50% of the men between the ages of 70 and 79 yr. Among 661 men who had not received surgery or radiation in the ﬁrst year following diagnosis, 245 received ADT. Quality of life was adapted based on several existing instruments. Men who received ADT reported greater physical discomforts and lower vitality (74). Investigators from the CAPSURE project examined the effect of ADT and watchful waiting on HRQOL after treatment, as measured by the SF 36 and PCI (75). At 1 yr, signiﬁcant declines in physical functioning, social functioning, and general health were evident for men undergoing surveillance. Moreover, urinary and sexual bother were greater, although functional differences were not signiﬁcant. In the same study, men who received ADT monotherapy reported that only sexual function and bother were signiﬁcantly worse after 1 yr (75). Finally, in a recent randomized controlled trial, urinary obstructive symptoms, such as a weak urinary stream, were signiﬁcantly more prevalent among men assigned to watchful waiting vs radical prostatectomy (45).

HRQOL Effects Across Therapies (Radical Prostatectomy vs External Beam Radiation Therapy vs Brachytherapy) Often faced with several treatment options, patients with localized prostate cancer will frequently ask their physician to compare side effects across therapies. A number of recent studies have now compared standard therapies for localized prostate cancer (Table 2). In these observational studies, men who received EBRT tended to be older and more frail and to have slightly higher stage and grade of disease. One must be mindful of these differences when comparing EBRT with other therapies. Brachytherapy patients, however, tend to have a demographic and disease profile similar to that of RP patients. One of the ﬁrst descriptions of HRQOL across therapies, using validated instruments, was a cross-sectional study with 214 clinically localized prostate cancer patients and 273 age-matched control patients (3). Patients treated with radiation therapy or observation had signiﬁcantly better urinary function compared with surgery patients, as measured by the PCI. This was explained primarily by the frequency of urinary incontinence; however, patients undergoing radiation therapy were equally bothered by their incontinence. In contrast to urinary function, RP patients were less likely to have bowel dysfunction compared with radiation therapy patients. Also using the PCI, Davis and coworkers (76) recently reported on a cross-sectional comparison of men undergoing surgery, EBRT, and brachytherapy from a single institution. The study compared 269 brachytherapy patients with a mean follow-up of 22 mo with 222 men who had had EBRT and 142 men treated with RP. Even after adjustment for patient age, follow-up time, and comorbidity, EBRT patients tended to have poorer health

Table 2 Health-Related Quality of Life (HRQOL) Studies Demonstrating Differences in HRQOL Across Therapiesa Mean HRQOL scores by therapy Author

Study design

Lee et al. (78)

Longitudinal

Davis et al. (76)

Cross-sectional

No.

HRQOL instrument

90

FACT P AUASI SF 36 domains Physical function Role limitation Bodily pain General health Vitality PCI domains Bowel function Bowel bother Sexual function Sexual bother Urinary function Urinary bother SF 36 domains Physical function Role limitation Bodily pain General health Vitality Social function Emotional function Mental health Physical component Mental component

528

384 Bacon et al. (81)

Cross-sectional

842

Follow-up 1 mo

Radical prostatectomy

EBRT

Brachytherapy

117.7 17.2

129.5 13.8

120.5 20.8

— —

83.3 74.6 82.9 70.9 67.8

74.3 58.6 78.0 63.9 65.5

80.8 69.1 78.8 66.3 62.5

— — — — —

85.5 83.0 17.9 25.2 68.4 73.9

76.8 71.8 26.0 40.0 86.4 82.6

82.5 79.3 32.2 40.4 86.8 76.8

— — — — — —

90 86 85 80 71 92 90 84 52 55

83 72 79 74 64 87 82 81 49 53

90 79 81 78 66 92 86 84 51 54

79 85 81 71 68 87 90 83 49 55

Watchful waiting

5 yr

5 yr

752

752

Wei et al. (44)

Cross-sectional

1014

385 Potosky et al. (5)

Litwin et al. (80)

Prospective

Prospective

1591

452

CARES domains Physical Psychosocial Medical interaction Sexual problems Marital interaction Cancer rehabilitation PCI domains Bowel function Bowel bother Sexual function Sexual bother Urinary function Urinary bother EPIC summary Measures Urinary irritative Urinary incontinence Bowel Sexual Hormonal FACT P PCOSb Incontinence bother Bowel bother Sexual bother, ages 55–59 yr Sexual bother, ages 60–74 yr SF 36 Mental health Role limitation Vitality Social function

0.20 0.36 0.17 1.04 0.41 0.26

0.33 0.43 0.22 1.09 0.43 0.31

0.26 0.37 0.22 0.93 0.45 0.27

0.16 0.27 0.01 0.70 0.19 0.19

86 86 26 43 76 82

81 78 34 51 89 83

80 72 36 54 87 75

91 89 54 74 93 89

89.6 77.5 93.2 33.9 90.9 36.9

84.2 92.8 85.2 38.8 87.2 36.4

71.5 82.1 76.0 26.9 83.7 32.4

— — — — — —

11.2% 3.3% 59.4% 53.2%

2.3% 8.4% 25.3% 46.1%

— — — —

— — — —

75 81 61 86

— — — —

81 86 66 89

4 yr

2 yr

2 yr 85 94 73 100

a Higher scores on the PCI, EPIC, SF 36 and FACT P represent better HRQOL, whereas lower scores on the CARES and AUASI represent better HRQOL. For instrument deﬁnitions, see Table 1. EBRT, external beam radiation therapy. b Percent of patients reporting being bothered for each domain.

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function as measured by the SF 36; however, RP subjects consistently reported worse sexual and urinary function compared with brachytherapy and EBRT patients. These investigators observed that both brachytherapy and EBRT were associated with better HRQOL in sexual and urinary function but with worse HRQOL in bowel function. A similar study of men undergoing RP, EBRT, and brachytherapy was conducted at the University of Michigan during the same period (44). In this study, brachytherapy patients reported poorer urinary function, primarily owing to the irritative symptoms. Similarly, bowel function was worse in the brachytherapy group. Although these ﬁndings may be attributable to differences in population or technique, it seems likely that the observed declines in HRQOL for brachytherapy patients simply reﬂect the greater sensitivity of the EPIC instrument to irritative urinary and bowel symptoms. An inherent limitation of cross-sectional study designs is the lack of baseline HRQOL data; therefore, a number of prospective studies are in progress. In one such study, the mean summary scores from the FACT G nearly returned to baseline levels by 3 mo following brachytherapy and were no longer different at 12 mo (77,78). Lee and colleagues (78) administered the FACT-P and the AUASI in a prospective study of brachytherapy, EBRT, and RP. In this analysis, in which HRQOL data were collected before treatment and again at 1, 3, and 12 mo after treatment, clinically and statistically signiﬁcant decreases in HRQOL were observed for all three groups. The changes were greatest following prostate brachytherapy and RP, but the differences disappeared by 12 mo. They also noted that moderate to severe urinary complaints persisted at least 3 mo following brachytherapy. Although the mean score for the AUASI was not statistically different from baseline, it is noteworthy that signiﬁcantly lower (better) scores were evident for the RP and EBRT groups. Although these studies have furthered our understanding of HRQOL, they often draw subjects from tertiary care centers. The PCOS study is unique in that a population-based sample was used to evaluate HRQOL effects of therapy (79). With an average of 2 yr of follow-up, urinary incontinence, deﬁned as “no control,” and impotence were more common among RP patients compared with EBRT patients (9.6% vs 3.5%) (47). Pain with bowel movements and rectal urgency were more common for EBRT patients (Table 2). A limitation of PCOS is that baseline HRQOL was based on patient recall rather than direct assessment. The CAPSURE observational cohort, based primarily on community urologists, measured HRQOL using the SF 36 and PCI (80). Based on 452 men, observations on mental health demonstrated signiﬁcant differences among RP, EBRT, and watchful waiting. Although these scores improved after treatment for both RP and EBRT, improvements were slower after EBRT. Based on prospectively collected data from the Health Professionals Followup Study, Bacon and colleagues (81) examined the impact of cancer therapy on HRQOL in a sample of 1201 men with localized prostate cancer. General health function as measured by the SF 36 was highest for the surgery group, even after adjusting for differences in demographic features. The same men tended to report worse sexual bother and urinary function, as measured by the PCI. In contrast, men treated with EBRT tended to have the lowest general health function. The radiation patients reported better sexual and urinary function but worse bowel function compared with the RP group. Although the brachytherapy group was small, these men did report health function on a par with surgery, but results of the PCI were more variable. The brachytherapy group tended to have worse bowel function, bowel bother, and urinary bother compared with

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the surgery group. Data from the PCOS have suggested that men receiving radiation therapy were less likely than men undergoing RP to be incontinent and to suffer from sexual dysfunction (5). In sum, these ﬁndings suggest that HRQOL outcome following brachytherapy is comparable to that of RP and EBRT in most domains but may be less favorable in the bowel and urinary domains.

HRQOL IN ADVANCED PROSTATE CANCER Several of the prostate cancer-speciﬁc measures (e.g., PCI, EPIC, FACT-P, and QLQC30 prostate module) described for localized prostate cancer have also demonstrated appropriate validity and responsiveness for advanced prostate cancer (21,27,44,82). Generally, much less investigation has gone into the evaluation of HRQOL in men with advanced disease. The dearth of research may reﬂect the diminishing numbers of patients presenting with advanced prostate cancer; however, these patients typically have the most symptoms and are often those with the largest decrements in HRQOL directly related to the progression of their cancer. In a prospective study, HRQOL was measured in men dying of advanced prostate cancer using the SF 36. A clear and inevitable decline in HRQOL was documented in the 12 mo prior to death (83). ADT is often used in patients with advanced stage prostate cancer. The impact of ADT on HRQOL has only recently been studied. Using Medicare data, Fowler et al. (84). examined the effect of ADT on post-RP HRQOL. As one might suspect, ADT was associated with signiﬁcantly lower scores in the areas of body image, mental health, general health, activities, and energy (84). The SF 36 instrument has also been used to compare quality of life outcomes among patients with metastatic prostate cancer treated with orchiectomy and combined androgen blockade (21). In a prospective study of 68 men followed for 24 mo, no clinically or statistically signiﬁcant differences were observed in any of the eight SF 36 domains, suggesting that global health function will probably be similar for men undergoing orchiectomy or combined androgen blockade.

HRQOL Effect of Cancer Recurrence In a cross-sectional study, poorer sexual and hormonal function were reported by men with recurrent cancer, compared with men who were progression-free (44). These effects were independent of the primary therapy received and were felt to be clinically signiﬁcant by the investigators. Pietrow and co-workers (85) from Vanderbilt independently conﬁrmed these ﬁndings. In their study of 348 men, 25% had a PSA recurrence with a mean follow-up of 3 yr after prostatectomy. Again, sexual function was found to be worse among men with PSA recurrence. In multivariate analyses, the authors attributed some of this effect to lower incidence of nerve sparing among men who ultimately had a PSA recurrence (85). Taken together, these ﬁndings suggest an HRQOL beneﬁt for men without evidence of disease progression following primary therapy.

CONCLUSIONS Health-related quality of life assessment for prostate cancer is a rapidly evolving ﬁeld. A diagnosis of prostate cancer, therapies for prostate cancer, disease progression, and disease recurrence have all been shown to have a signiﬁcant and measurable effect on a patient’s HRQOL. In spite of recent progress in the evaluation of prostate cancerrelated HRQOL, more research is still necessary. Several prospective studies that seek to compare HRQOL between therapies are currently under way. The American College

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of Surgeons’ Oncology Group has commenced the SPIRIT trial, which is the ﬁrst randomized clinical trial to compare RP with brachytherapy. An important SPIRIT substudy will examine HRQOL in these patients using the EPIC instrument. Examination of other aspects of HRQOL, such as patient and spouse satisfaction and how satisfaction relates to HRQOL, is currently in progress at the University of Michigan. This prospective, multicenter observational study will provide a detailed examination of HRQOL and satisfaction with cancer care in men who self-selected treatment with RP, EBRT, or brachytherapy. In considering HRQOL as an endpoint, one has to be cognizant of other factors that affect HRQOL, including disease and sociodemographic factors. Investigators should select HRQOL tools that are reliable and valid and meet the needs of their study objectives. In some cases, generic HRQOL would sufﬁce, whereas cancer-speciﬁc and prostate cancer-speciﬁc HRQOL assessments may be desirable in other studies. With the proliferation of HRQOL tools, one has to keep in mind that these tools generally only provide summary scores and do not in and of themselves quantify urinary incontinence and sexual impotence. Results from such evaluations must be considered together with the clinical condition of the patient. Assessments of HRQOL are an established component of prostate cancer clinical research and are poised to become a valuable addition to the clinical care of our prostate cancer patients.

REFERENCES 1. Albertsen PC, Hanley JA, Gleason DF, et al. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998;280:975–980. 2. Staquet MJ, Hays RD, Fayers PM. Quality of Life Assessment in Clinical Trials—Methods and Practice. Oxford University Press, New York, 1999. 3. Litwin MS, Hays RD, Fink A, et al. Quality-of-life outcomes in men treated for localized prostate cancer. JAMA 1995;273:129–135. 4. Litwin MS, Pasta DJ, Yu J, et al. Urinary function and bother after radical prostatectomy or radiation for prostate cancer: a longitudinal, multivariate quality of life analysis from the Cancer of the Prostate Strategic Urologic Research Endeavor. J Urol 2000;164:1973–1977. 5. Potosky AL, Legler J, Albertsen PC, et al. Health outcomes after prostatectomy or radiotherapy for prostate cancer: results from the Prostate Cancer Outcomes Study. J Natl Cancer Inst 2000;92:1582–1592. 6. Schapira MM, Lawrence WF, Katz DA, et al. Effect of treatment on quality of life among men with clinically localized prostate cancer. Medical Care 2001;39:243–253. 7. Ware JE Jr, Brook RH, Davies AR, et al. Choosing measures of health status for individuals in general populations. Am J Public Health 1981;71:620–625. 8. Barry MJ. Quality of life and prostate cancer treatment. J Urol 1999;162:407. 9. Browne JP. Health-related quality-of-life studies in urology: conceptual and methodological considerations. World J Urol 1999;17:193–198. 10. Litwin MS. Examining health-related quality of life in men treated for prostate cancer. World J Urol 1999;17:205–210. 11. Sloan JA, Varricchio C. Quality of life endpoints in prostate chemoprevention trials. Urology 2001;57:235–240. 12. Moinpour CM, Hayden KA, Thompson IM, et al. Quality of life assessment in Southwest Oncology Group trials. Oncology 1989;4:79–84. 13. Moinpour CM, Lovato LC, Thompson IM Jr, et al. Proﬁle of men randomized to the Prostate Cancer Prevention Trial: baseline health-related quality of life, urinary and sexual functioning, and health behaviors. J Clin Oncol 2000;18:1942–1953. 14. Moinpour CM, Lovato LC. Ensuring the quality of quality of life data: the Southwest Oncology Group experience. Stat Med 1998;17:641–651. 15. Macdonagh R. Quality of life and its assessment in urology. Br J Urol 1996;78:485–496. 16. Testa MA, Simonson DC. Assessment of quality-of-life outcomes. N Engl J Med 1996;334:835–840.

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44. Wei JT, Dunn RL, Sandler HM, et al. Comprehensive comparison of health-related quality of life after contemporary therapies for localized prostate cancer. J Clin Oncol 2002;20:557–566. 45. Steineck G, Helgesen F, Adolfsson J, et al. Quality of life after radical prostatectomy or watchful waiting. N Engl J Med 2002;347:790–796. 46. Walsh PC. Radical retropubic prostatectomy with reduced morbidity: an anatomic approach. NCI Monogr 1988;133–137. 47. Stanford JL, Feng Z, Hamilton AS, et al. Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the Prostate Cancer Outcomes Study. JAMA 2000;283:354–360. 48. Wei JT, Dunn RL, Marcovich R, et al. Prospective assessment of patient reported urinary continence after radical prostatectomy. J Urol 2000;164:744–748. 49. Eastham JA, Kattan MW, Rogers E, et al. Risk factors for urinary incontinence after radical prostatectomy [Review]. J Urol 1996;156:1707–1713. 50. Talcott JA, Rieker P, Propert KJ, et al. Patient-reported impotence and incontinence after nerve-sparing radical prostatectomy. J Natl Cancer Inst 1997;89:1117–1123. 51. Scardino PT, Kim ED. Rationale for and results of nerve grafting during radical prostatectomy. Urology 2001;57:1016–1019. 52. Kim ED, Scardino PT, Kadmon D, et al. Interposition sural nerve grafting during radical retropubic prostatectomy. Urology 2001;57:211–216. 53. Kim ED, Nath R, Kadmon D, et al. Bilateral nerve graft during radical retropubic prostatectomy: 1year followup. J Urol 2001;165:1950–1956. 54. Kim ED, Nath R, Slawin KM, et al. Bilateral nerve grafting during radical retropubic prostatectomy: extended follow-up. Urology 2001;58:983–987. 55. Pasticier G, Rietbergen JB, Guillonneau B, et al. Robotically assisted laparoscopic radical prostatectomy: feasibility study in men. Eur Urol 2001;40:70–74. 56. Guillonneau B, Vallancien G. Laparoscopic radical prostatectomy: the Montsouris technique. J Urol 2000;163:1643–1649. 57. Guillonneau B, Vallancien G. Laparoscopic radical prostatectomy: the Montsouris experience. J Urol 2000;163:418–422. 58. Olsson LE, Salomon L, Nadu A, et al. Prospective patient-reported continence after laparoscopic radical prostatectomy. Urology 2001;58:570–572. 59. Sandler HM, Dunn RL, McLaughlin PW, et al. Overall survival after prostate-speciﬁc-antigen-detected recurrence following conformal radiation therapy. Int J Radiat Oncol Biol Phys 2000;48:629–633. 60. Michalski JM, Winter K, Purdy JA, et al. Trade-off to low-grade toxicity with conformal radiation therapy for prostate cancer on Radiation Therapy Oncology Group 9406. Semin Radiat Oncol 2002;12(1 suppl 1):75–80. 61. Dearnaley DP, Khoo VS, Norman AR, et al. Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial. Lancet 1999;353:267–272. 62. Hanlon AL, Watkins BD, Peter R, et al. Quality of life study in prostate cancer patients treated with three-dimensional conformal radiation therapy: comparing late bowel and bladder quality of life symptoms to that of the normal population. Int J Radiat Oncol Biol Phys 2001;49:51–59. 63. Nguyen LN, Pollack A, Zagars GK. Late effects after radiotherapy for prostate cancer in a randomized dose-response study: results of a self-assessment questionnaire. Urology 1998;51:991–997. 64. Fransson P, Damber JE, Tomic R, et al. Quality of life and symptoms in a randomized trial of radiotherapy versus deferred treatment of localized prostate carcinoma. Cancer 2001;92:3111–3119. 65. Widmark A, Fransson P, Tavelin B. Self-assessment questionnaire for evaluating urinary and intestinal late side effects after pelvic radiotherapy in patients with prostate cancer compared with an agematched control population. Cancer 1994;74:2520–2532. 66. Janda M, Gerstner N, Obermair A, et al. Quality of life changes during conformal radiation therapy for prostate carcinoma. Cancer 2000;89:1322–1328. 67. Michalski JM, Purdy JA, Winter K, et al. Preliminary report of toxicity following 3D radiation therapy for prostate cancer on 3DOG/RTOG 9406. Int J Radiat Oncol Biol Phys 2000;46:391–402. 68. Hamilton AS, Stanford JL, Gilliland FD, et al. Health outcomes after external-beam radiation therapy for clinically localized prostate cancer: results from the Prostate Cancer Outcomes Study. J Clin Oncol 2001;19:2517–2526. 69. Caffo O, Fellin G, Graffer U, et al. Assessment of quality of life after radical radiotherapy for prostate cancer. Br J Urol 1996;78:557–563. 70. Lee WR, McQuellon RP, Harris-Henderson K, et al. A preliminary analysis of health-related quality of life in the ﬁrst year after permanent source interstitial brachytherapy (PIB) for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2000;46:77–81.

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71. Egawa S, Shimura S, Irie A, et al. Toxicity and health-related quality of life during and after high dose rate brachytherapy followed by external beam radiotherapy for prostate cancer. Jpn J Clin Oncol 2001;31:541–547. 72. Talcott JA, Clark JA, Stark PC, et al. Long-term treatment related complications of brachytherapy for early prostate cancer: a survey of patients previously treated. J Urol 2001;166:494–499. 73. Hollenbeck BK, Dunn RL, Wei JT, et al. Neoadjuvant hormonal therapy and older age are associated with adverse sexual health-related quality-of-life outcome after prostate brachytherapy. Urology 2002;59:480–484. 74. Potosky AL, Reeve BB, Clegg LX, et al. Quality of life following localized prostate cancer treated initially with androgen deprivation therapy or no therapy. J Natl Cancer Inst 2002;94:430–437. 75. Lubeck DP, Grossfeld GD, Carroll PR. The effect of androgen deprivation therapy on health-related quality of life in men with prostate cancer. Urology 2001;58(suppl):94–100. 76. Davis JW, Kuban DA, Lynch DF, et al. Quality of life after treatment for localized prostate cancer: differences based on treatment modality. J Urol 2001;166:947. 77. Lee WR, McQuellon RP, Case LD, et al. Early quality of life assessment in men treated with permanent source interstitial brachytherapy for clinically localized prostate cancer. J Urol 1999;162:403–406. 78. Lee WR, Hall MC, McQuellon RP, et al. A prospective quality-of-life study in men with clinically localized prostate carcinoma treated with radical prostatectomy, external beam radiotherapy, or interstitial brachytherapy. Int J Radiat Oncol Biol Phys 2001;51:614–623. 79. Potosky AL, Harlan LC, Stanford JL, et al. Prostate cancer practice patterns and quality of life: the Prostate Cancer Outcomes Study. J Natl Cancer Inst 1999;91:1719–1724. 80. Litwin MS, Lubeck DP, Spitalny GM, et al. Mental health in men treated for early stage prostate carcinoma: a posttreatment, longitudinal quality of life analysis from the Cancer of the Prostate Strategic Urologic Research Endeavor. Cancer 2002;95:54–60. 81. Bacon CG, Giovannucci E, Testa M, et al. The impact of cancer treatment on quality of life outcomes for patients with localized prostate cancer. J Urol 2001;166:1804–1810. 82. Albertsen PC, Aaronson NK, Muller MJ, et al. Health-related quality of life among patients with metastatic prostate cancer. Urology 1997;49:207–216. 83. Litwin MS, Lubeck DP, Stoddard ML, et al. Quality of life before death for men with prostate cancer: results from the CaPSURE database. J Urol 2001;165:871–875. 84. Fowler FJ Jr, McNaughton CM, Walker CE, et al. The impact of androgen deprivation on quality of life after radical prostatectomy for prostate carcinoma. Cancer 2002;95:287–295. 85. Pietrow PK, Parekh DJ, Smith JA Jr, et al. Health related quality of life assessment after radical prostatectomy in men with prostate speciﬁc antigen only recurrence. J Urol 2001;166:2286–2290. 86. Lim AJ, Brandon AH, Fiedler J, et al. Quality of life: radical prostatectomy versus radiation therapy for prostate cancer. J Urol 1995;154:1420–1425. 87. Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 1993;11:570–579. 88. Da Silva FC, Reis E, Costa T, et al. Quality of life in patients with prostatic cancer. A feasibility study. The Members of Quality of Life Committee of the EORTC Genitourinary Group. Cancer 1993;71:1138–1142.

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The Evaluation and Management of Postprostatectomy Urinary Incontinence Adonis Hijaz, M. Louis Moy, Sandip P. Vasavada, and Raymond R. Rackley

INTRODUCTION Adenocarcinoma of the prostate is the most common malignancy in men. The treatment options for prostate cancer are growing, but radical prostatectomy remains the treatment of choice for localized prostate cancer in age- and health-appropriate men. Although cancer control is the most important aspect of a radical prostatectomy, minimization of postoperative morbidity, especially urinary incontinence and erectile dysfunction, is becoming a greater concern. Urinary incontinence after radical prostatectomy ranges from 2.5 to 87% (1). This large discrepancy is owing to a number of factors, including the lack of a standard definition for incontinence, the method of data collection, and the availability of study parameters. In this chapter we review the pathophysiology, evaluation, and management of postprostatectomy incontinence.

ANATOMY Continence is dependent on the urethral pressure being greater than the bladder pressure at all times, except when voiding. This requires a competent bladder neck and a bladder that is compliant and free of involuntary contractions. In the absence of voiding dysfunction, there is a complex interplay between the components of the lower urinary tract, which include striated muscles, smooth muscles, nerves, neuromediators, vasculature, and support structures, which is still not fully understood. In males, the bladder outlet can be divided into two separate units, the proximal urethral sphincter (or internal sphincter) and the distal sphincter (or external sphincter) (2). The proximal urethral sphincter is composed of the bladder neck, smooth muscle, prostate gland, and prostatic urethra to the verumontanum. These smooth From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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muscle fibers are arranged largely in a circular fashion at the bladder neck and are innervated by parasympathetic fibers. The distal urethral sphincter extends from the verumontanum to the perineal membrane. It is composed of the intrinsic rhabdosphincter, which is smooth and striated muscle, and extrinsic skeletal muscle or levator ani. Mucosal and fascial supports are also part of the continence mechanism. The rhabdosphincter is composed of slow twitch muscle fibers that resist fatigue and may be responsible for passive continence. When active continence is needed, there is a contraction of the levator ani muscles, which are extrinsic paraurethral muscles of the fast twitch type, which do fatigue (3). The distal sphincter has dual innervations from the sympathetic and somatic nervous systems. Fascial and musculature support probably contribute to the competence of the distal sphincter. When a radical prostatectomy is performed, the proximal urethral sphincter is removed, and continence is dependent solely on the distal sphincter.

SURGICAL TECHNIQUE The surgical technique for performing a radical prostatectomy has been evolving over time. Anatomy has been more clearly deﬁned, and modiﬁcations in the operative technique have been developed to minimize morbidity. In particular, the effects of preservation of the neurovascular bundles, bladder neck, and puboprostatic ligaments on the maintenance of postprostatectomy continence have been studied. O’Donnell and Finan (4) published continence rates following nerve-sparing radical prostatectomies. In this study, there was a 94% vs 70% rate of continence in the nerve-sparing groups vs non-sparing group. They concluded that preservation of the pelvic nerves during surgery has a major role in the maintenance of continence (4). Other studies have not shown a significant difference in continence rates whether nerves were spared or not as long as the prostatectomy was performed in an anatomic manner (5,6). They concluded that anatomic factors and meticulous dissection at the apex rather than preservation of autonomic innervation were responsible for complete urinary control. The role of bladder neck preservation in maintaining continence has also been studied. Licht et al. (7) performed a prospective analysis of 206 consecutive patients undergoing radical prostatectomy with preservation of the bladder neck. They found that this technique did not necessarily have an impact on the return of urinary control but was associated with a lower incidence of bladder neck contracture (7). Lowe (8) compared bladder neck preservation with bladder neck resection and its effect on continence. Results showed that bladder neck preservation in the context of a good cancer operation was feasible; the procedure did not improve the continence rate, but it did shorten the duration of incontinence (8). The effect of the preservation of the pubourethral ligaments on continence after radical prostatectomy has been examined. Lowe (9) found that in 51 patients who had a radical prostatectomy with preservation of anterior attachments of the posterior urethra to the posterior pubis compared with 70 patients who had these attachments cut, the time to urinary continence was shortened and the overall rate of continence was improved. Jarrow (10) similarly found that sparing of the puboprostatic ligaments led to a more rapid and fuller return to urinary continence. Klein (11) describes a technique in which the fascia posterior to the urethra is incorporated in the vesicourethral anastamosis, resulting in earlier continence. He also

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found that preservation of the neurovascular bundles and bladder neck preservation did not affect the rate of continence. In summary, it appears as though careful apical dissection, with care not to injure the distal urethral sphincter, is the most important factor in the maintenance of continence. Bladder neck preservation does not seem to have a major impact on continence but may decrease anastamotic stricture rates, whereas preservation of the pubourethral ligaments may be beneﬁcial.

ETIOLOGY Postprostatectomy incontinence as well as any incontinence can be described by Wein’s (12) functional classiﬁcation for voiding dysfunction as a failure to store. This failure to store is caused by either a bladder or sphincter abnormality. Bladder dysfunction that causes incontinence is either bladder overactivity or poor compliance. Sphincteric dysfunction is secondary to a poorly functioning or nonfunctioning sphincter. Overﬂow incontinence can be the result of an underactive bladder or anastamotic stricture. Multiple studies have been published to determine the relative contributions of bladder and sphincteric dysfunction to postprostatectomy incontinence. Leach et al. (13) examined 215 men who underwent prostatectomy (162 had radical prostatectomy for cancer). One hundred ﬁfty-nine of these men who had a radical prostatectomy underwent urodynamic evaluation. Fifty-six percent had high-pressure voiding and 40% pure stress incontinence (13). In a study by Goluboff et al. (14), multichannel pressure/ﬂow studies were performed in 25 post radical prostatectomy patients, with 40% showing detrusor instability, 8% having genuine stress urinary incontinence, and 52% having a combination. Other studies have shown sphincter dysfunction as the main cause of postprostatectomy incontinence. Chao and Mayo (15) performed urodynamic studies on 74 men undergoing radical prostatectomy with incontinence: 57% had sphincter weakness alone, 39% had bladder and sphincteric dysfunction, and only 4% had bladder dysfunction alone (15). Desautel et al. (16) also performed urodynamic studies on 39 patients who had prostatectomies for cancer; they found that in 59%, sphincteric dysfunction was the sole cause of incontinence. Groutz et al. (17) examined 83 consecutive men after radical prostatectomy. In 32.5%, intrinsic sphincter deﬁciency was the sole cause of incontinence, whereas detrusor instability was the sole cause in 3.6%; overall, they concluded that sphincteric deﬁciency was the cause in 88% of the cases and detrusor instability in 7.2% (17). Ficazzola and Nitti (18) studied 60 men after radical prostatectomy with at least 6 mo of follow-up. Intrinsic sphincter deﬁciency was seen alone in 67%, whereas bladder dysfunction was seen alone in only 3% (18). Winters et al. (19) followed 92 patients who had had video urodynamic studies performed and found the predominant urodynamic ﬁnding to be sphincteric incompetence in 92%; 37% had detrusor instability. In only 3.3% was detrusor instability the sole cause of incontinence. In summary, after radical prostatectomy, sphincteric dysfunction appears to be the main cause of incontinence. Bladder dysfunction is rarely the sole cause, but it may often coexist with sphincteric dysfunction. Determining the presence of sphincteric and/or bladder dysfunction in the patient with postprostatectomy incontinence is important to deliver the optimal treatment and maximize outcomes.

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EVALUATION The initiation of a workup for postprostatectomy incontinence depends on the severity of symptoms and bothers to the patient. Most patients have some degree of incontinence immediately after catheter removal, with a progressive reduction in incontinence up to 1 yr after prostatectomy. In general, it is prudent to wait for urinary symptoms to become stable prior to commencing an evaluation for and treatment of postprostatectomy incontinence. As with any medical evaluation, the assessment of postprostatectomy incontinence begins with a thorough history and physical examination. Every effort should be made to quantify and characterize the incontinence. The patient should be asked speciﬁc questions including the number of incontinent episodes per day, the need for protection, and the number of pads used. Actions that may precipitate the incontinence, whether the leakage is intermittent or constant, and the presence of nocturnal incontinence are also important. The current and preoperative voiding and storage symptoms should be elicited, which include the symptoms of slow stream, hesitancy, straining to void, feeling of incomplete emptying, frequency, nocturia urgency, and urge incontinence. The patient should be asked to keep a 3- to 5-d voiding diary, as this will give valuable information regarding ﬂuid intake, number of incontinence episodes, and functional bladder capacity; also, 24-h urine output can be determined. A voiding diary may prove to be more accurate than the patient’s own accounts. Validated quality of life (QOL) questionnaires should be completed and will help to determine the timing and extent of intervention, although a dedicated QOL instrument does not exist for postprostatectomy incontinence. A list of current medication should also be obtained, with a special emphasis on medications such as anticholinergics, diuretics, tricyclic antidepressants, and sympathomimetic medications that may affect bladder function. A past medical and surgical history should emphasize any issues that may have an affect on voiding such as previous back, pelvic, and urologic surgery, radiation, diabetes, stroke, vascular or neurologic disease. Physical examination should include a general urologic and focused neurologic assessment. The abdomen should be palpated; the presence of a distended bladder may indicate urinary retention and overﬂow incontinence. The patient should perform Valsalva straining or coughing in either the supine or upright position to demonstrate urinary leakage. Perineal sensation, deep tendon, and bulbocavernosus reﬂexes need to be tested. On the rectal examination, anal sphincter tone as well as cancer recurrence can be evaluated. Abnormalities in reﬂexes or anal tone may indicate a neurologic cause for voiding dysfunction. Useful laboratory tests include a urinalysis, prostate-speciﬁc antigen (PSA), and creatinine. Urinalysis will exclude urinary tract infection, whereas an elevated PSA may suggest a cancer recurrence. Noninvasive testing such as a ﬂow rate and postvoid residual can be helpful. For the ﬂow rate to be accurate, the patient should void at least 150 cc, which may not be possible if the patient is completely incontinent. A postvoid residual can be measured using an ultrasound probe or via catheterization. A low ﬂow rate or high postvoid residual may suggest either obstruction or bladder dysfunction, but these tests alone cannot make the distinction. Cystourethroscopy may add important information to the cause of incontinence. Examination of the bladder may reveal urothelial lesions, calculi, or foreign bodies that

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may irritate and inﬂame the bladder. The existence of trabeculations, cellules, or diverticuli may suggest a dysfunctional bladder. The presence of outlet obstruction can be evaluated by visualizing the vesicourethral anastamosis and the length of the urethra for stricture. The presence and function of the striated sphincter can also be assessed cystoscopically. Direct visualization of the lower urinary tract may also give the practitioner some idea of the feasibility of future therapies such as an injectable bulking agent or the placement of an artiﬁcial sphincter.

URODYNAMICS Urodynamic evaluation is valuable in the assessment of postprostatectomy incontinence because a proper study can differentiate between sphincter and bladder dysfunction. This allows the practitioner to make an accurate diagnosis and initiate the appropriate therapy and optimize treatment. Urodynamic testing is an interactive study between the patient and examiner. It begins with a cystometrogram, which is the ﬁlling or storage phase of the study. During this phase, important information that can be obtained includes the presence of normal or abnormal bladder sensation, bladder compliance, bladder capacity, and the presence of detrusor overactivity. In a multichannel urodynamic study, vesical and abdominal pressures can be measured. From these, the detrusor pressure, which is the vesical pressure minus abdominal pressure, can be calculated. Pressure recordings are performed as the bladder is being ﬁlled with room temperature water, normal saline, or radiographic contrast. The physiologic ﬁlling rate as determined by the International Continence Society (ICS) is deﬁned as a ﬁlling rate less than the patient’s body weight in kilograms divided by four, expressed as mL/min (20). For example, an 80-kg man undergoing a cystometrogram should have his bladder ﬁlled at a rate < 20mL/min. During bladder ﬁlling, the patient and examiner should be engaged in a conversation, with questions regarding sensation and urgency being asked. As the bladder is being ﬁlled, care should be taken to look for detrusor overactivity, which is an “urodynamic observation characterized by involuntary detrusor contractions during the ﬁlling phase which may be spontaneous or provoked” (20). There is no lower limit for the amplitude of an involuntary detrusor contraction. The examiner should watch carefully for associated leakage. Bladder compliance is calculated by dividing the change in volume by the change in detrusor pressure. The ICS recommends that two standard points should be used for compliance calculations. They are at the start of bladder ﬁlling and immediately before the start of any detrusor contraction that causes signiﬁcant leakage. Compliance values of >12.5 mL/cm H2O are considered normal (21). During the storage phase the abdominal leak point pressure (ALPP) or Valsalva leak point pressure can be determined. It is a measure of sphincteric competence. To perform the test, the bladder is ﬁlled with a volume of about 200 cc, and the patient is asked to perform a Valsalva maneuver, cough, or an activity that would usually cause leakage. The detrusor pressure at which leakage occurs in the absence of a detrusor contraction is the ALPP. In the normal continent male patient the ALPP is inﬁnity, as no leakage should occur. Higher ALPP values are associated with minor sphincteric weakness, whereas lower ALPP values are associated with more severe sphincteric weakness (22). After the cystometrogram, a pressure ﬂow study can be performed. Detrusor contractility and urinary ﬂow rates can be measured during this phase. An idea of how well

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the detrusor functions and whether obstruction is present can be determined. Bladder outlet obstruction is deﬁned as elevated voiding pressure with a low urinary ﬂow rate. Simultaneous electromyographic measurements during the voiding and ﬁlling phases may give an indication of sphincter dysfunction. Urethral pressure proﬁlometry may be done. Pressure at the bladder neck, the maximal urethral closing pressures, and the functional urethral length can be measured. This testing is associated with signiﬁcant error in performance and is generally not useful.

BLADDER DYSFUNCTION Postprostatectomy incontinence secondary to bladder dysfunction is owing to either bladder overactivity or decreased compliance. The management options available for patients with postprostatectomy incontinence owing to bladder dysfunction are the same as those available for those who have not had a radical prostatectomy. Treatments range from noninvasive behavioral therapy to open surgery. Nonsurgical management includes behavioral therapy and pharmacotherapy. Even early on, behavioral modiﬁcations can be initiated that include ﬂuid restrictions, double voiding, avoidance of caffeine, and so on. Pharmacotherapy can be initiated after or along with behavioral therapy. Anticholinergics are the most popular medications for treating the overactive bladder. At the present time oxybutynin and tolterodine are the two most common. These are both available in immediate-release and long-acting forms. Oxybutynin hydrochloride is an antimuscarinic agent with muscle relaxant and local anesthetic activity. Studies have shown its efﬁcacy for the treatment of overactive bladder (23,24). An extended-release formulation, oxybutynin XL, avoids the peaks of immediate-release oxybutynin. Equal efﬁcacy with immediate-release oxybutynin with reduced side effects has been demonstrated (25). Currently there is a transdermal oxybutynin patch available. This is changed twice a week and has a lower side effect proﬁle as it bypasses the gastrointestinal tract and is absorbed into the bloodstream. Tolterodine is a competitive muscarinic receptor antagonist. In various studies, tolterodine has been shown to have equal efﬁcacy to oxybutynin, but with fewer side effects (26,27). A series comparing immediate-release tolterodine vs extended-release tolterodine LA vs placebo showed a decrease in the number of incontinence episodes in patients taking tolterodine, and fewer side effects in those taking tolterodine LA compared with immediate-release tolterodine (28). Another commonly used medication in bladder dysfunction is imipramine, a tricyclic antidepressant. It can decrease bladder contractility while increasing outlet resistance. It has central and peripheral anticholinergic activity, inhibits the reuptake of norepinephrine and serotonin, and has a mild sedative effect. Other medications are currently under development that take advantage of a number of other pathways including nonpurinergic nonadrenergic pathways. Another promising pharmacologic therapy on the horizon is duloxetine, which is a norepinephrine and selective serotonin reuptake inhibitor. It is believed to decrease parasympathetic activity and increase sympathetic and somatic activity in the lower urinary tract. It may be very useful in that it may suppress the overactive bladder and increase sphincter tone. It is currently undergoing clinical trials in the treatment of female stress urinary incontinence (29). Neuromodulation consists of a set of evolving therapies in the management of the overactive bladder. These may take the form of chemical (botulinum A toxin) or elec-

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trical (sacral nerve stimulation) treatments. No studies using these modalities in the treatment of postprostatectomy incontinence have been published. Botulinum A toxin, the most potent toxin known, has been used to treat a number of medical maladies involving muscle spasticity (30). It works by blocking the presynaptic release of acetylcholine that is necessary for bladder contractions. The usual dose is 300 IU diluted in 3 or 30 mL of injectable saline. Ten IU are then injected into 30 areas via a cystoscopic needle into the bladder in a trigone-sparing fashion. It has been used in the treatment of neurogenic bladder overactivity with promising results (31). Currently sacral nerve stimulation has been used in refractory nonobstructive urinary retention, urgency–frequency, and urge incontinence. The exact mechanism of action is not completely understood, but it is believed that local reﬂex pathways that control the lower urinary tract can be modulated through continuous low-level nerve stimulation. A number of studies have documented good initial results for the treatment of this difﬁcult patient population with long-term data (32,33). The procedure itself can be performed percutaneously with a temporary lead and permanent implantation of lead and generator at a future date, or in a staged manner in which a permanent quadripolar lead is implanted with generator placement after satisfactory results. When bladder overactivity persists despite the implementation of the above therapies, augmentation cystoplasty may be necessary. It is typically performed using a 15- to 20cm patch of detubularized distal ileum, although stomach or other bowel segments can be used. The use of stomach or bowel segments for augmentation cystoplasty is associated with a variety of electrolyte abnormalities that the practitioner should be familiar with prior to choosing the segment to be used. Autoaugmentation has also been described, which is the removal of the detrusor from the epithelium, allowing the lumen of the bladder to expand. These procedures have usually been performed via an open approach, but laparoscopic augmentation cystoplasty is feasible (34).

SPHINCTER DYSFUNCTION Injectable Therapy Injectable therapy for postprostatectomy incontinence has been notoriously associated with low success rates of 20–35% cure and socially improved rates (35–37). Issues related to the success of injectable therapy include patient selection, technique of injection, volume of each injection, and number of injections. Patient selection remains the most important determinant in success of injectable therapy, with low success rates observed in patients with severe postprostatectomy incontinence judged clinically by number of pads per day and urodynamically by ALPP. Cespedes et al. (38) reported that 72% of patients who used fewer than six pads per day were dry or signiﬁcantly improved at 7 mo after injection vs 29% using more than six pads. Smith et al. (36) reported that patients who required more than three pads daily or an external device (penile clamp or condom catheter) had a success rate of 28.1% compared with 50% for those who used one to three pads daily before therapy at 29 mo of follow-up. Patients with ALPP > 60 cm of water responded favorably in 70% of cases compared with 19% in patients with ALPP < 60 cm of water (35). Poor predictive factors were postoperative radiation therapy, adjuvant cryotherapy, and vigorous bladder neck incision for a postoperative anastamotic stricture. Martins et al. (39) assessed the poor prognostic factors in an analysis of outcome in 46 patients. He found that all patients who failed had a grade 3 classiﬁcation of incontinence severity according to the stress,

Table 1 Injectable Treatment for Postprostatectomy Incontinence Author

Age (yr)

No. of patients

Kaufman et al. (74)

69

Stanisic et al. (75)

20

Politano et al. (76)

720

Follow-up (mo)

17

Material and volume injected

Method

Teﬂon

Transurethral

Teﬂon

Periurethral

Teﬂon

Transurethral

400

Aboseif et al. (77)

68

88

10

Collagen Mean 25 cc

Transurethral

Appell et al. (44)

69

24

12–15

Collagen Av. 7.1 cc

Antegrade

Klutke et al. (43)

72

20

28

Collagen Av. 14.5 cc

Antegrade

15.5

Polydimethylsiloxane

Transurethral

38

Mean 7.5 cc/pt Collagen Av. 36 cc

Transurethral

Colombo et al. (47)

Faerber and Richardson (37)

6

45–75

68

Outcome (%) 85.1 in post TURP 79.9 in post open 48.1 in post RRP 35 long-term improvement 88 in post TURP 74 in post open 67 in post RRP 47.7 nearly dry 21.6 1–3 ppd 30.7 >3 ppd + no improvement 75 dry at 6 mo 37.5 dry at 12 mo 10 subjective cure 35 sig. improvement 55 failure 5/6 cure

1/6 2 pads during day 10 cured 10 improved 67 min.–no improvement 13 worse

No. of injections

Range 3.5

Single

3 pts. got second injection 5× Range 3–15

Reek et al. (78)

19

12.7

Collagen Mean 16 cc Collagen 26.1 cc

Periurethral

401

Sanchez-Ortiz et al. (35)

62.7

31

14.9

Gottfried et al. (79) Griebling et al. (80)

69.7

26 25

9.2 13.3

Collagen Collagen 35.5 cc

Transurethral Transurethral

Martins et al. (39)

67

46

26

Collagen 31 cc

Transurethral

Elsergany and Ghoniem (81)

68.8

35

17.6

Collagen 8.2 cc

Transurethral

Smith et al. (36)

69.5

62

29

Transurethral

10

14

Collagen 20 cc Collagen 20 cc Macroplastique

After 3 mo treatment failed in all pts. 35 (6 cure, 29 improved) ALPP > 60 cured in 70% ALPP < 60 19% cure rate 47.3 beneﬁted 8 sig. improvement 32 min. improvement 60 failure 24 dry 41 improved 30 no beneﬁt 20 dry 31.4 improved 48.6 failed 35.2 success, social cure

Perineal, US guided

6 success, 1 cured

Transurethral

40 success at 1 mo 71 at 3 mo 33 at 6 mo 26 at 12 mo 5 dry 57 improved 38 failed

Kageyama et al. (82) Bugel et al. (46)a

66.4

15

12

Tiguert et al. (83)

69.5

21

12.5

Collagen 18.4 cc

Transurethral

Transurethral

58 underwent 2× 2.45×

1.5×

1.8× 2.6×

2.8×

2×

4×

2.9×

Abbreviations: ALPP, abdominal leak point pressure; ppd, pads per day; RRP, radical retropubic prostatectomy; TURP, transurethral resection of the prostate; US, ultrasound. a Prospective.

402

Hijaz et al.

emptying, anatomy, protection, instability (SEAPI) classiﬁcation, 79% had detrusor overactivity with decreased compliance, and 43% had radiation exposure. This was signiﬁcantly different from ﬁndings in cured or improved patients. Anastamotic strictures and ALPP were not factors in outcome. Wainstein and Klutke (40) reported on the antegrade transvesical approach as an alternative to the transurethral approach with a proposed advantage of better visualization of vesicourethral anastamosis, improved access to the bladder neck, and unimpeded delivery of collagen to regions of the bladder neck where the submucosa accommodates the injectable agent. Furthermore, suprapubic catheter drainage avoids the risks of collagen molding around the catheter (40,41). They reported a 45% improved and a 25% cure rate with a mean follow-up of 8.5 mo (40,42). Long-term follow up (mean 28 mo) of the same cohort of patient revealed a cure rate of 10%, improvement rate of 35%, and failure rate of 55% (43). Appell et al. (44) reported a 75% dry rate after 6 mo of follow-up. This decreased to 37.5% after 12 mo. However, all their patients had failed transurethral injection of collagen prior to the antegrade approach (44). Most authors advocate the injection of small volumes of collagen (2.5–5 mL) at each procedure and performing multiple procedures about 4 wk apart. Usually, there is no or little improvement following the ﬁrst one or two injections (36,38,45). Newer materials have been used. Silicone macroparticles (Macroplastique) has been injected in 15 postprostatectomy incontinence patients (nine post radical prostatectomy). Rapid deterioration of the initial improvement was observed (40% success at 1 mo, 71% at 3 mo, 33% at 6 mo, and 26% at 12 mo) (46). Colombo et al. (47) reported a better sustained result with polydimethylsiloxane. After a mean follow-up of 15.5 mo, ﬁve of six patients with severe incontinence were dry.

Male Slings Recently male slings have been introduced as a minimally invasive management of postprostatectomy incontinence. Two techniques for male sling were introduced over the last 5 yr. Schaeffer et al. (48) describe a bulbourethral sling based on the technique used for female pubovaginal slings. This procedure places three (4-cm-long, 6-mmdiameter) bolsters underneath the bulbar urethra tied to the rectus fascia using no. 1 nylon sutures tied to the edges of the bolster. The bolsters consist of Cooley soft vascular graft material or polyethylene terephthalate covered by a polytetraﬂuoroethylene sleeve. The nylon sutures are passed using a modiﬁed Stamey needle. With the patient in the lithotomy position, a single transverse suprapubic incision is made and carried down to the rectus fascia. Following placement of a Foley catheter, a midline perineal incision is made. Colle’s fascia is incised laterally to the bulbocavernosus muscle so that the perineal membrane can be felt by blunt ﬁnger dissection. This ﬁnger dissection is medial to the ischial arch, where the crura of the penis can often be felt, and lateral to the bulbocavernosus muscle that is usually not seen. A four-hole, 60-degree angled modiﬁed Stamey needle is passed retropubically from the suprapubic incisions, lateral to the vesical neck and urethra. The needle exits through the perineal membrane anteriorly, at the top of the ischial-symphyseal arch, between the bulbocavernosus muscle and the ischial bone. The needle can be passed under continuous cystoscopic inspection or blindly with cystoscopic evaluation subsequently. Sutures from one end of each of the three bolsters are passed through the eyes of the needle (each eye admits both nylon sutures at one end of the bolster), and the needle is withdrawn into the suprapu-

Table 2 Male Slings in Management of Postprostatectomy Incontinence Author Madjar et al. (51)

Mean age (yr) 67

Deﬁdio et al. (52) 403

No. of patients

Incontinence severity

Mean follow-up (mo)

Sling material

Cure (%)

Improved (%)

16 (8 post RRP)

Mean VLPP = 16 cm water

12.2

75

25

15

20% mixed incontinence

2–9

Mean VLPP = 26 cm water 50% total 50% 4.7 pads per d

12

Gelatin-coated polyethylene terephthalate or cadaveric fascia lata Cadeveric fascia lata, reinforced with prolene Prolene

Comiter et al. (53)a

67

21

Schaeffer et al. (48)b

67.9

64

Abbreviations: RRP, UI, urinary infection; VLPP, a Prospective. b Bulbourethral sling.

22.4

Cooley soft vascular graft material or polyethylene terephthalate covered by a polytetraﬂuoroethylene sleeve

86.6

6.6

Failed (%)

6.6

76

19

5

56

5

39

Complications Perineal discomfort in 3 patients that subsided in 2–6 wk 20% UI controlled medically No erosion, infection, or UI Revision 27% Erosion 6% Infection 3% Persistent perineal discomfort 52%

404

Hijaz et al.

bic incision, carrying six nylon sutures. The procedure is repeated on the other side. The bolsters are placed in parallel over the bulbocavernosus muscle and urethra so as to form a sling. The posterior most bolsters are sutured to the bulbocavernosus muscle to minimize bolster migration. The bladder is ﬁlled with approx 200 cc and baseline values for ALPP or maximum urethral pressure are obtained using a 7-F dual channel urethral catheter. Tension is placed on the sutures and, using the pressure measurements as a guide, the sutures are tied to each other across the midline. Target values are a maximum urethral pressure of <130 cm of water and a leak point pressure of >150 cm of water. Repeat leak point pressure and maximum urethral pressure measurements are performed after the bolsters are tied. The urethral catheter is removed, and the wounds are irrigated and closed. If leakage recurs, a retightening procedure may be performed. The patient is returned to the operating room, the suprapubic incisions are opened, and the sutures are identiﬁed and retied with increased tension. Schaeffer et al. (48) popularized the bulbourethral slings with a reported cure and signiﬁcantly improved rate of 61% (56% + 5%) on a mean follow-up of 22.4 mo. The reported revision rate when the sling was tightened was 27%. Erosion and infection rates were 6 and 3%, respectively (48). A questionnaire-based response rate was reported by Clemens et al. (49) a year later on their patients. This revealed a 41% complete cure rate at a median follow-up of 9.6 mo. Interestingly, persistent perineal numbness or discomfort was present in 52% of the patients. Radiation therapy was associated with high failure rate in this analysis: out of 12 patients who received adjuvant radiation therapy only 1 (8%) was cured (49). When the patients were studied urodynamically, there was a signiﬁcant increase in Valsalva Leak Point Pressure (VLPP) postoperatively; nevertheless their voiding pattern did not reveal obstruction (50). Madjar et al. (51) introduced a less invasive male sling with bone anchors. Four miniature bone screws with preattached pairs of no. 1 polypropylene sutures are placed directly into the medial aspect of the inferior rami of the pubic bone. A pair of bone anchors is placed just below the symphysis on each side, and the second pair is inserted 3–4 cm lower. To support the bulbar urethra, a gelatin-coated polyethylene terephthalate trapezoid-shaped sling or cadaveric fascia lata is tied to the pubic bone using the four pairs of sutures attached to the bone anchors. Urethral resistance is increased to 30–50 cm of water above baseline pressure. The outcomes in 16 patients followed for a mean of 12.2 mo were as follows: 12/16 patients were subjectively cured (dry or using one protective pad with no leakage), 2/16 were subjectively improved with >50% reduction in daily pad use, and 2/16 with preoperative mixed incontinence had resolution of stress incontinence urodynamically with persistent urge incontinence controlled on medical therapy. No erosion, infection, or revision were reported (51). Defidio et al. (52) reported an 86.8% cure rate using the same procedure with cadaveric fascia lata reinforced with prolene mesh on 15 patients followed for 2–9 mo. Comiter (53) prospectively followed up 18 patients with stress urinary incontinence after radical prostatectomy treated with male slings for a mean of 12 mo (range 5–21 mo). Only two titanium screws loaded with polypropylene suture were placed in each descending pubic ramus, and then polypropylene mesh was placed over the urethra and tied to the bone anchors, adjusting the sling tension to a compression pressure of 60 cm of water. Thirteen patients were cured, including one of two with previous artificial urinary sphincter placement and two of three with adjuvant radiation (53).

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405

Artiﬁcial Urinary Sphincter The artiﬁcial urinary sphincter (AUS) remains the standard of therapy of postprostatectomy incontinence. Since its introduction and development by American Medical Systems (Minnetonka, MN) in 1973 (54), the prototype artiﬁcial sphincter has been modiﬁed over the years to the current AMS-800 model introduced in the 1980s. More than 10 yr of follow-up on the use of the AUS has proved its efﬁcacy and safety. Nowadays, with the encouraging 1–2 yr of outcome data for the male slings, the AUS is moving into a position of second-line surgical therapy. However, to conﬁrm the present data, randomized prospective studies comparing the outcome of both methods in different patient populations with similar incontinence severity are necessary. Short of that, some authorities still consider AUS as the ﬁrst line of therapy, especially for patients with severe incontinence. Regardless of the indication, patients who are to undergo AUS implantation should be good surgical candidates, and have good manual dexterity and mental capability to operate the pump. Fulford and colleagues (55) reported on the 10–15-yr follow-up on AUS in 61 patients with predominantly neurogenic causes of sphincter dysfunction. The postprostatectomy incontinence population in this series was 25%. Overall, the percentage of patients with functioning AUS after 10 yr was 75%. Another, nonspecific population long-term follow-up was reported by Venn and colleagues (56). They reported an 84% dry rate at 10 yr after implantation of the AUS including 36% of patients with the original device, 27% in whom the device was replaced owing to mechanical failure, and 21% in whom the device was replaced after removal for erosion or infection. Montague and colleagues (57) reported on AUS outcome in 113 patients with a mean follow-up of 73 mo (range 20–170 mo). There were 4 (4%) patients who were dry and continent and 68 (60%) who were incontinent, using 0 to one pad daily. An additional 35 (31%) patients required two to three pads daily, and 5 (4%) used more than three pads daily. Of the 113 patients 31 (28%) were very satisfied, 50 (45%) were satisfied, 20 (18%) were neutral, 7 (6%) were dissatisfied, and 4 (4%) were very dissatisfied. Other contemporary series reported a socially acceptable urinary control (dry or mild incontinence) range between 76 and 96% and patient satisfaction in the 90% range (58–67). The need for revision of the AUS is the main complication of the procedure. Clemens et al. (66) constructed Kaplan-Meier curves for actuarial freedom from operative revision. The 5-yr actuarial rate for freedom from any operative revision was 50%, and the corresponding rate for cuff revision was 60%. A single operative revision did not predispose the patient to further revision. Causes for revisions can be classiﬁed into mechanical or erosion/infection related. Montague et al. (57), in their long-term review reported a revision rate of 12%. Haab et al. (68) reported a similar revision rate of 12.4% for sphincters implanted after 1987 when the narrow back cuff was introduced compared with 44.4% for those prior to 1987. Similar rates were reported by Elliot and Barrett (69) and Gousse et al. (70). The revision rate in the latter series was predominately for mechanical failure with device erosion and infection accounting for 4 and 1.4% of the total population of patients followed. Interestingly, patient dissatisfaction with the procedure was not correlated with the number of surgical revisions but with the number of pads used (70). In an analysis of the determinants of outcome, Perez and Webster (71) reported that the presence of preoperative features such as detrusor hyperactivity, bladder neck or

406

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urethral stricture disease, previous radiation therapy, and metastatic prostate cancer did not affect outcome of patients followed for 3.5 yr. However, recent reports had contradictory results on effects of radiation therapy (72,73). Gomha and Boone (72) reported similar reoperation, urethral atrophy, erosion, infection, continence, and global satisfaction rates in both groups of patients (irradiated and nonirradiated). Walsh et al. (73) reported a signiﬁcantly higher rate of urethral atrophy, infection, and erosion requiring surgical revision in irradiated patients (41% vs 11%). Overall surgical revision rate was equally common in irradiated (36%) and nonirradiated (24%) patients, and continence outcome and satisfaction were comparable despite previous irradiation and/or the need for surgical revision.

CONCLUSIONS Postprostatectomy incontinence continues to affect a great number of men. As prostate cancer screening improves, more operations will be performed, placing more men at risk. With better surgical techniques and understanding of the physiology of male continence, the incidence should continue to decrease. The evaluation of the patient should be aimed at determining the etiology of the incontinence, so that treatment can be optimized. As research continues in the development of new medications, neuromodulation, and operative procedures, a variety of options are available for treatment of most such patients.

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43. Klutke JJ, Subir C, Andriole G, Klutke CG. Long-term results after antegrade collagen injection for stress urinary incontinence following radical retropubic prostatectomy. Urology 1999;53:974–977. 44. Appell RA, Vasavada SP, Rackley RR, Winters JC. Percutaneous antegrade collagen injection therapy for urinary incontinence following radical prostatectomy. Urology 1996;48:769–772. 45. Carlson KV, Nitti VW. Prevention and management of incontinence following radical prostatectomy. Urol Clin North Am 2001;28:595–612. 46. Bugel H, Pﬁster C, Sibert L, et al. [Intraurethral Macroplastic injections in the treatment of urinary incontinence after prostatic surgery]. Prog Urol 1999;9:1068–1076. 47. Colombo T, Augustin H, Breinl E, et al. The use of polydimethylsiloxane in the treatment of incontinence after radical prostatectomy. Br J Urol 1997;80:923–926. 48. Schaeffer AJ, Clemens JQ, Ferrari M, Stamey TA. The male bulbourethral sling procedure for post-radical prostatectomy incontinence. [erratum appears in J Urol 1998;160:136]. J Urol 1998;159:1510–1515. 49. Clemens JQ, Bushman W, Schaeffer AJ. Questionnaire based results of the bulbourethral sling procedure. J Urol 1999;162:1972–1976. 50. Clemens JQ, Bushman W, Schaeffer AJ. Urodynamic analysis of the bulbourethral sling procedure. J Urol 1999;162:1977–1981; discussion 1981–1982. 51. Madjar S, Jacoby K, Giberti C, et al. Bone anchored sling for the treatment of post-prostatectomy incontinence. J Urol 2001;165:72–76. 52. Deﬁdio L, Franco N, Baum N. [Suburethral sling for male urinary incontinence]. Arch Ital Urol Androl 2002;74:138–141. 53. Comiter CV. The male sling for stress urinary incontinence: a prospective study [comment]. J Urol 2002;167:597–601. 54. Scott FB, Bradley WE, Timm GW. Treatment of urinary incontinence by implantable prosthetic sphincter. Urology 1973;1:252–259. 55. Fulford SC, Sutton C, Bales G, et al. The fate of the ‘modern’ artiﬁcial urinary sphincter with a followup of more than 10 years. Br J Urol 1997;79:713–716. 56. Venn SN, Greenwell TJ, Mundy AR. The long-term outcome of artiﬁcial urinary sphincters. J Urol 2000;164:702–706; discussion 706–707. 57. Montague DK, Angermeier KW, Paolone DR. Long-term continence and patient satisfaction after artiﬁcial sphincter implantation for urinary incontinence after prostatectomy. J Urol 2001;166:547–549. 58. Bosch JL, Klijn AJ, Schroder FH, Hop WC. The artiﬁcial urinary sphincter in 86 patients with intrinsic sphincter deﬁciency: satisfactory actuarial adequate function rates. Eur Urol 2000;38:156–160. 59. Fishman IJ, Shabsigh R, Scott FB. Experience with the artiﬁcial urinary sphincter model AS800 in 148 patients. J Urol 1989;141:307–310. 60. Gundian JC, Barrett DM, Parulkar BG. Mayo Clinic experience with the AS800 artiﬁcial urinary sphincter for urinary incontinence after transurethral resection of prostate or open prostatectomy. Urology 1993;41:318–321. 61. Marks JL, Light JK. Management of urinary incontinence after prostatectomy with the artiﬁcial urinary sphincter. J Urol 1989;142:302–304. 62. Leo ME, Barrett DM. Success of the narrow-backed cuff design of the AMS800 artiﬁcial urinary sphincter: analysis of 144 patients. J Urol 1993;150:1412–1414. 63. Martins FE, Boyd SD. Artiﬁcial urinary sphincter in patients following major pelvic surgery and/or radiotherapy: are they less favorable candidates? [comment]. J Urol 1995;153:1188–1193. 64. Singh G, Thomas DG. Artiﬁcial urinary sphincter for post-prostatectomy incontinence. Br J Urol 1996;77:248–251. 65. Klijn AJ, Hop WC, Mickisch G, et al. The artiﬁcial urinary sphincter in men incontinent after radical prostatectomy: 5 year actuarial adequate function rates. Br J Urol 1998;82:530–533. 66. Clemens JQ, Schuster TG, Konnak JW, et al. Revision rate after artiﬁcial urinary sphincter implantation for incontinence after radical prostatectomy: actuarial analysis. J Urol 2001;166:1372–1375. 67. Litwiller SE, Kim KB, Fone PD, et al. Post-prostatectomy incontinence and the artiﬁcial urinary sphincter: a long-term study of patient satisfaction and criteria for success. J Urol 1996;156:1975–1980. 68. Haab F, Trockman BA, Zimmern PE, Leach G. Quality of life and continence assessment of the artiﬁcial urinary sphincter in men with minimum 3.5 years of followup. J Urol 1997;158:435–439. 69. Elliott DS, Barrett DM. Mayo Clinic long-term analysis of the functional durability of the AMS 800 artiﬁcial urinary sphincter: a review of 323 cases. J Urol 1998;159:1206–1208. 70. Gousse AE, Madjar S, Lambert MM, Fishman I. Artiﬁcial urinary sphincter for post-radical prostatectomy urinary incontinence: long-term subjective results. J Urol 2001;166:1755–1758. 71. Perez LM, Webster GD. Successful outcome of artiﬁcial urinary sphincters in men with post-prostatectomy urinary incontinence despite adverse implantation features. J Urol 1992;148:1166–1170.

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72. Gomha MA, Boone TB. Artiﬁcial urinary sphincter for post-prostatectomy incontinence in men who had prior radiotherapy: a risk and outcome analysis. J Urol 2002;167:591–596. 73. Walsh IK, Williams SG, Mahendra V, et al. Artiﬁcial urinary sphincter implantation in the irradiated patient: safety, efﬁcacy and satisfaction. BJU Int 2002;89:364–368. 74. Kaufman M, Lockhart JL, Silverstein MJ, Politano VA. Transurethral polytetraﬂuoroethylene injection for post-prostatectomy urinary incontinence. J Urol 1984;132:463–464. 75. Stanisic TH, Jennings CE, Miller JI. Polytetraﬂuoroethylene injection for post-prostatectomy incontinence: experience with 20 patients during 3 years. J Urol 1991;146:1575–1577. 76. Politano VA. Transurethral polytef injection for post-prostatectomy urinary incontinence. Br J Urol 1992;69:26–28. 77. Aboseif SR, O’Connell HE, Usui A, McGuire EJ. Collagen injection for intrinsic sphincteric deﬁciency in men [comment]. J Urol 1996;155:10–13. 78. Reek C, Noldus J, Huland H. [Experiences with local collagen injection in male stress incontinence]. Urologe (Ausg. A) 1997;36:40–43; discussion 44. 79. Gottfried HW, Maier S, Brandle E, et al. [Transurethral collagen injection for treatment of urinary stress incontinence]. Urologe (Ausg. A) 1997;36:413–419. 80. Griebling TL, Kreder KJ Jr, Williams RD. Transurethral collagen injection for treatment of postprostatectomy urinary incontinence in men. Urology 1997;49:907–912. 81. Elsergany R, Ghoniem GM. Collagen injection for intrinsic sphincteric deﬁciency in men: a reasonable option in selected patients [comment]. J Urol 1998;159:1504–1506. 82. Kageyama S, Kawabe K, Suzuki K, et al. Collagen implantation for post-prostatectomy incontinence: early experience with a transrectal ultrasonographically guided method. J Urol 1994;152:1473–1475. 83. Tiguert R, Gheiler EL, Gudziak MR. Collagen injection in the management of post-radical prostatectomy intrinsic sphincteric deﬁciency. Neurourol Urodynamics 1999;18:653–658.

21

Sural Nerve Grafting During Radical Prostatectomy Techniques and Results

Edward D. Kim

INTRODUCTION Advances in radical retropubic prostatectomy (RRP) technique have enabled surgeons to perform this procedure with diminished risks of troublesome morbidity, yet erectile dysfunction remains a signiﬁcant concern. When both neurovascular bundles (NVBs) are preserved during RRP, potency rates of up to 71%, but generally closer to 30–60%, are observed (1–4). When both NVBs are intentionally resected, return of function is the exception. Interposition sural nerve grafting (SNG) during RRP offers men the increased possibility of maintaining spontaneous erections, which is “quantitatively related to preservation of autonomic innervation” when the cavernous nerves are resected (4). This technique represents a potential advance for the preservation of potency in RRP patients.

BACKGROUND Nerve grafting is an established medical practice that has not yet had widespread application in urology. The principles of nerve grafting are well established in the plastic surgery literature (5). The basis for nerve regeneration and nerve grafting is the ability of axons to produce axon sprouts. The cut end of a nerve sprouts minifascicles that contain axon sprouts, ﬁbroblasts, Schwann cells, and capillaries. The nerve graft provides a conduit that regenerating nerve ﬁbers may use to connect eventually with the transected distal end. However, when gaps are present between nerve ends, functional recuperation is haphazard and negligible and results in neuroma formation. Thus, a graft converts disorderly growth into an orderly process by providing a structured framework for regenerating axons to restore previous gaps. The graft may further contribute neurotropic agents through its Schwann cells, products of axon-myelin breakdown, or activity of specialized cells of mesodermal origin. From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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Interposition nerve grafting using the sural nerve, considered standard for grafting purposes, has been used extensively with brachial plexus, facial nerve, and peripheral nerve injuries (5,6). The sural nerve is used for nerve grafting and peripheral nerve biopsy (7) because of its ease of harvest, high fascicular density, and minimal branching (8,9). The sural nerve is ﬂat and ovoid in shape, with a width of 1.5–3.0 mm. Studies in rat models clearly demonstrate the feasibility and return of erectile function after denervation and placement of nerve grafts. Quinlan et al. (10) from Johns Hopkins used a genitofemoral nerve graft after bilateral ablation of 5-mm segments and identiﬁed return of normal potency 4 mo postoperatively. Use of nerve grafts with nerve growth factor and fetal amniotic membrane as an alternative growth matrix further enhanced the return of function (11). In a separate but similar investigation from the Brigham and Women’s Hospital, 65% of rats had recovery of potency using a genitofemoral nerve graft (12). Even the use of a Silastic tube nerve growth conduit ﬁlled with nerve growth-enhancing media and fetal amniotic membrane with nerve growth factors has produced favorable results (13). Using electrical stimulation with resultant tumescence as the criterion, these investigators found that the nerve growth conduit with Matrigel and acidic ﬁbroblast growth factor resulted in a return of potency in 50–58% of rats, in comparison with 5–11% for the nerve-ablated group at 2 and 4 mo, respectively. Although criticisms include the facts that the rat model does not equate to the human situation and that the distance required for nerve regeneration in the rat is much smaller than in the human, these studies provided the necessary framework for further study in the RRP patient. Nerve regeneration occurs in speciﬁc stages. Stage 1 involves the growth of axons down the graft to re-establish the pathway. This process is variable, depending on the distance to end organs, and may take months to several years in the upper limb, and up to 3 yr in the lower limb. Stage 2 is the re-establishment of the complex inter-relationships between the nerve terminals and the tissues innervated. In muscle, the ﬁrst sign of motor recovery is the development of electrical activity with electromyography. Sensory recovery is evident with tenderness of the muscle to squeezing, as well as sensation to pinprick. Motor end plates typically become resistant to reinnervation after about 12 mo of denervation. There is no apparent time limit on sensory recovery. In stage 3, further myelination of the axons occurs, resulting in feeble voluntary motor contractions and a poorly localizable sensation to pinprick. Stage 4 is characterized by further improvement, leading to stage 5—the full restoration of motor and sensory functions. The recovery to stage 5 may take 3 yr. Finally, stage 6 involves the correction of deranged central mechanisms created by the nerve injury. This last stage does not involve further axonal regeneration, but rather the development of coordination and adaptive readjustment. The rate of nerve regeneration is about 1 mm/d in adult humans and may vary depending upon age, gap distance, and hormonal factors. Time to functional recovery is proportional to the distance the nerve is required to regenerate. A 5–6-cm graft will generally need 2–3 mo to traverse initially; further innervation of the end organ then takes place over a further 6–15 mo. Nerve regeneration must traverse the nerve graft as well as the distal in situ segment, which adds another 8–10 cm in the RRP-SNG technique. Although most nerve grafting has been performed for restoration of motor function, parasympathetic function can also return. van Lith-Bijl et al. (14,15) demonstrated

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laryngeal abductor reinnervation with a phrenic nerve transfer in a cat model. This model of phrenic nerve grafts for the vocal cord abductor muscles had been demonstrated by Crumley et al. (16,17) and Sato and Saito (18) in humans and in dog models. Although a graft was not employed speciﬁcally, numerous reports in the heart transplant literature support parasympathetic reinnervation to the heart, even after complete transsection of nerve ﬁbers (19–21). In the early 1990s, Walsh (22) performed the ﬁrst interposition nerve grafts during RRP in 12 men using the native genitofemoral nerve. Because most men had a contralateral nerve-sparing procedure, and the small caliber of the genitofemoral nerve may impair the reliability of nerve regeneration, results were difﬁcult to interpret, and the procedure was abandoned. Reﬁnements in the technique and a team approach with specialists in nerve reconstruction, prostate cancer surgery, and erectile dysfunction led to the rebirth of the technique in 1997 at Baylor College of Medicine (23). At present, this procedure is being performed routinely at approx six institutions, with a cumulative experience of over 500 cases, although the majority have been performed unilaterally.

METHODOLOGY AND TECHNIQUE Patient Selection The ideal patient has normal preoperative erectile function, has not received neoadjuvant hormonal or radiation therapy, and does not have a neuropathy. The presence of moderate to severe erectile dysfunction is a contraindication given the poor results of SNG in this group. The decision to spare or resect NVBs is based on the surgeon’s preference but is inﬂuenced by clinical staging, prostate-speciﬁc antigen (PSA) level, and transrectal ultrasound (TRUS)/biopsy results. Considerable variation in the indications and applications for performing nerve-sparing surgery exists among urologists. The patient should be counseled that nerve grafting can only be performed at the time of RRP, not afterwards, and that optimal return of function may not be apparent for several years. In addition, because these men have high-volume tumors, they may require adjuvant therapy with external beam radiotherapy or hormonal suppression, which may have adverse effects on sexual function. The lower extremities are examined for evidence of motor or sensory neuropathies, infection, large varicose veins, or other abnormalities that may preclude nerve harvest. The patient should be informed that the risks of nerve grafting include, but are not limited to: 1. At the site of the sural nerve procurement: hematoma, infection, pain, small sensory deﬁcit in the lateral aspect of the foot, neuroma formation, reﬂex sympathetic dystrophy, and delayed ambulation. 2. At the site of the interposition grafting: infection and blood loss related to increased duration of the procedure.

Surgical Technique The technique for interposition SNG is a modiﬁcation of the RRP described by Goad and Scardino (24). The key steps are described in detail in the ﬁgures: 1. Preparation and resection of the NVBs (Fig. 1) (25) 2. Harvesting the sural nerve (Figs. 2 and 3) (26).

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Fig. 1. (A) Wide resection of the right neurovascular bundle (NVB). The tumor is depicted encroaching upon the NVB at the midprostate level. The lateral dotted line indicates the limit of the complete resection of the NVB. The NVB will be dissected medially along the urethra (shorter set of dotted lines). The two sets of tied sutures are on the deep dorsal vein complex and the anterior surface of the prostate. (From Kim ED, Scardino PT, Kadmon D, Slawin KM, Nath R. Interposition sural nerve grafting during radical prostatectomy. Urology 2001;57:211–216, with permission.) (Figure continues)

3. Placement of the nerve graft (Figs. 4 and 5) (23). 4. Completion of the vesicourethral anastomosis.

Clinical Pearls 1. Preparation and resection of the NVBs (Fig. 1). a. Accurate identiﬁcation and preparation of the NVBs is critical to performing this procedure properly. If the surgeon is not facile and extremely comfortable with nervesparing techniques, this procedure will be quite difﬁcult to perform. b. A relatively bloodless ﬁeld is required for precise identiﬁcation of the transected ends of the NVBs, which are not a discrete nerve but a plexus of nerve ﬁbers and vessels.

Fig. 1. (continued) (B) The NVB is dissected medially at the level of the urethra using Metzenbaum scissors to facilitate creation of a stump. (C) To tag the NVB and minimize bleeding, a medium hemoclip and silk suture are very gently applied, taking care not to cause a crush injury. The NVB is then divided (dotted lines). (Figure continues)

Fig. 1. (continued) (D) A similar dissection of the NVB is performed just proximal to the base of the prostate. (E) The proximal NVB is divided.

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Fig. 2. Innervation, Upper Left Inset: The hemoclip is removed. The tagging silk suture has already been removed. The nerve is inspected for crush injury. If a signiﬁcant injury is present, the NVB stump may be resected several millimeters. Lower Left and Right Inset: The sural nerve is grafted to the neurovascular bundle using two interrupted 7-0 Prolene sutures at each end. Loupe magniﬁcation and a relatively dry operative ﬁeld are essential. Center: The right nerve graft has been completed. The left nerve is being prepared for grafting. We are now placing the nerve grafts after the vesicourethral anastomotic sutures have been placed but not tied down. (From Kim ED, Hampel O, Mills N, et al. Cavernous nerve grafting restores partial erections after non-nerve sparing radical retropubic prostatectomy. J Urol 1999;161:188–192, with permission.

2. Harvesting the sural nerve (Figs. 2 and 3). a. Harvesting the sural nerve may be performed by a plastic surgeon or neurosurgeon, although the author (E.D.K.) routinely harvests this nerve while the assistant prepares the bladder neck after removal of the prostate. If another surgeon is involved, scheduling issues may arise. b. Using the tendon stripper technique described avoids a large incision on the posterior calf and thereby decreases pain and morbidity. c. Because the typical length of sural nerve harvested is 18–20 cm, there is an excess of graft material available. On occasion, extra SNG segments may be used to place two grafts on a given side.

Fig. 3. (A) The sural nerve may be identiﬁed in the groove inferior (straight line) to the lateral malleolus (curved line). (B) After making a 3-cm incision, a thin adventitial layer is sharply separated and opened. The structures of signiﬁcance here are several branches of the small saphenous vein (vessel loop) and the sural nerve. Loupe magniﬁcation is helpful in distinguishing between the two structures. The superﬁcial course of the sural nerve may be appreciated when the vessel loop is pulled outward. Inadvertent division of these veins is of no clinical signiﬁcance. After division of the nerve, a ﬁne right-angled clamp is used to grasp the nerve end through the barrel of a tendon stripper (SSI Surgical, 5-mm diameter). The direction of the tendon stripper will be superﬁcial toward the back of the calf. (Figure continues)

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Fig. 3. (continued) (C) The barrel of the tendon stripper is palpated in the back of the calf approx 16–18 cm from the ankle incision. A 1-cm vertical incision is made directly onto the barrel. The barrel is then pulled back toward the foot for 2 cm. The nerve may then be isolated with a right-angled clamp. The remaining end is clamped and the nerve sharply divided. The sural nerve is then removed via the ankle incision. The remaining sural nerve end is coagulated. (D) The sural nerve harvested length typically measures 18–20 cm. This extra length is helpful when bilateral grafts are placed, or if a unilateral graft becomes damaged or lost. Segments up to 40 cm may be harvested with a resultant minimal sensory deﬁcit on the lateral non-weight-bearing aspect of the foot. (Figure continues)

419

Fig. 3. (continued) (E) Initial area numbness on the foot (circled). The incision has been marked. This numbness gradually decreases over several years to approx one-third the size demonstrated.

3. Placement of the nerve graft (Figs. 4 and 5). a. Experience with loupe magniﬁcation and long, ﬁne instruments is necessary. Long Cushing’s forceps and Castroviejo needle holders are preferred. Use of an operative microscope is not necessary and would be overly cumbersome. b. In addition to gentle handling of the sural nerve graft, it is important to have a tension-free repair, assisted by a graft 10–20% longer than the defect to compensate for shrinkage. Measuring the distance between the nerve stumps is helpful. c. The use of microclips to secure the crossed ends of the suture atop the anastomosis has reduced the difﬁculty of the procedure. d. The directionality of the nerve is probably not important (27,28). e. Minimal suction should be used near the graft. f. The learning curve is steep. It is best taught by those centers with extensive experience. With experience, the additional time per graft is 10–15 min. 4. Completion of the vesicourethral anastomosis. a. Special care must be taken while tying the sutures of the vesicourethral anastomosis to prevent disrupting the nerve grafts. b. Place the Jackson-Pratt suction drain away from the area of the grafts.

Postoperative Care Discharge to home is unaffected by this procedure. Patients have been advised and strongly encouraged to start intracavernous injection therapy and vacuum constriction devices as soon as continence has been restored, generally about 2–3 mo postopera-

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Fig. 4. The lateral cutaneous sural nerve, a branch of the common peroneal nerve, joins the medial cutaneous sural nerve in 75–80% to form the sural nerve. The medial cutaneous sural nerve originates from the tibial nerve just above the ﬂexion crease of the popliteal fossa. It then pierces the deep fascia at variable levels in the midportion of the calf. However, the lateral cutaneous sural nerve may not be present or may be completely separate from the medical cutaneous sural nerve. (From Kim ED, Seo JT. A minimally invasive technique for sural nerve harvesting. Urology 2001;57:921–924, with permission.)

tively (29). Results with sildenaﬁl citrate may not be optimal until 18–24 months postoperatively. These treatments may help to maintain cavernous smooth muscle integrity and function while awaiting for nerve regeneration to the end organ represented by the penis. Penile atrophy, corporal veno-occlusive dysfunction, and ﬁbrotic plaques suggestive of Peyronie’s disease are ﬁndings associated with RRP that may be a direct result of denervation.

RESULTS Over 600 men have had SNG placement performed at the following centers: Baylor College of Medicine (BCM; Houston, TX), M.D. Anderson Cancer Center (MDACC;

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A

Fig. 5. (A) Technique for anastomosis of the interposition sural nerve graft (SNG) to the NVB. The 7-0 polypropylene suture with a microclip attached through its midportion is placed through the epineurium of SNG and NVB. The microclip allows apposition of the graft with the NVB. (B) Both ends of the suture are gently lifted, bringing the nerve ends together. Microclips are placed on the suture at the graft site. This technique is much simpler to perform than hand-tying knots with a ﬁne suture deep in the pelvis.

Houston, TX), Memorial Sloan Cancer Center (MSKCC; New York, NY), and University of Tennessee (UT; Knoxville, TN). SNG placement has also been performed at the University of Washington (Seattle, WA), the University of Michigan (Ann Arbor, MI), Columbia University Medical Center (New York, NY), the Cleveland Clinic (Cleve-

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Table 1 Results of Bilateral Interposition Sural Nerve Graftinga

Series Kim et al. (30) Baylor College of Medicine Wood et al. (31) M.D. Anderson Cancer Center Total a

Viagra potency rate

Unassisted Intercourse intercourse with Viagra only

No intercourse 40–60%

<20%

43 (10/23)

26 (6/23)

17 (4/23)

9 (2/23)

48 (11/23)

43 (13/30)

23 (7/30)

20 (6/30)

17 (5/30)

40 (12/30)

43 (23/53)

25 (13/53)

19 (10/53)

13 (7/53)

43 (23/53)

Data are percents, with number/total in parentheses.

land, OH), and the Humboldt-Universitat zu Berlin (Germany). Most of these men had unilateral grafts performed during a unilateral nerve sparing and contralateral nerve resection RRP.

Bilateral Nerve Grafts In two series from the BCM and MDACC, a total of 53 men have had bilateral SNG placement with at least 1 yr of follow-up. (Table 1) The results are remarkably similar between these institutions. The BCM trial was a prospective, nonrandomized, controlled series of men undergoing RRP between 1997 and 1999 (30). These men had a deliberate wide excision of both NVBs, followed by the placement of bilateral SNGs. In the BCM series, 23 men had a follow-up of 23 ± 10 mo (range 12–49 mo). Overall, six (26%) men have had spontaneous, medically unassisted erections sufﬁcient for sexual intercourse with vaginal penetration. Six (26%) men with partial erections described “40–60%” (fullness, no rigidity, not able to penetrate) spontaneous erections, and 11 (48%) have had no significant erectile activity (<20% rigidity). Overall, 10 (43%) men have had intercourse with Viagra (sildenaﬁl citrate; Pﬁzer, New York, NY). Twelve potent men having bilateral nerve resections and no nerve grafts served as the control group. These men had their surgery performed during the same time frame as those men having nerve grafts. They were offered nerve grafting but declined, based on concerns regarding the investigational nature of the study. The mean follow-up for the control group was 18 ± 5 mo. The control and graft groups were statistically similar in preoperative characteristics such as tumor stage, age, and sexual function. The International Index of Erectile Function (IIEF) and a visual assessment scale (VAS) (0% no response; 20% slight enlargement; 40% moderate enlargement; 60% full, not able to penetrate; 80% full, able to penetrate; 100% rigid) were used for assessment of erectile function. The partner questionnaire scores also supported the ﬁndings of improved erectile function. A partner questionnaire conﬁrmed beneﬁt. Tumescence was not reported until at least 5–6 mo after surgery. Men who responded favorably consistently described a “tingling or twitching sensation” that appeared in their penis in the absence of sexual stimulation starting at approx 5–8 mo after surgery. This “tingling” could result in a “20%” tumescence. From 6 to 12 mo postop, steady improvement was evident. Men did not have the return of sufﬁcient

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Kim Table 2 Clinical Characteristics of the Baylor College of Medicine (BCM) Study Groupa

Parameter Age at surgery (yr) Months of follow-up Blood loss (mL) OR time (min) Preop PSA (ng/dL) Preop Gleason score cT stageb

Postop PSA (ng/dL) Postop Gleason score pT stageb

Demonstrable erectile activity (n = 12) 57 ± 5 25 ± 8 1505 ± 723 251 ± 46 14 ± 11 7±1 T1 (3) T2 (8) T3 (1) 0.3 ± 0.7 7±1 T2 (8) T3 (4)

No demonstrable erectile activity (n = 11) 59 ± 8 21 ± 9 790 ± 456 237 ± 28 12 ± 9 7±1 T1 (4) T2 (7) <0.1 ± 0 7±1 T2 (6) T3 (5)

Control (n = 12) 61 ± 4 20 ± 5 1025 ± 537 195 ± 28 19 ± 26 7±1 T1 (3) T2 (8) T3 (1) 0.2 ± 0.1 7±1 T2 (6) T3 (6)

a Men with demonstrable clinical erectile activity had return of partial erections (visual analog score 40–60%) or better. The Mann-Whitney rank sum test was used for comparison. Differences are not signiﬁcant when all men with nerve grafts were combined and compared with the control group. b Data in parentheses are numbers of patients.

erectile activity for intercourse for at least 1 yr after surgery. Men who responded had a slow, but gradual improvement of erectile activity from 12 to 24 mo post-op. Best results have been evident at 24–30 mo post-op. Except for the placement of bilateral nerve grafts, no factors were clearly associated with a favorable outcome. Trends observed included greater operative time and blood loss (no transfusions were required) for nerve graft patients (Table 2). One patient in each of the graft and control groups had developed a PSA recurrence. In the MDACC series, 30 potent men were enrolled in a phase I protocol to study the benefit of bilateral SNG placement. The Cavermap™ (Alliant Medical Technologies, Norwood, MA) was used for NVB identification and resection intraoperatively. With a median follow-up of 22 mo, the Viagra potency rate was 43% (13/30 men) (31). Overall, 18/30 (60%) men had both objective and subjective evidence of at least partial erectile activity. Seven men (23%) were able to have unassisted intercourse, and an additional six men (20%) required sildenafil for intercourse. Regarding cancer control, two patients had a rising PSA after initially having an undetectable PSA after surgery. The authors concluded that SNG placement following non-nerve-sparing RRP was a promising means of preserving sexual functioning while maximizing cancer control, with potency rates approaching those in published series that utilize nerve-sparing techniques.

Unilateral Nerve Grafts All available data from four institutions suggest beneﬁt of SNG placement compared with unilateral nerve resection without SNG (Table 3). Data from men having a unilateral SNG with a contralateral nerve sparing procedure may be difﬁcult to interpret at the present time without having a randomized prospective clinical trial. This

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Table 3 Results of Unilateral Interposition Sural Nerve Grafting Series

Viagra potency rate

Kadmon et al. (33) BCM Wood et al. (31) MDACC Eastham and Scardino (34) MSKCC

Kim et al. (30) UT Total

29% (12/41) 48% (13/27) 65% (28/43) 65% (13/20) 50% (66/131)

Control 9% UNS (3/34) Not provided 22% predicted cohort UNS 67% BNS 47% UNS (7/15)

Abbreviations: UNS, unilateral nerve sparing; BNS, bilateral nerve sparing; BCM, Baylor College of Medicine; MDACC, M.D. Anderson Cancer Center; MSKCC, Memorial Sloan Kettering Cancer Center; UT, University of Tennessee.

project is currently ongoing under the direction of Dr. Christopher Wood at MDACC. At issue in interpretation of results is whether the return of potency is from the spared nerve or the SNG. At the 2002 Annual Meeting of the American Urological Association (AUA), MDACC reported that 13/27 (48%) men having a unilateral SNG regained potency using Viagra (32). Potency was deﬁned as the ability to have an erection sufﬁcient for vaginal penetration. These men had a mean age of 55 ± 6 yr and an average follow-up of 13 ± 8 mo. The average time to return of function was 9 ± 5 mo. Cavermap ﬁndings were not helpful in predicting return of function. Kadmon et al. (33) presented the BCM series at the same meeting. Twelve of 41 (29%) men having a unilateral SNG regained potency, whereas only 3 of 34 (9%) men without SNG placement regained potency. The seemingly poor overall results may be as a result of the deﬁnition of potency—an IIEF erectile function domain score of at least 17/30 without any therapy. The most recent data from MSKCC indicates that 28/43 (65%) men had return of potency (34). In comparison, using a validated nomogram, only 22% of an age-matched cohort having a unilateral nerve sparing without SNG would be expected to regain potency. The criterion for potency was an IIEF erectile function domain of >15. A controlled series of men at UT demonstrated a Viagra potency rate of 65% in men with unilateral SNG (13/20 men) compared with 47% (7/15 men) of a control group having a unilateral nerve resection only. With a minimum of 1 yr of follow-up, the mean follow-up was 18 mo.

Preliminary Observations At the 2002 AUA Annual Meeting, the BCM group reported that SNG status is an independent predictor of urinary control, as well as the recovery of potency, when controlling for age (35). Although it is unlikely that the improved urinary control is owing to a SNG contribution, subtle differences in surgical technique associated with the SNG may be contributory.

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Kadmon et al. (33) presented data suggesting that unilateral nerve grafting decreases the time to recovery of potency. The mean time to recovery of potency was 18 mo for the SNG men vs 22 mo for the control group (p = 0.049). Longer follow-up with larger groups of men is required before this observation can be validated. Scardino from MSKCC has been placing SNGs in men undergoing salvage RRP, although speciﬁc data have not been presented (36).

Positive Margins Men having SNG placement should be at high risk for extracapsular disease and positive surgical margins if the NVB is spared. In men with a large, high-grade cancer adjacent to the posterolateral capsule, SNG placement may assist in the surgical dilemma of whether to spare or resect the NVB. Scardino and Kim (37) found that 40% of SNG cases had extracapsular extension of cancer, whereas only 9% had a positive surgical margin posterolaterally. In contrast, whereas 8% of men having bilateral nerve-sparing procedures had extracapsular extension, 6% had posterolateral positive margins (38).

Morbidity of Sural Nerve Harvest Sural nerve harvesting in preparation for interposition grafting during RRP is well tolerated and carries minimal morbidity. Urologists have been hesitant to harvest the sural nerve because of a lack of familiarity with the technique and basic knowledge about the sural nerve. Using the minimally invasive technique described, urologists should be able to harvest the nerve successfully with few problems. In a series of 12 men studied with validated pain questionnaires, no signiﬁcant leg morbidity or bothersome pain was observed (26). Average operative time for the entire harvesting procedure, including skin closure, was 15 min. Estimated blood loss was less than 5 mL. No wound infection or unexpected skin erythema from a small skin incision was present with a minimum of 6 mo of follow-up. Discharge to home and ambulation were not delayed compared with the usual length of stay after RRP. Two men noticed occasional, minor tingling in the lower calf between 1 and 3 mo postoperatively. There were no other complications, and none of the men expressed any regret at having the nerve grafting procedure performed. Men are instructed to expect incisional discomfort for approx 2–3 mo in the leg from which the nerve graft was harvested. Bothersome discomfort will resolve in nearly all men by 5–6 mo. A sensory deﬁcit approx 6 × 3 cm on the lateral aspect of the side of the foot can be expected as a long-term sequela.

DISCUSSION Feasibility and Beneﬁt The placement of bilateral SNGs, which is well tolerated and carries minimal morbidity, can successfully restore erectile function in men who otherwise would have no chance of return of spontaneous erectile function. Although the initial results of a 43% Viagra potency rate at BCM were viewed by many with skepticism, the nearly identical results from the MDACC group has provided the necessary external validation of this new procedure. This combined experience has provided the proof-of-principle that cavernous nerve regeneration can and does occur. Patience on the part of both the physician and patient must be present because the full beneﬁt of these nerve grafts may not be appreciated until at least 24–36 mo postoperatively.

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The data trend from four institutions for men with unilateral SNG points toward improvements in results over nerve resection with SNG placement. Because of the potential contribution to potency of the spared contralateral nerve, the true beneﬁt of the SNG may be difﬁcult to interpret. A prospective, multi-institutional study with large numbers of men will deﬁne the beneﬁt of unilateral SNG placement. The large cumulative experience from multiple institutions has provided evidence that SNG placement can be performed without undue difﬁculty. Precise identiﬁcation of both ends of the NVB is critical for successful performance. Surgeons not extremely comfortable and adept with nerve-sparing surgery and with the use of loupe magniﬁcation and ﬁne instrumentation will not be able to perform this procedure. SNG placement is a ﬁnesse procedure that will be best suited for those urologists who are facile and have expertise in nerve-sparing surgery. It is important to emphasize that the erections may not be as rigid as before surgery. Although the pathophysiology of erectile dysfunction after RRP is traditionally considered neurogenic, arterial and corporeal smooth muscle alterations have also been implicated—factors that contribute to the failure of some patients to recover erectile function even after meticulous bilateral nerve-sparing procedures or nerve grafting.

Indications Although the initial criticisms of SNG focused on the feasibility of SNG placement and the capacity of cavernosal nerves to regenerate, present questions relate to the appropriate role of this procedure for men undergoing RRP. Bilateral nerve resection is uncommon, comprising less than 10% of RRPs for most urologists. Therefore, the number of men likely to beneﬁt from bilateral SNG placement will probably be small. However, a substantially larger group of men will undergo unilateral nerve resection and may beneﬁt from this procedure. In the BCM series of Slawin et al. (39), 33% of men between 1996 and 2001 had a unilateral nerve-sparing procedure. Walsh (22) has argued that because of his 91% Viagra potency rate in men undergoing unilateral nerve-sparing procedures, very few of these men require SNG placement. For most urologists, however, potency rates are far from 91%. SNG placement is not a substitute for a nerve-sparing procedure. The native nerve should be spared whenever possible. When the decision is made to resect the nerve because of high risk for a positive margin, then SNG can be considered. In the presence of established extracapsular disease in the region of the NVB, nerve-sparing RRP is more likely to result in positive margins (39). Because a positive surgical margin is an independent predictor of PSA progression-free survival, avoidance of this positive margin adds signiﬁcant beneﬁt for cancer control.

Future Study After 6 yr of experience, SNG has generated intense interest in the ﬁeld of urology. Undoubtedly, our present knowledge represents only the tip of the iceberg. Areas for future study with nerve graft are exciting and include the following: 1. Use of cavernous nerve stimulation (40). The beneﬁt of Cavermap nerve stimulation during nerve-sparing RRP has yet to be determined. Slawin et al. (39) have published their technique of Cavermap stimulation during SNG placement, but beneﬁt for erectile function outcome has yet to be established. 2. Determination of the beneﬁt of unilateral SNG placement. As more institutions perform SNG placement, the beneﬁt will be more clearly deﬁned. However, when surgeons with

428

3.

4.

5.

6.

7.

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inadequate training and experience perform SNG placement, a decline in the positive outcomes may be evidenced. Improvements and simpliﬁcation of the NVB-SNG anastomosis. Further advances in technique may help to simplify the procedure and further increase the popularity of SNG placement. Possible examples include the use of ﬁbrin glue, nerve growth factors, and quick-connector types of systems. Although 43% of men with bilateral SNG placement are potent and a total of 56% of men have return of erectile activity, most men are not potent. These results need to be improved with reﬁnements in technique. Laparoscopic SNG placement. Because laparoscopy is associated with much improved visualization and decreased blood loss, this approach may provide a signiﬁcant advance. The ﬁrst procedures were performed in Berlin, Germany by Turk around 2000. In 2002, Kaouk and Gill at the Cleveland Clinic performed the ﬁrst robotic-assisted SNG placement using the DaVinci system (41). Determination of the beneﬁt of adjuvant external beam radiotherapy and hormonal suppression. Although a school of thought from the BCM is that these adjuvant therapies do not adversely affect potency, they certainly do not help. Radiotherapy is associated with scatter to the crural bodies and can adversely impact the corporal bodies, in addition to detrimental effects on the SNG. The long-term effect of temporary hormonal suppression is unknown. Determination of the effect of different types of nerve grafts. The sural nerve is ideal given its large caliber and minimal morbidity of harvest. The genitofemoral and ilioinguinal nerves have also been used recently because of their proximity and relative ease of harvest using the retropubic technique (42). However, their small caliber in comparison with the NVB may limit the effectiveness of the anastomosis. Basic science studies. Further demonstration of the beneﬁt of SNG placement on the distal in situ NVB will be helpful in determining the physiology of nerve regeneration. The role of neurotrophic factors and neuronal mediators of penile erection in preserving the smooth muscle function of the cavernous bodies will also be important. For example, because nitric oxide synthase expression mediates terminal neuronal differentiation (43), the interplay of nitric oxide with neurotrophins may affect the functional integrity of the penis. As another example, the immunophilin ligand FK506 can prevent axonal degeneration in a rat model of cavernous nerve crush injury (44).

CONCLUSIONS Interposition sural nerve grafting during RRP can restore spontaneous erections in men undergoing nerve resection. Multi-institutional experience has been consistent and conﬁrms the feasibility and beneﬁt for bilateral and unilateral SNG placement. Although this procedure remains promising, it is not a substitute for nerve sparing, which should be performed whenever possible. The largest group of men likely to beneﬁt are those undergoing unilateral nerve resection because of the relatively commonplace nature of this procedure. Given the minimal morbidity consisting of a choice between a small area of numbness on the side of the foot and the potential for recovery of spontaneous erections, interest and demand for this procedure is likely to increase in upcoming years.

REFERENCES 1. Catalona WJ, Carvalhal GF, Mager DE, et al. Potency, continence and complication rates in 1,870 consecutive radical retropubic prostatectomies. J Urol 1999;162:433–438.

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2. Davidson PJ, van den Ouden D, Schroeder FH. Radical prostatectomy: prospective assessment of mortality and morbidity. Eur Urol 1996;29:168–173. 3. Geary ES, Dendinger TE, Freiha FS, et al. Nerve sparing radical prostatectomy: a different view. J Urol 1995;154:145–149. 4. Quinlan DM, Epstein JI, Carter BS, et al. Sexual function following radical prostatectomy: Inﬂuence of preservation of neurovascular bundles. J Urol 1991;145:998–1002. 5. Sunderland S. Nerve grafting and related methods of nerve repair. In: Sunderland S, ed. Nerve Injuries and Their Repair: A Critical Appraisal. Churchill Livingstone, Edinburgh, 1991, pp. 467–497. 6. Mackinnon SE, Dellon AL. Nerve injury and regeneration. In: Mackinnon SE, Dellon AL, eds. Surgery of the Peripheral Nerve. Thieme Medical Publishers, New York, 1988, pp. 140–152. 7. Schroder JM. Recommendations for the examination of peripheral nerve biopsies. Virchows Arch 1998;432:199–205. 8. DeMoura W, Gilbert A. Surgical anatomy of the sural nerve. J Reconstr Microsurg 1984;1:31–39. 9. Coert JH, Dellon AL. Clinical implications of the surgical anatomy of the sural nerve. Plast Reconstruct Surg 1994;94:850–855. 10. Quinlan DM, Nelson RJ, Walsh PC. Cavernous nerve grafts restore erectile function in denervated rats. J Urol 1991;145:380–383. 11. Burgers JK, Nelson RJ, Quinlan DM, et al. Nerve growth factor, nerve grafts and amniotic membrane grafts restore erectile function in rats. J Urol 1991;146:463–468. 12. Ball RA, Richie J, Vickers MA. Microsurgical nerve graft repair of the ablated cavernosal nerves in the rat. J Surg Res 1992;53:280–286. 13. Ball RA, Lipton SA, Dreyer EB, et al. Entubulization repair of severed cavernous nerves in the rat resulting in return of erectile function. J Urol 1992;148:211–215. 14. van Lith-Bijl JT, Stolk RJ, Tonnaer JA, et al. Laryngeal abductor reinnervation with a phrenic nerve transfer after a 9-month delay. Arch Otolaryngol Head Neck Surg 1998;124:393–398. 15. van Lith-Bijl JT, Stolk RJ, Tonnaer JA, et al. Selective laryngeal reinnervation with separate phrenic and ansa cervicalis nerve transfers. Archiv Otolaryngol Head Neck Surg 1997;123:406–411. 16. Crumley RL. Selective reinnervation of vocal cord adductors in unilateral vocal cord paralysis. Ann Otol Rhinol Laryngol 1984;93:351–356. 17. Crumley RL, Horn K, Clendenning D. Laryngeal reinnervation using the split-phrenic nerve-graft procedure. Otolaryngol Head Neck Surg 1980;88:159–164. 18. Sato F, Saito H. Functional reconstruction for unilateral recurrent laryngeal nerve paralysis caused by thyroid cancer. Auris Nasus Larynx 1985;12(suppl 2):S210–S216. 19. Bernardi L, Valenti C, Wdowczyck-Szulc J, et al. Inﬂuence of type of surgery on the occurrence of parasympathetic reinnervation after cardiac transplantation. Circulation 1998;97:1368–1374. 20. Tio RA, Reyners AK, van Veldhuisen DJ, et al. Evidence for differential sympathetic and parasympathetic reinnervation after heart transplantation in humans. J Autonom Nerv Syst 1997;67:176–183. 21. Wesche J, Orning O, Eriksen M, Walloe L. Electrophysiological evidence of reinnervation of the transplanted human heart. Cardiology 1998;89:73–75. 22. Walsh PC. Nerve grafts are rarely necessary and are unlikely to improve sexual function in men undergoing anatomic radical prostatectomy. Urology 2001;57:1020–1024. 23. Kim ED, Scardino PT, Hampel O, et al. Interposition of sural nerve restores function of cavernous nerves resected during radical prostatectomy. J Urol 1999;161:188–192. 24. Goad JR, Scardino PT. Modiﬁcations in the technique of radical retropubic prostatectomy to minimize blood loss. Atlas Urol Clin North Am 1994;2:65–74. 25. Kim ED, Scardino PT, Kadmon D, Slawin KM, Nath R. Interposition sural nerve grafting during radical prostatectomy. Urology 2001;57:211–216. 26. Kim ED, Seo JT. A minimally invasive technique for sural nerve harvesting. Urology 2001;57:921–924. 27. Millesi H. Healing of nerves. Clin Plast Surg 1977;4:459–473. 28. Sotereanos DG, Seaber AV, Urbaniak JR, et al. Reversing nerve-graft polarity in a rat model: the effect on function. J Reconstr Microsurg 1992;8:303–307. 29. Kim ED. Improving radical prostatectomy-induced erectile function: new concepts pts. Contemp Urol November: 12–23, 20002. 30. Kim ED, Kadmon K, Slawin KM, Tang V, Nath R. Bilateral nerve grafts during radical retropubic prostatectomy: an extended follow-up. Urology 2001;58:983–987. 31. Wood CG, Chang D, Kroll S, et al. Erectile function is preserved after non-nerve sparing radical prostatectomy through sural nerve interposition grafting. J Urol 2000;167:157, abstract 629.

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32. Huang S, Swanson D, Pisters L, et al. Contralateral sural nerve grafting (SNG) after unilateral nerve sparing radical prostatectomy (RP) improves post-operative potency rates. J Urol 2002;167:344, abstract 1365. 33. Kadmon D, Nath R, Shariat S, et al. Unilateral interposition sural nerve grafting following ipsilateral neurovascular bundle resection at radical prostatectomy (RP) decreases the time to potency recovery. J Urol 2002;167:153. 34. Eastham J, Scardino P. Update on nerve grafting during radical prostatectomy. AUA News. 2003;January/February:40–41. 35. Singh H, Shariat S, Canto E, Kattan M, Karakiewicz P, Slawin K. Impact of interposition sural nerve graft on urinary control in patients undergoing radical prostatectomy. J Urol 2002;167:346, abstract 1374. 36. McKiernan J, Ohori M, Gerigk C, et al. Cavernous nerve graft reconstruction following radical prostatectomy in 77 patients: feasibility, safety and early results J Urol 2002;167:153, abstract 613. 37. Scardino PT, Kim ED. The rationale for nerve grafting during radical prostatectomy. Urology 2001;57:1016–1019. 38. McKiernan JM, Ohori M, Gerigk C, et al. Cavernous graft reconstruction following radical prostatectomy in 77 patients: feasibility, safety and early results. J Urol Suppl 2001;165:149, abstract 613. 39. Slawin KM, Canto EI, Gore J, et al. Sural nerve interposition grafting during radical prostatectomy. Rev Urol 2002;4:17–23. 40. Canto EI, Nath RK, Slawin KM. Cavermap-assisted sural nerve interposition graft during radical prostatectomy. Urol Clin North Am 2001;28:839–848. 41. Kaouk JH, Desai MM, Abreu SC, Papay F, Gill IS. Robotic-assisted laparoscopic sural nerve grafting during radical prostatectomy: initial experience. J Urol 2003;3:909–912. 42. Srougi M, Pereira D, Dall‘Oglio M. Sexual rehabilitation after radical retropubic prostatectomy: new technique using ilio-inguinal nerve graft.” Int Braz J Urol 2002;28:446–451. 43. Peunova N, Enikolopov G. Nitric oxide triggers a switch to growth arrest during differentiation of neuronal cells. Nature 1995;375:68–73. 44. Sezen SF, Hoke A, Burnett AL, et al. Immunophilin ligand FK506 is neuroprotective for penile innervation. Nat Med 2001;7:1073–1074.

22

Management of Erectile Dysfunction Following Radical Prostatectomy Craig D. Zippe and Rupesh Raina

INTRODUCTION Radical prostatectomy (RP) has been the gold standard treatment for organ/specimen-conﬁned prostate cancer for several decades. Improved surgical techniques have decreased the rate of “total” and stress-induced incontinence to <10%, but urologists still report that most patients experience erectile dysfunction (ED) following RP (1–3). Although the surgical technique and experience remain the dominant variables in outcome, other factors affecting postoperative ED include the patient’s age, preoperative sexual function, psychological adjustment to a cancer diagnosis, and coexisting medical diseases (i.e., diabetes, hypertension). Other preoperative variables include the stage of disease, preservation of the neurovascular bundles, urinary incontinence, and adjuvant treatments (radiation therapy, hormonal therapy) (3–4). A current dilemma surrounding ED following RP is the wide variation in potency rates reported in the literature. ED following RP in the hands of experienced surgeons at centers of excellence ranges between 40 and 85% (2,4–6); however, for most urologists, the return of erectile function ranges from 9 to 40% (3,7–11). This variance appears to be surgeon-dependent, but it may also reflect the nonuniformity in data collection. The criteria of either a positive erectile response or sexual satisfaction are not applied universally. Variables include the qualitative difference between a partial and a full erection, the percentage of rigid erections/attempts, and the duration of vaginal intercourse. Although ED is a common surgical complication that needs to be addressed, it is amenable to treatment if the patients have the interest and desire. Safe, nonsurgical treatments with reasonable efficacy include intracorporeal injection of vasoactive drugs, transurethral vasodilators, vacuum constriction devices, and oral therapy (sildenaﬁl citrate). All of these erectaid treatments can potentially work and can have excellent compliance in an individual patient.

From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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This article summarizes the standard treatments used to treat ED as well as the newer options, using oral medications. We also discuss investigational studies being conducted at our institution on “penile preservation” to enhance recovery of rigid erections during the period of neuropraxia that exists immediately following surgery.

PREVALENCE Despite the high prevalence of ED following RP, most men are pleased with their decision to have surgery and can accept transient or permanent dysfunction (9). The younger, healthier men with good sexual function are the group most likely to experience distress at the prospect of losing erectile capacity as a result of treatment (10). Recently, Navarro and associates (11) reported that 91% of patients were satisﬁed with the results of surgery but only 2.6% were potent enough to achieve vaginal intercourse after radical prostatectomy. Furthermore, only 29% of men with ED sought treatment for their condition (11). This loss of interest in seeking help is speciﬁc to any one individual. The variables include spousal and patient reaction to the cancer, urinary incontinence, and the delay in advising treatment. A recent study at the Cleveland Clinic analyzed the erectile status and treatment options of patients 1 yr after nerve sparing (NS) and non-nerve-sparing (NNS) RP. A sexually active population of 176 patients (mean age 61 yr) underwent NS RP (112/176 [63.6%]), and NNS RP (64/176 [36.3%]). Although 42% (74/176) of the patients regained spontaneous erections (61% [69/112] NS, 8% [5/64] NNS) sufﬁcient for successful vaginal intercourse, 71% (52/74) of these patients were dissatisﬁed with the quality of erections and sought adjuvant treatment. The interesting aspect of the study was that 58 of 102 (57%) men with ED did not seek any treatment despite counseling (12). This discrepancy in sexually active men between preoperative and postoperative interest is being addressed with more informed preoperative teaching and early postoperative activity with the use of erectaids. Currently, patients are enrolled in clinical studies investigating the early “prophylactic” use of vacuum erection devices and intracorporeal penile injections. This article summarizes the standard treatments used to treat erectile dysfunction as well as the newer option and oral medications. We also discuss our institution’s ongoing studies on “penile preservation” to enhance recovery of rigid erections during the period of neuropraxia that exists immediately following surgery.

STANDARD TREATMENTS FOR ERECTILE DYSFUNCTION: THE PRE-VIAGRA ERA Vacuum Constriction Device Vacuum constriction devices (VCDs) were described as early as 1917 but did not achieve acceptance in the urologic community until the early 1980s. The VCD consists of a clear plastic cylinder, a vacuum pump, and a constriction ring. After application of a lubricant, the open end of the cylinder may be placed over the ﬂaccid penis and compressed against the abdominal wall to create an airtight seal. Erection is achieved by creating a vacuum inside the cylinder using a pump directly connected to the cylinder or connected by tubing. After an adequate erection is achieved, a constriction band can be applied around the base of the penis to help maintain the erection. The device can then be removed and the patient can engage in intercourse with the constriction band(s)

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maintaining the erection. The band can remain for a maximum of 30 minutes. The erection produced by this device differs from a normal erection and is thought to involve venous occlusion from the constriction band, resulting in generalized swelling of the entire penis, presumably with preservation of arterial inﬂow. Numerous published reports exist that describe VCD as being very effective. These devices have been used successfully in a variety of patients with organic ED, including patients treated for prostate cancer with either RP or radiation therapy (13). Cookson and Nadig (14) reported long-term efﬁcacy and patient satisfaction rates of more than 80%, with a statistically signiﬁcant increase in the frequency of successful intercourse attempts in 79% of the patients using the device for 1 yr, which were maintained in 77% beyond the ﬁrst year. However, despite this excellent satisfaction in this subset of patients, the overall dropout rate was 30–40%. The primary reasons for discontinuation were bruising and petechiae (5%), pivoting at the base of the penis (6%), coldness and numbness around the penis (5%), pain related to the VCD or the constriction band (10%), and decreased ability to achieve orgasm with the device (10%) (14). Turner and his associates (15) did a prospective comparison of intracorporeal (IC) injection of papaverine/phentolamine and external vacuum devices in term of usage rates, effectiveness, side effects, dropout rates, and impact on patient sexual and psychological functioning. Both treatments were efficacious and safely used by patients, although dropout rates were higher for the group using IC injections (60% vs 20%). There were no differences between the two treatments in sexual or psychological impact (15). Although IC injections can reproduce a more natural and satisfactory erection, the efﬁcacy is not 100% and the continued use of needles lends itself to 40–60% noncompliance rate after 1 yr (16). For the these patients, VCD may be a reasonable alternative. Gould and colleagues (17) reported that 71% patients who failed to achieve satisfactory erections by IC injection subsequently received adequate rigidity and satisfactory erection with VCD. Although the published reports describe efﬁcacy rates of 60–80%, the compliance after 1 yr of activity decreases to 50 to 70% (18). Noncompliant patients typically complain of tightness or pain from the constriction ring, diminished sensation of the phallus and glans, swiveling of the base of the penis with erection, and the laborious mechanics of just using the vacuum device (19). In addition, there is variability in the success of using the VCD each time, which leads to frustration. EARLY USE OF VACUUM CONSTRICTION DEVICE Currently, this is considerable interest in early intervention protocols in the use of VCD to encourage corporeal rehabilitation and prevention of post-RP veno-occulsive dysfunction, theorectically by increasing the frequency of tissue oxygenation. Early sexual rehabilitation after RP may enhance earlier recovery of nocturnal erections by enhancing oxygenation of the corpora cavernosa and preventing formation of collagen and ﬁbrosis, a cofactor in smooth relaxation and erectile function. We sought to determine the efﬁcacy and compliance of early use of VCD following RP in facilitating earlier sexual activity and potentially earlier return of potency following RP. In our experience, daily use of VCD after RP (with/without the constriction ring) to maintain corporeal engorgement or to achieve vaginal intercourse during periods of neuropraxia was associated with a high compliance rate 60/74 (80%) and few complications. In this series, at 6–9 mo 80% of the patients reported having sexual activity

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Table 1 IIEF-5 (SHIM) Scores Following Early Use of VCD After Radical Prostatectomy (N = 74) IIEF-5 domain

Presurgery

Postsurgery

After VCD use

Maintenance ability, Q5 Erection conﬁdence, Q15 Maintenance frequency, Q4 Erection ﬁrmness, Q2 Intercourse satisfaction, Q7 Total IIEF-5 score

4.10 ± 0.86 4.33 ± 0.96 4.76 ± 0.86 4.81 ± 0.74 4.46 ± 0.80 22.5 ± 4.22

0.99 ± 0.72 0.86 ± 0.75 0.91 ± 0.65 0.91 ± 0.75 1.11 ± 0.75 4.8 ± 3.62

3.61 ± 1.47 3.24 ± 1.43 2.64 ± 1.46 3.14 ± 1.40 3.12 ± 1.57 16 ± 7.33

Abbreviations: IIEF, International Index of Erectile Function; SHIM, Sexual Health Inventory of Men; VCD, vacuum constriction device.

Table 2 Comparison Between Patients With Nerve-Sparing (NS) and Non-Nerve-Sparing Prostatectomies in Response to Early Use of VCDa Variable

Bilateral NS (n = 31)

Using VCD for sexual intercourse 25/31 (80.6) Return of natural erection with VCD at 6–9 mo 9/25 (36) Natural erection sufﬁcient for intercourse at 6–9 mo 5/9 (55) Spouse satisfaction 13/25 (52)

Unilateral NS (n = 22)

Non-NS (n = 21)

19/22 (86) 7/19 (37) 4/7 (57) 11/19 (57)

16/21(76) 3/16 (19) 1/3 (33) 9/16 (57)

Abbreviation: VCD, vacuum constriction device. a Data are number of patients/total, with percent in parentheses.

(vaginal intercourse) with the VCD at a frequency of twice a week (Table 1). This level of activity in the ﬁrst 6–9 mo helped maintain the sexual interest and comfort between the couples that existed preoperatively. At a mean interval of 9 mo, the early (daily) use of VCD resulted in natural erectile function in 55% (19/60) of patients, with 10 of these 19 patients (52%) having erections sufﬁcient for vaginal penetration (Table 2) (20). This potency rate (deﬁned as vaginal penetration) of 52% at 9 mo is signiﬁcantly higher than the potency rate in a contemporary series (without early VCD), which had a 24% natural potency rate at 12 mo. Longer follow-up is needed to determine whether early VCD use can increase the return of both nocturnal erections and rigid erections sufﬁcient for vaginal intercourse. It does appear that early VCD encourages early sexual activity and interest in patients (and partners) who previously were inactive for a year or more, waiting for the period of neurapraxia to resolve. This improvement in sexual satisfaction within the ﬁrst year with early VCD use is apparent by the increase in International Index of Erectile Function (IIEF) scores seen at 9 mo in our study (Tables 1 and 2) (20). COMBINATION THERAPY: SILDENAFIL CITRATE ENHANCES SEXUAL SATISFACTION IN VCD FAILURES We assessed the effectiveness of combining sildenaﬁl citrate with VCD in men unsatisﬁed with the results of VCD alone. Thirty-one patients unsatisﬁed with the early

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Table 3 IIEF-5 (SHIM) Scores Before Surgery, After Surgery, and After VCD Use and Combination Therapy (VCD Plus Sildenaﬁl)a

IIEF-5 domain Maintenance ability, Q5 Erection conﬁdence, Q15 Maintenance frequency, Q4 Erection ﬁrmness, Q2 Intercourse satisfaction, Q7 Total IIEF-5 score

Mean score before surgery (n = 31)

Mean score after surgery (n = 31)

Mean score after VCD use alone (n = 31)

Mean score after VCD plus sildenaﬁl use (n = 24)

4.10 ± 0.65 4.33 ± 1.21 4.76 ± 1.32 4.81 ± 0.55 4.46 ± 0.65 22.5 ± 4.38

0.99 ± 0.21 0.86 ± 0.21 0.91 ± 0.32 0.91 ± 0.22 1.11 ± 0.65 4.8 ± 1.61

3.61 ± 1.41 3.24 ± 1.12 2.64 ± 1.23 2.38 ± 1.12 2.65 ± 0.75 14.5 ± 5.63

3.80 ± 1.65 4.21 ± 1.56* 3.24 ± 1.60* 3.80 ± 1.62 3.60 ± 1.77 18.5 ± 8.20

Data are mean ± SD. For abbreviations, see Table 1 footnote. * p < 0.05 VCD and VCD + Sildenaﬁl. a

Table 4 Patient and Partner Responses Using VCD Alone and Combination Therapy (VCD + Sildenaﬁl)a Comb. VCD + Sildenaﬁl citrate

Variable

VCD Alone

Able to penetrate (%) Patient rigidity score (0–100) Partner rigidity score (0–100) Spousal satisfaction (%) Total IIEF-5 score Return of natural erection (8 mo) (%)

52 55

70 76

59

82

55 14.5 ± 5.63 0

64 18.5 ± 8.20 29 (7/24)

a

For abbreviations, see Table 1 footnote.

use of VCD alone following RP (mean follow-up of 4.5 mo) were instructed to take 100 mg of sildenaﬁl 1–2 h prior to VCD use for sexual intercourse. Patients used combination therapy for a minimum of ﬁve attempts prior to assessment with the Sexual Health Inventory of Men (SHIM, IIEF-5) and a visual analog scale to gauge rigidity. The effect of combination therapy on total IIEF-5 score and penile rigidity score was assessed (21). Of the 31 patients, 7 (22%) had no improvement with the addition of sildenaﬁl with VCD and discontinued the drug, whereas 24 (77%) reported improved penile rigidity and sexual satisfaction. In these 24 patients, the IIEF-5 score showed signiﬁcant improvement in each domain, and patients reported that sildenaﬁl enhanced their erections 100% of the time (Table 3). Rigidity scores on a scale of 0–100 with VCD alone averaged 55% (23–85) for men and 59% (26–90) for their partners (Table 4). With the addition of sildenaﬁl, it increased to 76% for men and 82% for their partners. Thirty

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percent (7/24) reported the return of natural erections at 18 mo using combination therapy with 5/7 sufﬁcient for vaginal penetration (21). Thus, addition of sildenaﬁl with VCD improved sexual satisfaction and penile rigidity in patients unsatisﬁed with VCD alone. FUTURE ROLE OF VCD VCD will remain an important option in the armamentarium for clinicians who treat ED following RP. The current devices are safe and are applicable to patients with mixed etiologies and risk factors. The rigidity is sufﬁcient for vaginal penetration and intercourse in a very high percentage of cases. The satisfaction scores are high for both patients and partners in individual circumstances, and the dropout rates and complications are less than those of IC injection.

Intraurethral Alprostadil (PGE1; MUSE) In November 1996, intraurethral alprostadil therapy received Food and Drug Administration (FDA) approval for use in ED. This therapy currently represents as alternative method of delivering prostaglandin E1 (PGE1) to the erectile tissue by means of a medicated pellet. Through the medicated urethral system for erection, a pellet containing alprostadil (an analog of PGE1) is delivered into the male urethra, which is absorbed by the cavernosal tissue through vascular communications from the corpus spongiosum (22). Intraurethral alprostadil, when introduced by Padma-Nathan et al. (23) in 1997, was reported to have an overall efﬁcacy rate of 44%, but subsequent investigations could not conﬁrm these initially favorable results and reported signiﬁcant urethral pain and burning. Raymond and associates (24) examined the effect of transurethral alprostadil in 384 men with ED after RP and reported overall success rate of 40%. However, Lankin and colleagues (25) at the Cleveland Clinic reported that a medicated system for erection (MUSE) was effective in only 15% in men who had pelvic surgery. Subsequent investigations could not conﬁrm these initially favorable results and reported signiﬁcant urethral pain and burning. LONG-TERM EFFICACY OF MUSE Recently, the efﬁcacy and compliance of MUSE was studied in a contemporary RP series (27 patients, from 1996 to 2000) at the Cleveland Clinic, using the IIEF questionnaire to validate responses. The results showed that MUSE (2.251 ± 1.2 yr) was effective in 13/27 (48.2%) of patients. The mean presurgery SHIM score in these patients was 19.13 ± 1.26, which decreased to 5.18± 0.43 after surgery and increased to 16.26 ± 3.45 post treatment (Table 5). Moreover, 14/27 (52%) patients discontinued treatment (mean use of 8 ± 1.4 mo), mainly because of an inadequate response or side effects. There were no signiﬁcant differences in the IIEF-5 responses between the patients who had a nerve-sparing technique (n = 17) and those who did not (n = 10) or among the types of dosage: 250 µg, 25.9% (7/27); 500 µg, 59.2% (16/27); 1000 µg, 14.8% (4/27) (Table 6) (26). Our study demonstrates that although MUSE was effective in many postprostatectomy patients, one of every two patients discontinued therapy. The main reasons for discontinuation were insufﬁcient erectile response, a preference for oral therapy, and a progressive global dissatisfaction with transurethral insertion of the alprostadil. Despite the high discontinuation rate, MUSE is a very durable treatment modality in

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Table 5 Response of MUSE After Radical Prostatectomy (N = 27): IIEF-5 (SHIM) Analysisa Variable (IIEF-5 domain)

Before surgery (N = 27)

After surgery (N = 27)

After MUSE use (N = 27)

Maintenance ability, Q5 Erection conﬁdence, Q15 Maintenance frequency, Q4 Erection ﬁrmness, Q2 Intercourse satisfaction, Q7 Total mean IIEF-5 score

4.36 ± 0.19 3.43 ± 0.28 4.21 ± 0.22 3.35 ± 0.29 3.78 ± 0.28 19.13 ± 1.26

1.34 ± 0.13 1.11 ± 0.04 1.17 ± 0.06 1.20 ± 0.08 0.36 ± 0.12 5.18 ± 0.43

3.00 ± 0.36* 3.05 ± 0.29 3.33 ± 0.06 3.21 ± 0.12* 3.67 ± 0.40* 16.26 ± 0.23*

Abbreviations: MUSE, mediated system for erection. For other abbreviations, see Table 1 footnote. a Data are mean ± SD unless otherwise noted. * p < 0.05 before vs after MUSE use was considered signiﬁcant: by Wilcoxon signed-rank test.

Table 6 Response to MUSE in Patients Following Bilateral NS, Unilateral NS, and Non-NS Radical Prostatectomya Variable Age (mean yr) IIEF-5 domain Maintenance ability, Q5 Erection conﬁdence, Q15 Maintenance frequency, Q4 Erection ﬁrmness, Q2 Intercourse satisfaction, Q7 Total mean IIEF-5 score

Bilateral NS (12/27)

Unilateral NS (5/27)

Non-NS (10/27)

61.8

60.5

61.2

3.35 ± 0.21 3.34 ± 0.13 3.38 ± 0.21 3.23 ± 0.28 3.37 ± 0.29 16.67

3.42 ± 0.57 3.28 ± 0.52 3.34 ± 1.46 3.14 ± 0.55 2.71 ± 0.28 15.89

3.38 ± 0.72 2.96 ± 0.18 2.85 ± 0.40 3.14 ± 0.50 2.73 ± 0.20 15.06

Abbreviations: IIEF, International Index of Erectile Function; NS, nerve sparing. a Data are mean ± SD unless otherwise noted. p < 0.05 nerve sparing vs non-nerve sparing was considered signiﬁcant, by chi-square test.

selected patients and will continue to have an important role following RP until the results from nerve-sparing procedures improve. It should be offered as a salvage option for inpatients who fail oral therapy and should be tried as a ﬁrst option for inpatients following non-NS surgery. Our data suggests that a mean SHIM score of ≥16 stratiﬁes for a successful and durable outcome with MUSE therapy. COMBINATION THERAPY: MUSE ENHANCES SEXUAL SATISFACTION IN SILDENAFIL CITRATE FAILURES A recent area of interest is the use of combination therapy for ED following RP when individually therapies are ineffective. Corpus cavernosum smooth muscle relaxation and hence penile erection are regulated in part by increases in smooth muscle synthesis of the second-messenger cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (27). Phosphodiesterase-5 (PDE-5) inhibitors such as sildenaﬁl act indirectly and require sexual stimulation and endogenous nitric oxide production for efﬁcacy, activating the cGMP pathway. In contrast, agents such as PGE1 act

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Table 7 IIEF-5 (SHIM) Scores Before Radical Prostatectomy (RP), After RP, After Sildenaﬁl Citrate Use and Combination Therapy (MUSE and Sildenaﬁl)a

IIEF-5 domain Maintenance ability, Q5 Erection conﬁdence, Q15 Maintenance frequency, Q4 Erection ﬁrmness, Q2 Intercourse satisfaction, Q7 Total IIEF-5 Score

Mean score Mean score Mean score Mean score after sildenaﬁl after MUSE before surgery after surgery citrate use alone + sildenaﬁl use (n = 23) (n = 23) (n = 23) (n = 19/23) 4.10 ± 0.65 4.33 ± 1.21 4.76 ± 1.32 4.81 ± 0.55 4.46 ± 0.65 22.5 ± 4.38

0.99 ± 0.21 0.86 ± 0.21 1.91 ± 0.32 0.91 ± 0.22 1.11 ± 0.65 5.67 ± 1.61

2.61 ± 1.41 2.24 ± 1.12 2.64 ± 1.23 2.38 ± 1.12 2.42 ± 0.75 12.1 ± 5.63

3.80 ± 1.65 4.21 ± 1.56* 3.24 ± 1.60* 3.97 ± 1.62 3.60 ± 1.77 18.6 ± 8.20

Data are mean ± SD. For abbreviations, see Table 1 footnote. * p < 0.05 sildenaﬁl alone vs MUSE + sildenaﬁl citrate. a

directly on the trabecular smooth muscle, binding to speciﬁc E-prostanoid (EP) receptors and increasing cAMP synthesis (28,29). Thus, combination therapy using both cAMP- and CGMP-mediated vasodilation may be more efﬁcacious in the salvage of patients who desire noninvasive therapy but in whom single-treatment modality fails. A study conducted by Nehra and colleagues (30) at the Mayo Clinic demonstrated that the addition of sildenaﬁl (100 mg) in combination with intraurethral PGE1 (1000 µg) salvaged a refractory population of men with erectile dysfunction using intraurethral prostaglandin alone. We also examined the effectiveness of MUSE-sildenaﬁl combination therapy, but in population of patients who were unsatisﬁed with sildenaﬁl citrate alone (Viagra™ failures) for ED following RP. Of the 23 patients, 4 patients (17%) had no improvement with the addition of MUSE in combination with sildenaﬁl and discontinued the drug, whereas 19 (83%) reported improved penile rigidity and sexual satisfaction (Table 7). In these 19 patients, the IIEF-5 score showed signiﬁcant improvement in each domain, and patients reported that erections were sufﬁcient for vaginal penetration 80% of the time. Rigidity scores on a scale of 0–100 with sildenaﬁl alone averaged 38% (23–53) for men and 46% (26–67) for their partners. With the addition of MUSE, it increased to 76% for men and 62% for their partners (Table 8). The addition of MUSE in combination with sildenaﬁl improved sexual satisfaction and penile rigidity in most patients unsatisﬁed with sildenaﬁl alone. EARLY MUSE TREATMENT Theoretically, early pharmacologic intervention, which activates the neurotransmitters after RP, should improve and maintain vascular perfusion of the corpus cavernous better (vs the passive dilation obtained from early VCD) and should subsequently inhibit corporeal hypoxia and ﬁbrosis (39,40). We are currently studying whether early pharmacologic intervention with MUSE after RP may potentially facilitate early erections and earlier sexual activity. Following nerve-sparing RP and Foley catheter removal (avg. 3–10 d), 12 patients were instructed to use a 125-µg dose of MUSE 3 times/wk for 6 wk. Early use of MUSE began at an average of 2.9 wk (2–4 wk). The

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Table 8 Patient and Partner Responses Following Use of Sildenaﬁl Alone and Combination Therapy (MUSE + Sildenaﬁl) Variable Able to penetrate (%) Patient rigidity score (0–100) Partner rigidity score (0–100) Total mean IIEF-5 score Erection ﬁrmness Ability to maintain erection Satisfactory intercourse Spousal satisfaction (%)

Sildenaﬁl alone

Comb. MUSE + Sildenaﬁl citrate

52% 38

70%* 76*

46

62

12.17 2.38 ± 1.12 2.61 ± 1.41 2.42 ± 0.75 52

18.67 3.97 ± 1.62* 3.80 ± 1.65* 3.60 ± 1.77* 69

Abbreviations: IIEF, International Index of Erectile Functions; MUSE, mediated system for erection. * p < 0.05 sildenaﬁl alone vs MUSE + Sildenaﬁl citrate was considered signiﬁcant, by Student’s t-test used.

treatment efﬁcacy was analyzed by responses to the SHIM (IIEF-5) questionnaire. All 12 patients experienced the side effect of mild penile aching (urethral burning included), but only 3/12 discontinued the treatment. In the remaining nine patients, three elevated their dose to 250 µg to improve erectile function. With a mean follow-up of 3.5 mo, the nine patients improved their pretreatment IIEF-5 score from 6.8 ± 3.62 to 12 ± 2.33 (p ≤ 0.05). Two of nine patients were able to achieve vaginal penetration. Our preliminary observations suggest that an early MUSE (125 µg) treatment program is safe and tolerable and can produce erections in the early postoperative period. Whether regaining earlier erections results in higher potency rates (deﬁned as vaginal penetration) remains to be seen. FUTURE ROLE OF INTRAURETHRAL ALPROSTADIL (PGE1) When intraurethral therapy is compared with IC injections, most patients who have tried both intraurethral therapy (MUSE) and IC injection therapy will prefer IC injections, since it produces a firmer erection. Porst et al. (31) compared intraurethral and IC injected PGE1 and reported significantly higher success rates and decreased side effects with low-dose IC injections of PGE1 compared with intraurethral application of PGE1. Similarly, compared with oral therapy, most patients will prefer effective oral therapy over MUSE, and comparative studies show that sildenafil has better long-term compliance. The most common complication related to intraurethral therapy (at the higher doses, 500–1000 µg) is discomfort in the penis, testicles, legs, and perineal area, probably owing to the hyperalgesia related to the use of PGE1. Additional complications include warmth or burning sensation in the urethra, minor urethral bleeding, and occasional leg vein swelling (23–25,30,31). Intraurethal therapy (MUSE) is effective in selected patients and should remain in the armamentarian when considering options for ED. In many post-RP patients who do not respond to oral therapy, this treatment

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option is preferred over IC injections and VCD. Early use of MUSE at the lower doses (125 µg) following RP can restore nocturnal erections earlier (both frequency and duration), can facilitate vascular perfusion of the corpus cavernosum, and may shorten the period of neurapraxia.

Intracavernosal Injection Therapy IC injection became a standard treatment for erectile dysfunction in 1983 when it was introduced in the United States at the 1983 Meeting of the American Urological Association. With this therapy, patients could inject drugs such as PGE 1 (alprostadil) or alprostadil in combination with papaverine and phentolamine (as a triple mixture) directly into the cavernosal blood vessels to obtain an erection (32). Although phentolamine is a direct adrenoceptor blocker, alprostadil and papaverine act by modulating levels of cyclic 3′, 5′-adenosine monophosphatase in the cells, eventually increasing the penile blood flow by relaxing the arterial and trabecular smooth muscles (33). This combination of papaverine, phentolamine, and PGE1 or Trimix solution permits a reduced dosage of each agent with increased safety and decreased morbidity (34). Although sildenaﬁl citrate has been very successful in treating ED following RP, IC penile injections with PGE1 alone (33) or in combination with papaverine and phentolamine (37) continue to be an important therapeutic option. Although the use of an oral agent (sildenaﬁl citrate) as a ﬁrst-line agent is optimal, this option in postprostatectomy patients depends on the presence of one or two neurovascular bundles (49–54). Patients who had non-nerve-sparing (non-NS) procedures and those who have failed oral therapy will require other options such as IC injections (41). The successful use of IC injection therapy for ED after RP was reported in the very early clinical series, documenting the effectiveness of the technique. Dennis and McDougal (35) were the ﬁrst to document the use of IC therapy in previously potent RP patients, with success rates of 85%. A recent study by Rodriquez Vela et al. (36) in 1999 revealed that IC PGE1 injection provided adequate rigidity in 95% of patients. Despite their high degree of effectiveness, many patients do not readily accept penile injections as a long-term option. Dropout rates in many series exceed 40%, despite a therapeutic efﬁcacy of over 85% (37). Factors that compromise success of therapy include pain associated with the injection (14%), difﬁculty in reproducing a successful injection (10–20%), penile ﬁbrosis (2–15%), and availability of oral medications (37–39). Despite multiple technological attempts to devise better delivery systems, many patients continue to have both physical and emotional difﬁculty using a needle for any length of time. Using an institutional questionnaire, Mulhall et al. (39) found a good response in 75% of their patient group, which included patients with ED of all etiologies. They reported an attrition rate of 31% over a 38-mo period, with cost, penile discomfort, and patient-partner problems being the major reasons for discontinuation. Lack of efficacy was the primary reason for discontinuation in only 14.1% patients (39). In a similar study, Purvis et al. (40) also found that 87% of their patient sample (which included all etiologies) were fully or partially satisfied with IC injections. The discontinuation rate in their study was 58% over 2 yr, with lack of spontaneity, penile discomfort, and cost of therapy being the main reasons for dissatisfaction. Inadequate rigidity or lack of efficacy was the primary reason for discontinuation in 18% of the patients (40).

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Table 9 IIEF-5 (SHIM) Scores Before Surgery, Before Treatment, and After IC Injections in 102 Men With Erectile Dysfunction Caused by Radical Prostatectomy (RP)a IIEF-5 domainb Maintenance ability, Q5 Erection conﬁdence, Q15 Maintenance frequency, Q4 Erection ﬁrmness, Q2 Intercourse satisfaction, Q7 Total mean IIEF-5 score

Before surgery

Before treatment

After IC use

4.25 ± 1.33 2.96 ± 2.08 4.84 ± 0.55 4.88 ± 0.56 4.82 ± 0.71 21.75 ± 5.23

0.66 ± 1.32 0.08 ± 0.28 1.42 ± 1.41 1.29 ± 1.12 1.43 ± 1.33 4.23 ± 3.48

3.90 ± 1.56* 3.83 ± 1.66* 3.67 ± 1.66 4.45 ± 1.60* 3.61 ± 2.02 19.46 ± 8.78*

Abbreviations: IC, intracorporeal; IIEF, International Index of Erectile Function; SHIM, Sexual Health Inventory of Men. a Data are mean ± SD. b Each IIEF domain was scored from 0 to 5: 0, did not attempt intercourse; 1, never/occasionally; 2, less than half the time; 3, sometimes/half the time; 4, more than half the time; 5, almost always. The total IIEF5 score was calculated by totaling and taking the mean of the response to all ﬁve domains of the IIEF-5. * p < 0.05 after RP vs after IC injection IIEF-5 domain was considered signiﬁcant.

LONG-TERM EFFICACY AND COMPLIANCE OF IC INJECTIONS The literature contains no reports on the long-term effects and durability in patients using IC injections for ED following RP. Therefore, we conducted a study to evaluate the long-term efﬁcacy and compliance of IC injection therapy in a postprostatectomy population and to detail the reasons for its discontinuation. Baseline and follow-up data from 102 patients using IC injection for ED following RP were retrospectively collected. We compared baseline IIEF questionnaires with the abridged IIEF-5 questionnaires (referred to as the SHIM) to determine drug efﬁcacy. In this study, we found that 69 (68%) of our 102 postprostatectomy patients were satisﬁed with IC injection therapy and that 49/102 (48%) chose to continue with the therapy long term (mean, 3.5 yr). The mean presurgery SHIM score was 21.75 ± 5.23, which decreased to 4.23 ± 3.48 after surgery and increased to 19.46 ± 8.78 posttreatment (Table 9). Fifty-two percent (53/102) of patients discontinued IC therapy after a mean use of 14.5 mo for the following reasons: insufﬁcient erections, 33% (18/53); preference for oral therapy, 32% (17/53); fear of injections, 11%, (6/53); troublesome procedure, 11% (6/53); loss of partner, 8% (4/53); priapism, 1% (1/53); and natural return of erections, 1% (1/53). When patients were included who preferred oral therapy to IC injections and who had loss of partners and return of natural erections, the compliance to IC injections was 70.6% (71/102). The type of RP surgery (bilateral NS, unilateral NS, and non-NS; Table 10) and type of regimen (single, high-dose triple therapy, or low-dose triple therapy) did not affect the efﬁcacy of this therapy (41). This latter ﬁnding (no difference in the type of regimen) is not consistent with the results of a prospective study performed by Bechara et al. (42), who showed that the three-drug mixture is more effective than high-dose PGE1 alone in achieving erections suitable for penetration. However, our patient satisfaction and compliance rates are similar to those of Mulhall et al. (39) and Purvis et al. (40). The primary reasons for discontinuation in our study were inadequate erections and a preference for oral treatment with

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Zippe and Raina Table 10 IIEF-5 (SHIM) Scores Stratiﬁed by Type of Nerve-Sparing (NS) Surgerya

IIEF-5 domainb

Bilateral NS (n = 40)

Unilateral NS (n = 19)

Non-NS (n = 43)

Maintenance ability, Q5 Erection conﬁdence, Q15 Maintenance frequency, Q4 Erection ﬁrmness, Q2 Intercourse satisfaction, Q7 Total IIEF-5

4.10 ± 0.86 4.33 ± 0.96 4.76 ± 0.86 4.81 ± 0.74 3.46 ± 0.80 21.5 ± 4.22

4.12 ± 0.19 3.91 ± 0.28 4.31 ± 0.22 3.85 ± 0.29 3.98 ± 0.28 20.01 ± 1.26

3.62 ± 0.36 4.07 ± 0.29 4.01 ± 0.06 3.78 ± 0.40 4.05 ± 0.40 19.51 ± 1.23

Data are mean ± SD. Each International Index of Erectile Function (IIEF) domain was scored from 0 to 5: 0, did not attempt intercourse; 1, never/occasionally; 2, less than half the time; 3, sometimes/half the time; 4, more than half the time; 5, almost always. The total IIEF-5 score was calculated by totaling and taking the mean of the response to all ﬁve domains of IIEF-5. a b

sildenaﬁl citrate. Like both of these authors, we found side effects to be an infrequent reason for discontinuing treatment. The advantage of IC injection agents is that the ensuing smooth muscle relaxation is independent of the production of endogenous vasoactive substances such as nitric oxide, which is impaired by nerve damage. The degree of smooth muscle relaxation may be more complete with pharmacologically induced erections so that a patient with a mild venous leak may still veno-occlude to the point of a functional erection (34,35). We feel that periodic follow-up of our injection patients to discuss their technique, examine for penile plaques, and review their injection formula increases patient compliance and lowers the attrition rate. Further studies are required to determine whether other injectable agents that may be less painful (forskalin, vasoactive intestinal peptide, and moxisylete), alone or in combination, can provide better efﬁcacy and long-term compliance (43–45). ROLE OF IC INJECTIONS IN EARLY PENILE REHABILITATION Although penile injection therapy is often not routinely advised in the early postoperative period because of penile discomfort and patient lack of interest, there is some thought that early rehabilitation of the penis may be necessary to prevent corporeal ﬁbrosis during the neuropraxia period following RP (46,47). In our experience the neuropraxia may persist from 6 to 24 mo. This concept supports the 1997 study of Montorsi et al. (48), who suggested that early postoperative IC injection limited the development of hypoxia-induced tissue damage and produced an overall improvement in the recovery of spontaneous erections, with a 67% potency rate at 6 mo. Since sildenaﬁl citrate shows a limited effect in the early postoperative period, the temporary use of IC injections during this time may become an important adjuvant treatment for postprostatectomy patients. However, our early penile rehabilitation using IC injections to improve long-term penile function was not satisfactory, with most patients discontinuing the early program mainly because of penile discomfort and burning. In our early injection program, we tried three different combinations unsuccessfully: low-dose PGE1 (5 µg/0.5 cc),

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Table 11 IIEF-5 (SHIM) Scores on IC Alone, Switching From IC to Sildenaﬁl Citrate, and Combination Therapy (IC injections + Viagra)a Variableb IIEF domain Maintenance ability, Q5 Erection conﬁdence, Q15 Maintenance frequency, Q4 Erection ﬁrmness, Q2 Intercourse satisfaction, Q7 Total IIEF-5 score Partner satisfaction (%)

On IC alone

Successful switch to sildenaﬁl (n = 15)

Combination therapy (n = 7)

4.24 (4, 5) 3.96 (3, 4) 4.28 (4, 5) 4.12 (4, 5) 3.61 (3, 4) 20.21 (20, 25) 71.8

2.6 (2, 3)* 2.22 (2, 3)* 2.54 (2, 3)* 2.36 (2, 3)* 2.45 (2, 3) 12.17 (10, 15) 60.7

4.64 (4, 5) 4.23 (4, 5)** 4.64 (4, 5) 4.27 (4, 5) 4.80 (4, 5)** 22.58 (20, 25) 72.8

Abbreviations: IC, intracorporeal; IIEF, International Index of Erectile Function; SHIM, Sexual Health Inventory of Men. a Data are presented as mean (range) unless speciﬁed. b Each IIEF domain was scored from 0 to 5: 0, did not attempt intercourse; 1, never/occasionally; 2, less than half the time; 3, sometimes/half the time; 4, more than half the time; 5, almost always). The total IIEF5 score was calculated by totaling and taking the mean of the response to all ﬁve domains of IIEF-5. * p < 0.05 vs IC alone and switch to sildenaﬁl citrate. ** p < 0.05 vs IC alone and on IC + sildenaﬁl citrate.

low-dose triple (papaverine (8.8 mg), phentolamine (0.3 mg)/0.5 cc, and pure papaverine (15 mg/0.5 cc). The routine use of IC injections as adjuvant therapy immediately following RP may require the development of new vasoactive agents that produce less penile discomfort and pain. Similar to our results with early VCD, early IC injections may just promote more sexual activity and satisfaction, but not necessarily any earlier return to natural potency. These studies need to be randomized and stratiﬁed by age, baseline sexual activity, and comorbidities. LONG-TERM IC INJECTIONS RESPONDERS CAN POTENTIALLY SWITCH TO SILDENAFIL CITRATE Not surprisingly, when oral therapy was introduced, many patients switched from the traditional treatments to sildenaﬁl citrate. Even before sildenaﬁl became available, patients with ED strongly preferred the least invasive form of therapy, such as oral medication. As a result, many patients have asked about the feasibility of switching from IC injection therapy to oral agents such as sildenaﬁl citrate. The study was conducted at Cleveland Clinic Foundation to determine whether patients with ED managed with long-term IC injections following RP could successfully be switched to oral sildenaﬁl citrate. Various parameters to predict which long-term users of IC injections after RP can successfully switch to oral therapy with sildenaﬁl citrate were also assessed. Of the 49 patients using IC injections, only 36 patients agreed to receive open-label sildenaﬁl orally (50–100 mg) for a minimum of 4 wk/8 attempts. Of the 36 patients, 41% (15/36) successfully switched to sildenaﬁl and discontinued IC injection (Table 11). Thirty-eight percent (14/36) found sildenaﬁl ineffective and remained on IC injection. Patients who switched to oral therapy had a higher (p < 0.001) total mean SHIM (IIEF-5)

444

Zippe and Raina Table 12 Factors Predicting the Successful Switch From IC Injection Therapy to Oral Therapy

Variable Age (± SD; yr) Hypertension (%) Diabetes (%) Coronary heart disease (%) Pretreatment IIEF-5 score IIEF-5 score after RP Time from RP to IC (yr) IIEF-5 score after IC Spousal satisfaction (%) Nerve sparing (%)

Failed switch to oral therapy

Successful switch to oral therapy

Univariate p value

63.6 ± 5.27 36 12 11 23.3 ± 3.4 3.8 ± 3.3 2.3 ± 1.1 12.3 ± 7.8 52 55

60 ± 6.3 33 2 6 19.9 ± 2.6 4.7 ± 3.7 2.6 ± 1.2 20 ± 4.9 75 63

0.71 0.73 0.07 0.04* 0.06 0.10 0.17 < 0.001* 0.03* 0.44

Abbreviations: IC, intracorporeal; IIEF, International Index of Erectile Function; RP, radical prostatectomy. * Signiﬁcant at p < 0.05.

score on IC injections than those who did not switch (12.3 ± 7.8 vs 20.0 ± 4.9; Table 12). Nineteen percent (7/36) found sildenaﬁl alone to be suboptimal but continued using it, enhancing the efﬁcacy of IC injections alone (49). Thus, although injections may be more efﬁcacious than sildenaﬁl citrate, the discomfort and anxiety weigh heavily in the patient’s preference for oral therapy. Our study suggested that patients who are successfully managed with IC injection therapy should be offered the option of using oral therapy. Patients will accept a lower degree of sexual satisfaction by IIEF-5 (SHIM) score if oral therapy is effective. Since oral therapy shows limited effect in the early postoperative period, the temporary use of IC injections (similar to the early use of MUSE) needs to be revisited with different doses and perhaps new regimens. The use of injectable substances undoubtably provides and provokes the greatest degree of neurotransmitter stimulation and should potentially enhance nerve regeneration the best. Our data on the percentage of patients using long-term injections who can switch to oral therapy suggest that injections may facilitate functional nerve recovery since sildenaﬁl requires functioning nerve tissue (46,47). Further conﬁrmatory studies are necessary to support this concept that IC injections may be our “best” therapy currently to promote nerve regeneration, thus shortening the period of neurapraxia. FUTURE ROLE OF IC INJECTIONS FOR ED Intraurethral and oral agents for the treatment of erectile dysfunction have been introduced over the past few years, but early reports of the patient satisfaction and reproducibility of erectile rigidity have not matched those of intracavernosal injection in the patient population with severe ED that occurs after RP (50). The introduction of sildenaﬁl citrate heralded a new era as patients now have an oral agent they can use on an ondemand basis. However, although sildenaﬁl citrate has provided promising results as ﬁrst-line therapy for treatment of ED following RP, these patients usually were younger, had bilateral nerve-sparing procedures, were sexually active before surgery, and demonstrated drug efﬁcacy after a time interval of 12 mo or so after surgery. Since oral therapy,

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MUSE, or VCD therapies are often suboptimal in patients with severe ED, penile IC self-injections are often the most efﬁcacious means of re-establishing functional erection without the need for penile prosthesis implantation. In patients undergoing non-nervesparing procedures IC injection therapy remains the ﬁrst and best treatment option. Improvements in the formulation and agents used in vasoactive cocktails have evolved over time as the physiology of erections has been elucidated. Both speciﬁc and nonspeciﬁc factors have been cited as reasons for high attrition rates of intracavernous therapy. A thorough knowledge of vasoactive agents and their efﬁcacy and side effects, as well as a multifactorial assessment of erectile dysfunction, is imperative to ensure a favorable outcome. Detailed instruction, guidance, and follow-up are also essential to the success of self-injection therapy.

Problems With Standard Treatments Although these three treatments (VCD, MUSE, and IC injections) have acceptable efficacy rates (33–68%), they also have high discontinuation rates (50–80%) (4,14,15,23–26,48–49). The reasons for dissatisfaction include insufﬁcient response to therapy, unacceptable side effects, or the feeling of anxiety and “unnaturalness” associated with using devices or injections. The discontinuation rates of our standard treatments become a greater concern as our radical prostatectomy population becomes younger and the period of sexual longevity increases to 10–15 yr. Not surprisingly, when oral therapy was introduced, most patients on these standard treatments ask their physicians to try sildenaﬁl citrate. Unfortunately, their requests were met with disappointment since the efﬁcacy of sildenaﬁl is dependent on the amount of functioning nerve tissue, or the success of neurovascular preservation. Since neurovascular preservation is still a “black box” regarding its efﬁcacy, it is important that we continue to introduce newer, more efﬁcacious agents; also, automated drug delivery systems can improve the long-term compliance of nonoral treatments, such as intraurethral and injectable agents. In the interim, it is important for prostate cancer surgeons to be aware of the long-term efﬁcacy and compliance rates of the standard treatment options when counseling patients about ED following RP.

THE VIAGRA ERA: 1998 AND BEYOND The treatment algorithm for patients with ED following RP improved dramatically in 1998 when the ﬁrst effective oral therapy—sildenaﬁl citrate (Viagra, Pﬁzer Pharmaceutical)—became available. Following the publication by Goldstein et al. (51) in 1998, sildenaﬁl revolutionized the evaluation and treatment of ED to the extent that oral therapy is now the ﬁrst treatment option for patients with ED caused by a variety of organic and psychogenic causes. Data from various clinical trials have demonstrated improved erectile function in patients with a cross-section of etiologies of ED (52). However, early reports did not stratify the various types of organic etiologies and did not include pertinent data in the subset of patients who had undergone RP, such as the impact of the presence or absence of the neurovascular bundles (52). Researchers at the Cleveland Clinic were among the ﬁrst to investigate the effects of this new oral medication in patients following RP and to study the impact of the presence or absence of the neurovascular bundles (53). Our initial publication reported that 12 of 15 patients undergoing bilateral NS procedures showed efﬁcacy with vaginal penetration with sildenaﬁl at 1 yr following

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Zippe and Raina Table 13 Characteristics of 91 Postprostatectomy Patients With Erectile Dysfunction Before Sildenaﬁl Citrate (Viagra) Therapy Overall (n = 91)

Patient characteristic Age (mean yr) Time from surgery to therapy (median mo) Presurgery erectile status (%) Full Partial None Able to penetrate (%) Nocturnal erections present (%)

Bilateral NS Unilateral NS Non-NS (n = 53) (n = 12) (n = 26)

61.8 18.4

60.5 22.0

61.2 14.0

65.6 14.5

0 15.1 84.9 0 21

0 18.2 81.8 0 24.2

0 14.3 85.7 0 28.6

0 11.5 88.8 0 15.4

Abbreviation: NS, nerve sparing.

Table 14 Comparison Between Patients With Nerve-Sparing and Non-Nerve-Sparing Prostatectomies in Response to Sildenaﬁl Citrate (Viagra) Variable No. of doses Able to penetrate (%, no./total) Mean duration of intercourse (min) Spouse satisfaction (%, no./total) IIEF (No. of responders) Frequency of penetration, Q3 Frequency of maintenance, Q4 Sexual satisfaction, Q7

Bilateral NS (n = 53)

Unilateral NS (n = 12)

Non-NS (n = 26)

p value

8.0 71.7 (38/53) 10 66 (35/53)

8.5 50 (6/12) 4.5 41.6 (5/12)

6.5 15.4 (4/26) 12 15.4 (4/26)

NS 0.001

38 1.2–4.8 1.2–4.8 1.3–4.2

6 1.0–2.8 –2.6 1.2–4.2

4 0.04* 1.5–3.3 1.3–3.0

NSF 0.001

0.02* 0.02*

Abbreviations: NS, nerve sparing; NSF, not signiﬁcant; IIEF, International Index of Erectile Function. * Bilateral NS vs unilateral NS/non-NS.

RP (53). This initial study showed the role and the value of neurovascular preservation in determining the response to sildenaﬁl citrate. Subsequently we updated our experience to include 91 (Table 13) patients treated with sildenaﬁl after RP (48). In the bilateral NS group, 71.7% (38/53) achieved vaginal intercourse; in the unilateral NS group, 50% (6/12) did so (Table 14). In the NNS group, only 15.4% (4/26) achieved vaginal penetration (54). Our study showed that sildenaﬁl citrate can improve ED in about 70% of impotent, motivated patients following RP if a bilateral NS procedure is performed and in 50% of patients if a unilateral NS procedure is done (54). This ﬁnding was conﬁrmed by Lowentritt et al. (55) a year later when they reported a response rate to sildenaﬁl citrate in 58% of men undergoing bilateral NS procedures. The

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Table 15 Comparison of IIEF-5 and EDITS Scores of Positive Responders to Sildenaﬁl Citrate Baseline at 1 and 3 Yearsa

IIEF-5

domainb

Maintenance ability, Q5 Erection conﬁdence, Q15 Maintenance frequency, Q4 Erection ﬁrmness, Q2 Intercourse satisfaction, Q7 Total mean IIEF-5 score Mean EDITS score

Baseline after surgery (n = 48) 1.34 ± 0.13 1.11 ± 0.04 1.17 ± 0.06 1.20 ± 0.08 0.36 ± 0.12 5.18 ± .43 —

Sildenaﬁl use At 1 yr (n = 48) 3.42 ± 0.36 3.87 ± 0.29 3.81 ± 0.06 3.57 ± 0.12 3.85 ± 0.40 18.52 ± 1.23 73.6 ± 3.2

At 3 yr (n = 43) 4.12 ± 0.19* 3.91 ± 0.28 4.31 ± 0.22* 3.85 ± 0.29* 3.98 ± 0.28 20.01 ± 1.26 71.9 ± 2.6

Abbreviations: EDITS, Erectile Dysfunction Inventory of Treatment Satisfaction; IIEF, International Index of Erectile Function. a Data are mean ± SD. b Each IIEF domain was scored from 0 to 5: 0, did not attempt intercourse; 1, never/occasionally; 2, less than half the time; 3, sometimes/half the time; 4, more than half the time; 5, almost always. The total IIEF5 score was calculated by totaling and taking the mean of the response to all ﬁve domains of IIEF-5. * p < 0.05 1 yr vs 3 yr IIEF-5 domain was considered signiﬁcant.

impact of nerve preservation and the efﬁcacy of sildenaﬁl were also reported by Zagaja et al. (56) from the University of Chicago, who showed an 80% response rate in men < 55 yr old when both nerve bundles were spared and a 40% response when one bundle was spared. However, in the 56- to 65-yr-old group, the response rate dropped to 45% in the group with two nerves spared and to 0% in those with one nerve preserved (56). Sildenafil has provided a tremendous benefit for the patient after RP. In clinical trials, the response to sildenafil was 43% (57). Subsequent investigators have reported satisfaction rates ranging from 15 to 80% (57–61). Variables include preoperative sexual function and activity, the reporting of successful intercourse/attempts, the nerve-sparing nature of the surgery, and the length of time following surgery before sildenafil administration. Improved results are seen the longer the patient is out from surgery (3,4,53–61).

Long-Term Effect of Sildenaﬁl Citrate: 3-Yr Follow-Up Following the launch of sildenaﬁl citrate, much has been learned about the mechanism of action of the drug, its safety proﬁle, and its clinical efﬁcacy speciﬁc to various etiologies of ED. However, there are no reports on its long-term effects and durability in patients with ED following RP. We conducted this study to evaluate the long-term efﬁcacy of sildenaﬁl citrate at the 3-yr interval. Our 3-yr follow-up study of the effect of sildenaﬁl citrate after RP demonstrates its long-term efﬁcacy and also patient compliance. Most who responded at 1 yr (72%) continued to have effective erections with sildenaﬁl citrate at 3 yr. The SHIM (IIEF-5) scores were comparable at 1 and 3 yr (Table 15). When the responses at 1 and 3 yr were stratiﬁed according to the neurovascular bundle status, the magnitude of improvement in SHIM (IIEF-5) was still higher in the bilateral NS group than in the unilateral NS

448

Zippe and Raina Table 16 Reason for Discontinuation of Sildenaﬁl Citrate at 3 Yearsa

Variables Return of natural erection sufﬁcient for vaginal penetration (mean use ± 2.5 yr) Lack of efﬁcacy Death of spouse

Bilateral NS (n = 33)

Unilateral NS (n = 6)

Non-NS (n = 4)

15 (5/33)

16 (1/6)

0 (0/4)

6 (2/33) 3 (1/33)

16 (1/6) 0 (0/6)

50 (2/4) 0 (0/4)

Abbreviation: NS, nerve sparing. a Data are percents, with number/total in parentheses.

and NNS group. The degree of neurovascular preservation continues to stratify the response rates to sildenaﬁl (64). Thirty-one percent (10/31) of these respondents had augmented their dose from 50 to 100 mg. The dropout rate was 27%; 50% (6/12) discontinued because of the return of natural erection, ﬁve patients because of loss of efﬁcacy and one patient because of the death of a spouse (Table 16). There were no differences in the 1-yr and 3-yr SHIM (IIEF-5) and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) scores between the NS groups. The most common side effects at 3 yr were headache (12%), ﬂushing (10%), and blue or blurred vision (2%). No patient discontinued the drug at 3 yr because of side effects (64). Our data suggest that ED following RP can be effectively treated with sildenafil citrate if some degree of neurovascular preservation is performed. Long-term results show that 76% of preoperative sexually potent men with good bilateral NS surgery can recapture that function with sildenafil treatment. Perhaps 50% or more of those undergoing a unilateral procedure can also have function restored (Table 17). Four (15%) of 26 men in the NNS cohort also recovered sexual function, with 2 of the 4 patients continuing to use sildenafil at 3 yr. This merits further exploration to determine whether this was a placebo effect or whether sexual function might be influenced by mechanisms outside the primary neurovascular bundles. Our study has important clinical implications for the surgical management of prostate cancer. The introduction of sildenaﬁl citrate coincides with the highly effective screening programs that detect localized prostrate cancer at stages associated with high cure rates. The mean age of newly diagnosed prostate cancer has dropped to the late 50s and early 60s, signiﬁcantly extending sexual life expectancy. This period of sexual longevity should encourage urologists to advance their understanding of uropelvic anatomy and recognize that subtle reﬁnements in their surgical technique can have a signiﬁcant impact on the sexual outcomes of their patients.

Efﬁcacy and Factors Associated With Successful Outcome of Sildenaﬁl Citrate Use Today, sildenaﬁl citrate is commonly prescribed to treat ED after RP. However, we still do not know the factors determining the drug’s clinical efﬁcacy, since the literature contains few reports on the predictors of satisfactory outcome in patients with ED following RP.

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Table 17 Response to Sildenaﬁl Citrate at 3 Years as Stratiﬁed by Nerve-Sparing (NS) Statusa Variablea IIEF-5 questionnaire (patients) Maintenance ability, Q5 Erection conﬁdence, Q15 Maintenance frequency, Q4 Erection ﬁrmness, Q2 Intercourse satisfaction, Q7 Total mean IIEF-5 score Mean EDITS score (patients) Spousal questionnaire Ability to achieve and maintain erection (%) Total spousal satisfaction (%)

Bilateral NS (25/33)

Unilateral NS (4/6) Non-NS (2/4)

4.35 ± 0.21* 3.54 ± 0.13* 4.38 ± 0.21* 3.93 ± 0.28* 3.87 ± 0.29* 19.97 ± 1.12* 74.2 ± 3.4

3.42 ± 0.57 3.28 ± 0.52 3.34 ± 1.46 3.14 ± 0.55 2.71 ± 0.28 15.89 ± 3.38 63.9 ± 8.1

2.38 ± 0.72 1.96 ± 0.18 1.85 ± 0.40 2.14 ± 0.50 1.73 ± 0.20 10.06 ± 2.00 47.6 ± 7.5

76 (19/25)

50 (2/4)

0 (0/2)

78.6 (20/25)

50 (2/4)

0 (0/2)

Data are mean ± SE unless otherwise noted. Each IIEF domain was scored from 0 to 5: 0, did not attempt intercourse; 1, never/occasionally; 2, less than half the time; 3, sometimes/half the time; 4, more than half the time; 5, almost always. The total IIEF-5 score was calculated by totaling and taking the mean of the response to all ﬁve domains of IIEF-5. The Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questions were scored using a 5-point scale (0–4), and the mean score was multiplied by 25 to get the total EDITS score. The total scores were calculated as follows: 0, very dissatisﬁed; 25, satisﬁed; 50, neither satisﬁed nor dissatisﬁed; 75, satisﬁed; and 100, very satisﬁed. A score of 50 or more was deﬁned as “satisﬁed with treatment” and a score of 50 or less was deﬁned as “not satisﬁed with treatment.” The spousal questionnaire was scored from 1 to 5:1, never/occasionally; 2, less than half of the time; 3, sometimes/half of the time; 4, more than half of the time; and 5, almost always. Total spousal satisfaction was calculated from these questions and expressed as a percentage. * p < 0.05 bilateral vs non-NS International Index of Erectile Function (IIEF-5) domain was considered signiﬁcant by Wilcoxon rank-sum test. a b

We studied the efﬁcacy of sildenaﬁl citrate and the predictors of satisfactory outcome, and we identiﬁed prognostic factors for treatment of ED following RP. We assessed the change in the quality of erection before and after treatment using the abridged 5-item version of the IIEF-15 questionnaire (SHIM). The drug response to sildenaﬁl citrate was assessed by using the EDITS questionnaire. We stratiﬁed the responses on the basis of patient age, number of neurovascular bundles preserved, preoperative erectile function as determined by SHIM analysis, and the interval after surgery to the initiation of drug treatment (65). Following treatment with sildenafil, 100/174 (57%) patients responded to the drug: 79/104 (76%) in the bilateral NS group, 15/28 (53.5%) in the unilateral NS group, and 6/42 (14.2%) in the NNS group. SHIM (IIEF-5) analysis showed that the magnitude of improvement was higher in the bilateral NS group (19.97 ± 1.12) than in the unilateral NS (15.89 ± 3.38) or non-NS groups (10.06 ± 2.0, p < 0.020; Table 18). Four factors were statistically significantly associated with successful outcome: the presence of at least one neurovascular bundle, preoperative SHIM (IIEF-5) score ≥ 15, age ≤ 65 yr, and interval from RP to drug use > 6 mo (p < 0.001) (Table 19). Thus, the degree of neurovascular preservation continues to affect the response rates to sildenafil. Besides neurovascular bundle status, we found three other factors that were

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Zippe and Raina Table 18 IEF-5, EDITS, and Spousal Satisfaction Scores: Responses Stratiﬁed by Status of Neurovascular Bundles

Variableb Mean age (yr) Able to penetrate (%) IIEF-5 (SHIM) questionnaire (patients) Maintenance ability, Q5 Erection conﬁdence, Q15 Maintenance frequency, Q4 Erection ﬁrmness, Q2 Intercourse satisfaction, Q7 Total mean IIEF-5 (SHIM) score Mean EDITS score (patients) *Spousal questionnaire Ability to achieve erection (%) Spousal satisfaction (%)

Bilateral NS (79/104) 61.8 76

Unilateral NS (15/28)

Non-NS (6/42)

60.5 53.5

61.2 14.2*

4.35 ± 0.21* (4–5) 3.42 ± 0.57 (3–4) 2.38 ± 0.72 (2–3) 3.54 ± 0.13* (3–4) 3.28 ± 0.52 (3–4) 1.96 ± 0.18 (2–3) 4.38 ± 0.21* (4–5) 3.34 ± 1.46 (3–4) 1.85 ± 0.40 (1–2) 3.93 ± 0.28* (4–5) 3.14 ± 0.55 (3–4) 2.14 ± 0.50 (2–3) 3.87 ± 0.29* (3–4) 2.71 ± 0.28 (2–3) 1.73 ± 0.20 (1–2) 19.97 ± 1.12* 15.89 ± 3.38 10.06 ± 2.0 (5–15) (15–25) (15–20) 74.2 ± 3.4 (50–100) 63.9 ± 8.1 (50–75) 47.6 ± 7.5 (25–50) 57.7 (60/104)

46.4 (13/28)

2.3 (1/47)

78.8 (82/104)

46.4 (13/28)

14.2 (6/42)

Data are mean ± SE (range) unless otherwise noted. The Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questions were scored using a 5point scale (0–4), and the mean score was multiplied by 25 to get the total EDITS score. The total scores were calculated as follows: 0, very dissatisﬁed; 25, unsatisﬁed; 50, neither satisﬁed nor dissatisﬁed; 75, satisﬁed; and 100, very satisﬁed. A score of 50 or more was deﬁned as “satisﬁed with treatment” and a score of 50 or less was deﬁned as “not satisﬁed with treatment.” The spousal questionnaire was scored from 1 to 5: 1, never/occasionally; 2, less than half of the time; 3, sometimes/half of the time; 4, more than half of the time; and 5, almost always. Total spousal satisfaction was calculated from these questions and expressed as a percentage. * p < 0.05 bilateral nerve sparing (NS) vs non-NS International Index of Erectile Function (IIEF-5) domain was considered signiﬁcant, by Wilcoxon rank-sum test. a b

associated with successful outcome: preoperative erectile function, age, and the interval between surgery and start of drug therapy (65). IMPACT OF NEUROVASCULAR BUNDLES The etiology of ED following RP appears to be transient or permanent injury to the neurovascular bundles that innervate the corpora cavernosum (2,3). Although the etiology can be mixed, with both vasculogenic and neurogenic insults, the primary problem appears to be a neurologic injury (1,2). With a neurologic injury, there is a decreased release of nitric oxide across the neuromuscular junction, limiting the amount of available cGMP (27). Sildenaﬁl citrate works by inhibiting the PDE-5 enzyme, and thus increases the amount of cGMP (27–30). Thus, the presence or absence of the neurovascular bundles, which inﬂuences the relative amount of nitric oxide secretion signiﬁcantly, inﬂuences a man’s ability to achieve vaginal intercourse (28,29). Without nitric oxide, cGMP is not activated and therefore, cannot convert guanosine triphosphate (GTP) into cGMP. cGMP is metabolized through enzymatic breakdown by PDE-5, which closes the potassium channel, and results in increased intracellular calcium and smooth muscle contraction (4,35,36,51–55). Without cGMP, there is no substrate in

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Table 19 Factors Associated With Successful Outcome of Sildenaﬁl Citrate Following Radical Prostatectomy (RP) Variable Neurovascular bundle status NS vs Non-NS Preoperative erectile function IIEF-5 ≥ 15 vs IIEF-5 < 15 Age, overall (yr) <60 vs 60–65 vs >65 Time interval from RP (mo) 3–6 vs 6–12 vs 12–18 vs >18

Percentage (Responders/Total)

p value*

71 (94/132) vs 14 (6/42)

<0.001a

67 (92/137) vs 22 (8/37)

<0.001a

75 (36/48) vs 57 (42/74) vs 42 (22/52)*

0.001b

24 (4/17)** vs 57 (24/42) vs 63 (66/104) vs 91 (10/11)

<0.001b

Abbreviations: IIEF, International Index of Erectile Function; NS, nerve sparing. a Chi-square test for overall association. b Cochran Armitage test for trend. * Signiﬁcantly different from < 60. ** Signiﬁcantly different from –12, 12–18, and >18 mo.

which PDE-5 can work. Hence, a PDE-5 inhibitor such as sildenaﬁl citrate is ineffective (28,29,52–54). This physiology emphasizes and explains why the presence and the amount of neurovascular tissue signiﬁcantly inﬂuences the response rates to sildenaﬁl citrate. IMPACT OF PREOPERATIVE ERECTILE FUNCTION In our updated study, we also found that preoperative sexual status (Table 19) inﬂuenced the response to oral sildenaﬁl (67% vs 22%). Lowentritt et al. (56) also found that men with pretreatment erectile activity had better outcomes with sildenaﬁl citrate therapy than men without such function (82% vs 20%). Similarly, Mark et al. (57) studied patients’ responses to sildenaﬁl citrate by stratifying them using a predrug ED severity classiﬁcation system: the men who reported some erectile function (severity class 1 and 2) responded to sildenaﬁl citrate much more efﬁcaciously than those with no function (severity class 4; 80% vs 53%). IMPACT OF AGE Potency rates after RP vary signiﬁcantly with age: young men regain natural erections more often that older men. Zagaja et al. (55) showed that the magnitude of a man’s response to sildenaﬁl after RP appears to be inversely correlated with his age. Among the patients who underwent a bilateral NS RP in that study, 80% of the patients who were younger than 55 yr of age reported an adequate response to the drug therapy vs 33% of those who were older than 65 yr. When analyzing the patients who had undergone a unilateral NS RP, Zagaja and his researchers (55) found that none of the patients who were older than 55 yr—and only 40% of those younger than 55 yr— reported an adequate response. Similarly, Lowentritt et al. (56) showed that patients age at the start of treatment signiﬁcantly affected response. In their study, 57% of the patients who were younger than

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55 yr and were treated within 6 mo of surgery responded to the treatment, whereas only 13% who were older than 55 yr and treated in the same manner were sexually satisﬁed with the treatment. These potency rates are quite similar to those reported in our updated series, with one exception: we found that 33–50% of patients >55 yr old who had unilateral nerve sparing also responded to sildenaﬁl citrate therapy. It is difﬁcult to explain the relationship of recovery of erectile function to age on a neurologic basis. If the neurovascular bundles are preserved, the patient should respond to sildenaﬁl regardless of age. The observation that the response to sildenaﬁl strongly correlates with age and the number of neurovascular bundles preserved suggests that yet unknown vascular factors contribute to the mechanism of injury and recovery of potency after RP (6,8,27–29). Additional investigations are required to identify these factors, which may lead to further modiﬁcations in the surgical technique and, ultimately, improved potency rates. Six of the 26 men (14%) in the NNS cohort also recovered sexual function. This merits further exploration to determine whether this was a placebo effect or whether sexual function might be inﬂuenced by a mechanism operating outside the primary neurovascular pathways. IMPACT OF INTERVAL FROM SURGERY AND DOSE OF DRUG Contrasting findings have been reported regarding the latency period following RP during which sildenafil citrate is effective. Our study showed that patients responded most optimally to sildenafil therapy when they were started on the drug at least 6 mo after surgery. This finding is similar to that of Lowentritt et al. (56), who found that patients who were started on the drug before the 6-mo mark did not respond well. Zagaja et al. (55) found that none of their patients responded to sildenafil sooner than 9 mo after RP. Hong et al. (59) found that treatment satisfaction improved from 26% when sildenafil was started at 0–6 mo after RP to 60% when it was started 18–24 mo after RP. The results of our study raise several interesting issues regarding the etiology of ED after RP. Although our clinical experience has shown that men can recover natural erections sufficient for vaginal penetration sooner than 12 mo after NS RP surgery, no patient in this series did so. During the early postoperative period, patients who undergo a NNS or NS RP usually report the absence of spontaneous erection (both nocturnal and at awakening). This time interval of reduced erectile function is potentially associated with impaired blood inflow to the corpora cavernosa, which ultimately leads to tissue hypoxia and significant damage to the cavernous smooth muscle (27–29,46–48). Despite the surgeon’s best effort to preserve penile nerves, some dissection around the prostate is necessary, resulting in variable degrees of nerve injury (2,3,5). Pharmacologic interventions to promote erections during this convalescent period have been shown to enhance the recovery of spontaneous erection (48). This neural recovery period appears to be at least 6–12 mo in duration and may actually be longer (3). Since oral therapy demonstrated limited effect in the early postoperative period, alternative treatments (IC injections, VCD, MUSE) can be used as adjuvant therapy for treatment of postprostatectomy patients during the recovery of temporary neurapraxia (4). Potency rates after RP vary a great deal, and the criteria for a positive response or a satisfactory erection are not universally applied. Ideally, uniformity in using universal validated questionnaires and comprehensive and objective evaluation of erectile function in an institution can address the problem of erectile function more accurately. Our

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studies using validated questionnaires has important clinical implications in the management of localized prostate cancer. Using the user-friendly IIEF-5 (SHIM) questionnaires, we can easily compare the effects of surgery vs I-125 seeds vs external beam radiation therapy on our patients’ sexual function and can monitor this outcome parameter as new techniques and procedures evolve. The use of questionnaires educates us and allows us to inform our patients properly in their own speciﬁc treating environment. Currently, IIEF-5 questionnaires are taken at baseline and on subsequent followup visits by our physicians treating prostate cancer patients with I-125 seed implants and external beam radiation therapy.

FUTURE DIRECTIONS AND STUDIES New Oral Therapies Many new therapeutic agents are emerging for the treatment of sexual dysfunction. Oral pharmacotherapy is currently considered the ﬁrst option for most patients with ED. A number of experimental drugs have been evaluated in phase I and II clinical studies. The closest to clinical use is apomorphine SL, which has been approved for marketing in Europe. This drug has a central mechanism of action, and it is administered sublingually 20 min prior to expected sexual activity. At the approved doses of 2 and 3 mg, apomorphine SL has been shown to induce a signiﬁcantly higher percentage of erections than placebo. At the 2–3-mg dose, the principal side effect of nausea was acceptable at 4.7%. There are currently new efforts to design PDE-5 inhibitors with increased potency and selectivity. Roger and colleagues sequenced three distinct isoforms of PDE-5 in human cavernosal tissue, heralding the advent of pharmacogeniomics into the field of ED. Giuliano and co-workers from Bicetre, France and several other European centers showed that IC351 (Cialis®, Lilly ICOS LIC), a PDE-5 inhibitor, significantly increased IIEF scores and was safe and well tolerated. The efficacy and safety of Cialis for the treatment of ED is currently being investigated in phase III clinical trials. The drug significantly improved erectile function and was equally well tolerated in 10- and 20-mg doses. Another PDE-5 inhibitor, BAY38–9456 (Vardenaﬁl) is a new potent and selective PDE-5 inhibitor that showed safety in phase I trials reported from two centers in Germany by Sachse. The results showed that Vardenaﬁl is a selective and potent PDE-5 inhibitor that potentiates NO-mediated relaxation and cGMP accumulation in human trabecular smooth muscle, supporting its use as a future therapeutic agent for the oral treatment of ED. Further clinical trials are required to assess the selectivity, pharmakinetics, and period of responsiveness of these new drugs and their potential beneﬁts in the treatment modality of ED after RP.

Intraoperative Cavernous Nerve Stimulation (Cavermap) The Cavermap system was used to identify the location of the cavernous nerves during RP by monitoring tumescence response to intraoperative cavernous nerve stimulation. Although most surgeons feel conﬁdent in identifying the neurovascular bundles, this may aid the surgeon in preserving the cavernous nerves in selected cases. It is still unclear whether the use of the Cavermap translates into an improvement in erectile potency. The real problem appears to be the presence of neurapraxia following the surgery and not necessarily the identiﬁcation of the neurovascular bundles. The main

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beneﬁt of the Cavermap may be that it forces the surgeon to pay particular attention to the nerve-sparing component of the operation and to optimize the effort to perform the apical dissection optimally (66).

Interposition of Sural Nerve Grafts Sural nerve grafts may act as templates for potential nerve regeneration after surgery. Although nerve grafting is a time-consuming procedure that prolongs the operative time, it may be a reasonable option in a young patient who has undergone a bilateral or unilateral NNS prostatectomy (67). Kim and associates (68) recently reported on 12 potent men (mean age: 57 yr) who underwent wide bilateral neurovascular bundle resection with sural nerve graft interposition. At 1 yr of follow-up, patient interviews were done and compared with a control group with bilateral nerve resection without nerve grafting. Of the 12 grafted patients, 4 (33%) had spontaneous unassisted erections sufﬁcient for sexual intercourse with vaginal penetration. An additional five patients described partial erections of “40–60%” but with insufﬁcient rigidity for penetration. The control group had signiﬁcantly poorer sexual function in all components of the IIEF, with only one patient achieving vaginal penetration. A follow-up period of 24 mo may be necessary to evaluate the functional status of these nerve grafts and to assess whether they will respond to oral treatment with sildenaﬁl citrate (68).

Early Penile Rehabilitation Nocturnal erections may play an important role in preserving normal erectile function by providing regular tissue oxygenation (48). It has been shown that penile oxygen tension is low under ﬂaccid conditions (pO2 = 35) but increases to levels seen in other tissues during an erection (69). Persistent penile hypoxia, such as that occurring during prolonged periods of penile inactivity, may lead to the formation of lacunar ﬁbrosis and ultimately a decline in erectile capacity (58). It has been hypothesized that erectogenic agents, through their erection-enhancing effects, will improve tissue oxygenation, prevent penile ﬁbrosis, and ultimately preserve erectile function or slow its decline. Following a bilateral NS RP, patients are generally unable to achieve penile erections, and nocturnal tumescence is greatly reduced or absent. ED following an RP has two components with different prognoses: acute (or temporary) and chronic (or sustained). Despite the surgeon’s best effort to preserve penile nerves, some dissection around the prostate is necessary, resulting in variable degrees of nerve injury. The temporary loss of erectile function appears to be mostly related to some degree of operative injury and is referred to as the period of neurapraxia. Neurapraxia gradually resolves following surgery. Pharmacologic intervention to promote erections during this convalescent period has been shown to enhance the recovery of spontaneous erections (46–48). This neural recovery period appears to be at least 3 mo in duration and may actually be longer. In contrast, sustained ED appears to be a function of degeneration of corporeal lacunar smooth muscle and its replacement with collagen, presumably a response to tissue hypoxia. Therapeutic postsurgical intervention with MUSE and VCD may restore nocturnal erections (both frequency and duration), facilitate vascular perfusion of the corpus cavernosum, and subsequently inhibit corporeal hypoxia and ﬁbrosis. Initial data with intracavernous agents have been very encouraging and lend support to this hypothesis (48). However, alternative mechanisms of action cannot be excluded, such

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as a direct effect on collagen synthesis. Numerous physiologic insults lead to the production of transforming growth factor-β (TGF-β) and subsequent tissue ﬁbrosis. It is possible that erectogenic agents modulate the expression of TGF-β or other factors, independently of tissue oxygenation (46). Although it has been suggested that early, daily use of sildenaﬁl in the early postoperative period can augment the recovery of nocturnal erections, the use of sildenaﬁl alone in the ﬁrst 9 mo or so rarely produces an erection sufﬁcient for vaginal penetration. Thus, we advise patients to augment the use of sildenaﬁl with the temporary use of a VCD or intraurethral MUSE. Currently, we are studying the use of sildenaﬁl and MUSE in combination two to three times/wk and assessing patient response with the IIEF-5 questionnaire. Currently, all early treatment programs following RP should be considered investigational until conﬁrmatory studies with randomized controls are done. Although early treatment programs using erectaids may increase the frequency of sexual activity, there are no data suggesting that the period of neurapraxia is shortened or the percentage of patients regaining natural potency is higher.

Growth Factors for Cavernous Nerve Regeneration Recent animal studies have provided promising results concerning the use of nerve and vascular growth factors in promoting the regrowth of damaged cavernous nerves and return of erectile function. Lue et al. (70) have shown that intracorporal administration of brain-derived neurotrophic factors after bilateral cavernous nerve cryoablation in rats prevents the degeneration of neural nitric oxide synthase-containing neurons, with an enhancement of recovery of erectile function. In addition, the intracorporeal injection of vascular endothelial growth factor in rats with arteriogenic ED can provide a protective effect on erectile function (70). It remains to be determined in the human model whether nerve regrowth can be stimulated without theoretically increasing the risk of prostate cancer recurrence or the stimulation of growth of microscopic residual cancer.

CONCLUSIONS Despite the advent of the NS radical prostatectomy, ED is still a common surgical complication. Dysfunction rates vary from 10% to 100%, depending on the experience of the surgeon, the frequency which he or she does the surgery, the decision to perform nerve sparing, the stage of the disease, the age and pre-operative potency of the patient, and the reporting of a successful response (defined as vaginal intercourse/ attempts). The natural recovery of erection function can take as long as 24 mo. Therefore, many men should be encouraged to receive adjuvant treatment. Although standard treatments (vacuum restriction, MUSE, and intracorporeal injections) are effective and still available, most patients prefer oral therapy because of its simplicity. Sildenafil citrate and the newer phosphodiesterase-5 inhibitors are only effective when functional nerve tissue is present. The enthusiasm and compliance of patients to oral therapies should encourage urologists to perform and perfect the NS approach to give their patients the best chance of resuming sexual activity after RP for treatment of ED. Oral therapy does not appear to be very effective within the first 9–12 mo while the neurapraxia exists, and standard treatment options should be encouraged during this time to maintain good sexual health and possibly an earlier return to natural potency.

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REFERENCES 1. Schrader-Bogan CL, Kjellberg JL, McPherson CP, et al. Quality of life and treatment outcomes: prostate carcinoma patients’ perspectives after prostatectomy or radiation therapy. Cancer 1997;79:1977–1986. 2. Walsh PC, Marschke P, Ricker D, et al. Patient-reported urinary continence and sexual function after anatomic radical prostatectomy. Urology 2000;55:58–61. 3. McCullough AR. Management of erectile dysfunction following radical prostatectomy. Sexual Dysfunction Med 2000;2:2–8. 4. Zippe CD, Raina R, Thukral M, et al. Management of erectile dysfunction following radical prostatectomy. Review article. Curr Urol Rep 2001;2:495–503. 5. Catalona WP, Basler JW. Return of erections and urinary continence following nerve-sparing radical retropubic prostatectomy. J Urol 1993;150:905–907. 6. Quinlan DM, Epstein JI, Carter BS, Walsh P. Sexual function following radical prostatectomy: inﬂuence of preservation of neurovascular bundles. J Urol 1991;145:998–1002. 7. Sexton WJ, Benedict JF, Jarow JP. Comparison of long-term outcomes of penile prosthesis and intracavernosal injection therapy. J Urol 1998;159:811–815. 8. Jarow JP, Nana-Sinkam P, Sabbagh M, et al. Outcome analysis of goal directed therapy for impotence. J Urol 1996;155:1609–1612. 9. Mazur DJ, Merz JF. Older patients’ willingness to trade off urologic adverse outcomes for a better chance at five-year survival in the clinical setting of prostate cancer. J Am Geriatr Soc 1995;43:979–984. 10. Talcott JA, Rieker P, Propert KJ, et al. Patient reported impotence and incontinence after nerve-sparing radical prostatectomy. J Natl Cancer Inst 1997;89:1117–1123. 11. Valdivia Navarro P, Gonzalvo A, Blas Marin M, et al. Quality of life after radical prostatectomy. Actas Urol Esp 1997;21:903–908. 12. Raina R, Agarwal A, Goyal K, Zippe CD. Deﬁning erectile dysfunction (ED) and treatment pathways following radical prostatectomy (RP) in a preoperative sexually active population. In: 28th Annual Meeting of the American Society of Andrology, Mar 29–Apr 1, 2003, Phoenix AZ, abstract #116, poster presentation. 13. Dutta TC, Eid JF. Vacuum constriction devices for erectile dysfunction: a long-term, prospective study of patients with mild, moderate, and severe dysfunction. Urology 1999;54:891–893. 14. Cookson MS, Nadig PW. Long term results with vacuum constriction device. J Urol 1993;149:290–294. 15. Turner LA, Althof SE, Levine SB, et al. Twelve-month comparison of two treatments for erectile dysfunction: self-injection versus external vacuum devices. Urology 1992;39:139–144. 16. Soderdahl DW, Thrasher JB, Hansberry KL. Intracavernosal drug-induced erection therapy versus external vacuum devices in the treatment of erectile dysfunction. Br J Urol 1997;79:952–957. 17. Gould JE, Switters DM, Broberick GA, deVereWhite RW. External vacuum devices: a clinical comparison with pharmacologic erections. World J Urol 1992;10:68–70. 18. Blackard CE, Borken WD, Lima JS, et al. Use of vacuum tumescence device for impotence secondary to venous leakage. Urology 1996;41:225–227. 19. Sidi AA, Becher EF, Zhang G, Lewis JH. Patient acceptance of and satisfaction with an external negative pressure device for impotence. J Urol 1990;144:1154. 20. Raina R, Klepacz H, Agarwal A, Zippe CD. Early use of vacuum constriction device (VCD) following radical prostatectomy (RP) facilitates early sexual activity and potential return of erection. J Urol 2002;167:279. 21. Raina R, Agarwal A, Lakin MM, Zippe CD. Combination therapy: sildenaﬁl citrate enhances sexual satisfaction in vacuum constriction device (VCD) failures following radical prostatectomy (RP). J Urol 2002;167:281 22. Wiles PG. Successful non-invasive management of erectile impotence in diabetic men. BMJ (Clin Res Ed) 1988;296:161–162. 23. Padma-Nathan H, Hellstrom WJ, Kaiser FE, et al. Treatment of men with erectile dysfunction with transurethral alprostadil. N Engl J Med 1997;336:1–7. 24. Costabile RA, Govier FE, Ferrigni RG, et al. Safety of transurethral alprostadil in patients with erectile dysfunction following radical prostatectomy. J Urol 1997;157:1424. 25. Paolone DR, Lankin MM, Ingleright BJ, et al. Intraurethral alprostadil therapy at The Cleveland Clinic Foundation. Abstract submitted to North Central Section AUA for presentation in October, 1998.

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26. Raina R, Agarwal A, Zippe CD. Long term efﬁcacy and compliance of MUSE therapy for erectile dysfunction following radical prostatectomy: SHIM (IIEF-5) analysis. J Urol 2003. 27. Burnett AL. Nitric oxide in the penis: physiology and pathology. J Urol 1997;157:320–324. 28. Burnett AL. Nitric oxide regulation of penile erection: biology and therapeutic implications. J Androl 2002;23:S20–S24. 29. Ballard SA, Gingell CJ, Tang K, et al. Effects of sildenaﬁl on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isoenzymes. J Urol 1998;159:2164–2171. 30. Nehra, et al. Combination of sildenaﬁl and intraurethral prostaglandin E1 salvaged a selected population of men with ED. Abstract submitted to the AUA for the 95th Meeting of the American Urological Association, May, 2000. 31. Porst H. Transurethral alprostadil with MUSE versus intracavernous alprostadil: a comparative study in 103 patients with erectile dysfunction. Int J Impot Res 1997;9:187–192. 32. Stakl W, Hasun R, Marberger N. Prostaglandin E-1 in the treatment of erectile dysfunction. World J Urol 1990;8:84–86. 33. Khan MA, Thomson CS, Sullivan ME, et al. The role of prostaglandins in the etiology and treatment of erectile dysfunction. Prostaglandin Leukotr Essent Fatty Acids 1999;60:169–174. 34. Cawello W, Schweer H, Dietrich B, et al. Pharmacokinetics of prostaglandin E1 and its main metabolites after intracavernous injection and short term infusion of prostaglandin E1 in patients with erectile dysfunction. J Urol 1997;158:1403–1407. 35. Dennis RL, McDougal WS. Pharmacological treatment of erectile dysfunction after radical prostatectomy. J Urol 1988;139:775–776. 36. Rodriguez VL, Gonzalvo IA, Bono AA, et al. Erectile dysfunction after radical prostatectomy. Etiopathology and treatment. Actas Urol Esp 1997;21:909–921. 37. Lakin MM, Chen RN, Llorens SA, et al. Prostaglandin E1 injection therapy for post-prostatectomy impotence: an outcome analysis. J Urol 1996;155:639. 38. Evans C. Complications of intracavernosal therapy for impotence. In: Carson C, Kirby R, Goldstein I, eds. Textbook of Erectile Dysfunction. Isis Medical Media, Oxford, 1999, pp. 365–370. 39. Mulhall JP, Jahoda A, Cairney M, et al. The causes of patient dropout from penile self-injection therapy for impotence. J Urol 1999;162:1291–1294. 40. Purvis K, Egdetveit I, Christiansen E. Intracavernosal therapy for erectile failure—impact of treatment and reasons for dropout and dissatisfaction. Int J Impot Res 1999;11:287–299. 41. Raina R, Lakin MM, Agarwal A, et al. Long-term efﬁcacy and compliance of Intracavernous injections following radical prostatectomy: SHIM (IIEF-5) analysis. J Impot Res 2003;15(5):318–322. 42. Bechara A, Casabe A, Cheliz G, et al. Prostaglandin E1 versus mixture of prostaglandin E1 papavereine and phentolamine in non-responders to high papaverine plus phentolamine doses. Urology 1996;155:913–914. 43. Mullhall JP, Daller M, Traish AM, et al. Intracavernosal forskalin: role in management of vasculogenic impotence resistant to 3-agent pharmacotherapy. J Urol 1997;158:1752–1758. 44. Mc Mohan CG. A pilot study of role of intracavernous injection of vasoactive intestinal peptide and phentolamine in the management of erectile failure. Int J Impot Res 1996;8:233–236. 45. Buvat J, Costa P, Morlier D, et al. Double blind multicenter study comparing alprostadil alpha-cyclodextrin with moxisylyte chlorohydratein chronic organic erectile dysfunction. J Urol 1998;159:116–119. 46. Moreland RB, Abdulmaged T, McMillin MA, et al. PGE1 suppresses the induction of collagen synthesis by transforming growth factor beta 1 in human corpus cavernosum smooth muscle. J Urol 1998;153:811–815. 47. Fraiman MC, Lepor H, McCullough AR. Changes in penile morphometrics in men with erectile dysfunction after nerve sparing radical prostatectomy. Mol Urol 1999;3:109–115. 48. Montorsi F, Guazzoni G, Strambi LF, et al. Recovery of spontaneous erectile function after nerve sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomized trial. J Urol 1996;155:639. 49. Raina R, Ausmundson S, Agarwal A, Lakin MM, Zippe CD. Long-term intracavernous (IC) therapy responders can potentially switch to sildenaﬁl citrate after radical prostatectomy (RP). Urology 2003, in press. 50. Willke RJ, Glick HA, McCarron TJ, et al. Quality of life effects of alprostadil therapy for erectile dysfunction. J Urol 1997;157:2124–2127. 51. Goldstein I, Lue TF, Padma-Nathan H, et al. for the Sildenaﬁl Study Group: Oral sildenaﬁl in the treatment of erectile dysfunction. N Engl J Med 1998;338:1397–1404.

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52. Steers WD. Viagra after one year. Urology 1999;54:12–17. 53. Zippe CD, Thurkal M, Agarwal A, et al. The erectile dysfunction following radical prostatectomy. Indian J Urol 2000. 54. Zippe CD, Jhaveri FM, Klein EA, et al. Role of Viagra after radical prostatectomy. Urology 2000;55:241–245. 55. Zagaja GP, Mhoon DA, Aikens JE, Brendler CB. Sildenaﬁl in the treatment of erectile dysfunction after radical prostatectomy. Urology 2000;56:631–634. 56. Lowentritt BH, Scardino PT, Miles BJ, et al. Sildenaﬁl citrate after radical retropubic prostatectomy. J Urol 1999;162:1614–1618. 57. Leonard S, Duda C, Jdorey J, PB. Treatment of erectile dysfunction with sildenafil. Urology 1999;53:19–24. 58. Jarow JP, Burnett AL, Geringer AM. Clinical efﬁcacy of sildenaﬁl citrate based on etiology and response to prior treatment. J Urol 1999;162:722–725. 59. Hong EK, Lepor H, McCullough AR. Time dependent patient satisfaction with sildenaﬁl for erectile dysfunction (ED) after nerve sparing radical retropubic prostatectomy. Int J Impot Res 1999;11:15–22. 60. Zippe CD, Kedia S, Kedia AW, Pasqualotto F. Sildenaﬁl citrate (Viagra) after radical retropubic prostatectomy: pro. Urology 1999;54:583–586. 61. Feng MI, Huang S, Kaptein J, Kaswick J, Aboseif S. Effect of sildenaﬁl citrate on post-radical prostatectomy erectile dysfunction. J Urol 2000;164:1935–1938. 62. Ajay N, Goldstein I. Sildenafil citrate after radical retropubic prostatectomy: con. Urology 1999;54:587–589. 63. Sadovsky R, Miller T, Moskowitz M, et al. Three-year update of sildenaﬁl citrate (Viagra) efﬁcacy and safety. Int J Clin Pract 2001;15–128. 64. Raina R, Lakin MM, Agarwal A, et al. Long-term effect of sildenaﬁl citrate following radical prostatectomy: 3-year follow-up. Urology 2003;62:110–115. 65. Raina R, Agarwal A, Mascha E, et al. Efﬁcacy and factors associated with successful outcome of sildenaﬁl citrate use following radical prostatectomy. J Urol 2003, submitted. 66. Klotz L, Herschorn S. Early experience with intraoperative cavernous nerve stimulation with penile tumescence monitoring to improve nerve sparing during radical prostatectomy. Urology 1998;52:537–542. 67. Sunderland S. Nerve grafting and related methods of nerve repair. In: Nerve Injuries and Their Repair: A Critical Appraisal. Churchill Livingstone, Edinburgh, 1991, pp. 467–497. 68. Kim ED, Nath R, Kadmon D, et al. Bilateral nerve graft during radical retropubic prostatectomy: 1 year follow-up. J Urol 2001;165:1950–1956. 69. Kim N, Vardi Y, Padma-Nathan H, Daley J, Goldstein I, Saenz de Tejada I. Oxygen tension regulates the nitric oxide pathway. Physiological role in penile erection. J Clin Invest 1993;91:437. 70. Lee MC, El-Sakka A, Bakircioglu E. The effect of vascular endothelial growth factor on a rat model of arterial impotence. J Urol 2000;163:198.

23

Counseling Patients With Localized Prostate Cancer Radiation or Surgery?

Eric A. Klein and Patrick A. Kupelian

INTRODUCTION The treatment of localized prostate cancer remains controversial because of the lack of conclusive well-controlled or randomized studies comparing outcomes of radiotherapy (RT) and radical prostatectomy (RP). A randomized trial published in 1982 showing an advantage to RP was never widely accepted because of randomization artifacts and worse than previously reported RT results (1,2). The Southwest Oncology Group closed a randomized study comparing these two modalities in the mid-1980s owing to poor accrual. In 1993, Stamey et al. (3) reported a 20% 5-yr biochemical cure rate with RT and suggested that radiation accelerates prostate cancer growth. Subsequently, large RT series were published with outcome results stratified by biopsy grade, T stage, and serum PSA, demonstrating similar short-term outcomes for RT and RP (4–6). A close examination of the patients treated by RT in the series of Stamey et al. (3) suggests that the observation of a 20% “cure” rate with RT can largely be explained by patient selection factors—all patients had high-volume cancers diagnosed by palpable lesions, 35% had clinical stage C disease, 50% had Gleason sum ≥7, and 15% had positive lymph nodes (7). Furthermore, Liebman et al. (8) have subsequently demonstrated that prostate-specific antigen (PSA) velocity is similar in those who fail radiation or surgery. None of these studies clearly answers the question of which is the best local therapy for localized prostate cancer. The unsettled nature of this issue is further complicated by the marked polarization of radiation oncologists and urologists in their counseling of patients with newly diagnosed localized disease, with surgeons recommending surgery and radiation therapists recommending radiation in virtually all circumstances (9). An important issue in judging comparative outcomes is the effect of PSA-based screening on pathologic stage migration. We have previously observed that during the

From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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Fig. 1. Comparison of pretreatment parameters in 2431 patients treated by radical prostatectomy (gray) and external beam radiotherapy (black) at the Cleveland Clinic between 1987 and 2000. All comparisons are statistically signiﬁcantly better in favor of radical prostatectomy (p < 0.001). PSA, prostate-speciﬁc antigen.

ﬁrst 10 yr (1987–1997) that PSA was widely available, the rate of organ-conﬁned disease for a given stage, grade, and pretreatment PSA value has increased markedly (10). We and others also observed that year of diagnosis is an independent predictor of the likelihood for cure (11), suggesting that the observed increase in the rate of organ-conﬁned disease has translated into improved disease-free survival for patients treated with RP. These observations also suggest that improvements in outcome for other therapies such as external beam radiation and brachytherapy reported during this interval may be related as much to downward pathologic stage migration as to improvements in speciﬁc therapeutic techniques and that it is inappropriate to compare current outcomes with historical controls. Another difﬁculty in comparing the relative efﬁcacy of different therapies arises from differences in patient selection. The ability of pretreatment parameters including biopsy grade, clinical stage, and PSA to predict the likelihood of cure for RP and all forms of RT is well established. Since Walsh’s admonition that the RP is best reserved for those likely to have organ-conﬁned disease (12), in the last 20 years there has been a tendency to restrict RP to those with the most favorable pretreatment characteristics and to refer those with the less favorable for RT. This tendency is apparent in the selection of patients with localized disease treated at the Cleveland Clinic in the PSA era (Fig. 1): for all parameters the most favorable features occurred in those treated by RP. Based on these differences in patient selection, one would predict that biochemical failure rates would be worse after RT, even if the two treatments were actually equally efﬁcacious. A related patient selection issue arises when trying to compare outcomes with different treatments among different institutions. Differences in subjective interpretation of digital rectal examination (DRE) findings, variations in pathologist’s assignment

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of Gleason’s grade, differences in the extent of pathologic sampling and interpretation of RP specimens, differences in PSA assays, and differing levels of expertise with a particular therapy all may confound interinstitutional comparisons. This problem is best illustrated by two reports comparing the results of brachytherapy with those of RP. In 1997, Ragde et al. (13) reported a 78% likelihood of biochemical cure (defined as PSA < 0.5 ng/mL) at 7 yr in patients undergoing brachytherapy with 125I. In a comparative study, Walsh’s group (14) reported a markedly better biochemical cure rate (98%, with cure defined as PSA <0.2 ng/mL) in a cohort of patients from their contemporaneous RP series, matched for grade and stage, and concluded that RP had a superior rate of cancer control. In an identical analysis, Catalona’s group (15) reported an 84% biochemical cure in similarly matched patients from their RP series but concluded that this result was not statistically different from Ragde’s results with brachytherapy. What should be concluded from these analyses? Is RP better than brachytherapy or not? The published Ragde series contained a disproportionate number (>50%) of low-grade tumors (Gleason sum <6), which are not representative of most modern radiotherapy or prostatectomy series. Theses biopsies were not centrally reviewed prior to publication, and subsequent review by Bostwick (personal communication) suggested that more than 80% of the tumors were actually Gleason sum 7. Seen in this light, these publications do not permit any meaningful conclusion about the relative efficacy of two different therapies performed at three different institutions, rather, the conclusion from these studies is that inherent biases in case selection among different institutions make it very difficult to compare outcomes, a sentiment echoed in print by the authors of both of the RP comparative studies. (“Our data point to the need for caution when comparing results from different unimodality series that contain disparities in prognostic indicators, ie, stage, Gleason score, and pretreatment PSA” [14, p. 880]; “No definitive conclusions about the relative efficacy of brachytherapy versus radical prostatectomy can be made using nonrandomized retrospective data” [15, p. 1215]). A comparison of different therapies for localized prostate cancer should include issues of cancer control, morbidity, quality of life, salvage of primary treatment failures, late effects, and cost. Of these, cancer control is the most important, since most patients would be willing to sacriﬁce some morbidity or quality of life for the best chance of cure.

CANCER CONTROL The issue of cancer control or cure is difﬁcult when we consider prostate cancer. The long natural history of this disease means that we still do not have meaningful overall or cancer-speciﬁc survival data even 21 yr after Walsh repopularized RP and 15 yr after PSA came into widespread use. In 2003, we simply are unable to tell our patients which of the various treatments for localized or locally advanced disease results in the best survival. Furthermore, we have no comparative data on metastasis-free survival, a good surrogate for cure since most men who die from prostate cancer do so within 3–5 yr after the onset of bony metastases. Another commonly used endpoint in other cancers is local control. Assessing local control and its impact on survival after RP is difficult because (1) in the era of stage migration palpable local recurrence is rare; (2) symptomatic local recurrences are even more rare; (3) it is likely that a blind biopsy of a normal feeling post-RP fossa

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undersamples the true number of local recurrences; (4) a positive biopsy of the prostatic fossa after RP does not exclude the simultaneous presence of distant disease; and (5) no imaging studies are sufficiently sensitive to detect a clinically silent local recurrence. Identifying local failures after prostate-preserving therapies such as RT or cryotherapy is also difficult because of a substantial undersampling error (16). The difﬁculties with standard endpoints of cancer control (cancer-speciﬁc survival, metastasis-free survival, and local control), which are commonly used in all other malignancies, leave only the use of biochemical failure for comparing the efﬁcacy for various therapies. Currently there are no data to support biochemical failure as a surrogate for survival, and the appropriate deﬁnition of biochemical failure after RT remains highly controversial. Several reports have addressed the issue of PSA failure as a surrogate for survival after deﬁnitive local therapy. We have previously reported that the likelihood of being alive 10 years after RP is unrelated to biochemical relapse, an observation that also holds for external beam radiotherapy (17,18). Pound et al. (19) reported that the median time to clinically apparent metastases after biochemical failure in untreated patients after RP is 8 yr and that the median time to death was an additional 5 yr. Paulson’s group (20) reported that PSA predicted death after perineal RP with a 10-yr lead time, but only for high-grade tumors (Gleason score 8–10). With up to 22 yr of follow-up in that series,the median time to death had not been reached for lower grade tumors. Together these observations emphasize the long natural history of treated prostate cancer. It is possible that with longer follow-up PSA will become a good surrogate for a well-deﬁned cancerrelated endpoint; however, it is also possible that (1) the lead-time bias effect of PSA will require even longer follow-up for a current cohort of newly diagnosed men to validate this endpoint; and (2) the signiﬁcant competing risk of non-cancer-related mortality in men undergoing therapy for localized disease will render biochemical endpoints meaningless, except for those with the most aggressive disease. Recognizing the limitations of a biochemical endpoint as a surrogate for survival, what is the best deﬁnition of biochemical failure after RP or RT? After prostatectomy, serum PSA levels are expected to be undetectable since all prostatic epithelium is removed. Although there is some controversy over the possibility of unresected residual normal prostate or benign prostatic hypertrophy (BPH) that could produce low but detectable PSA levels (21), there is general agreement that achieving a nadir PSA < 0.2 or 0.4 ng/mL is necessary for cure after surgery and that PSA levels above this are indicative of recurrence. The deﬁnition of biochemical failure after RT has been much more controversial. Since at least some normal prostate epithelium survives radiation, detectable PSA levels are to be expected after RT even if all tumor is eradicated. However, the exact level of acceptable serum PSA levels after RT has been hotly debated. As a compromise, in 1996 the American Society for Therapeutic Radiation and Oncology (ASTRO) consensus conference suggested that three consecutive rising levels after a nadir, with the time of failure backdated to halfway between the nadir and next PSA levels, was the most practical deﬁnition (22). The ASTRO deﬁnition was primarily intended as a tool to compare outcomes between different radiotherapy series. Its use is problematic when a comparison is made with prostatectomy series, since failure after RP requires only a single PSA value above a speciﬁed level and not repeated measurements over time. Furthermore, the backdating of the time of failure required by this deﬁnition generally yields more optimistic survival estimates compared with other commonly used deﬁnitions (23,24).

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To address the limitations of the ASTRO deﬁnition and to make it easier to compare results with surgical series, Critz et al. (25) have suggested the use of a nadir PSA level of 0.5 ng/mL to deﬁne failure after RT. Use of a nadir eliminates the time dependence of the ASTRO deﬁnition and avoids the problems associated with backdating the time of failure. Furthermore, Hanks et al. (26) recently presented data suggesting that not achieving a nadir of < 1.0 ng/mL after RT is associated with a higher likelihood of distant metastasis. However, owing to frequently observed ﬂuctuations of low PSA levels after RT and a proportion of patients after RT with PSA levels > 0.5 ng/mL who subsequently maintain stable levels and no evidence of progression, even a deﬁnition of failure at 0.5 ng/mL may not be ideal. Furthermore, using a nadir PSA level after RT cannot adequately deal with the PSA bounce effect, which may be observed in up to 25% of patients after intersitial brachytherapy (27). In addition to these limitations in deﬁnitions of biochemical failure, it is notable that: (1) compared with a nadir value of < 0.2 ng/mL, a nadir of < 0.5 ng/mL will overestimate the cure rate for RP, since some men with PSA values of 0.2–0.49 ng/mL after RP will progress with time; and (2) compared with the ASTRO deﬁnition, a nadir value of < 0.5 ng/mL will underestimate the cure rate with RT, since some men will have stable PSA values > 0.5 ng/mL and never show clinical progression. We have recently reported our comparative cancer control outcomes based on biochemical failure at 8-yr after RP or external beam RT (28). This series represents a prospectively followed cohort of all patients with nonmetastatic prostate cancer treated by RP or RT at the Cleveland Clinic since 1990. Although it is not a randomized trial, it does represent the efforts of a small number of urologists, radiation therapists, and pathologists with a similar approach to the management of localized and locally advanced disease working at a single institution over 10 years, a fact that should minimize difﬁculties encountered when comparing data from different institutions. Within this cohort there have been an insufﬁcient number of deaths to make meaningful statements about survival. To address the difﬁculties inherent in various deﬁnitions of biochemical failure, we have analyzed the outcomes using PSA nadir values of <0.2 and <0.5 ng/mL for the RP series and both the ASTRO and nadir deﬁnitions (<0.5 ng/mL) for the RT series. We have also recently reported that our results with RP in this cohort are similar to those of other large single-institutional series with respect to margin status and PSA outcomes when stratiﬁed by pre-RP staging criteria and pathologic outcomes (29). The cohort includes 1682 consecutive patients with clinical stage T1 and T2 adenocarcinoma of the prostate with either RP or RT to a dose of ≥68 Gy treated between January 1990 and December 1998. Pretreatment T stage, Gleason sum, and PSA values were available for all patients, and none received adjuvant radiation or hormonal therapy in the absence of biochemical relapse. Three-hundred twenty (19%) had neoadjuvant androgen deprivation (AD), all for 6 mo or less. RP was the primary treatment in 1054 patients (63%) and RT in 628 patients (37%). Seventeen percent of RP cases received neoadjuvant AD, compared with 23% of RT cases. Similar proportions of RP vs RT patients had bone scans (61 and 60%, respectively), and pelvic computed tomography (CT) scans (37 and 34%, respectively). None of these evaluations revealed definite bony or lymphatic metastases. Sixteen RT patients (3%) had pelvic lymph node dissection (PLND), whereas 793 (75%) of surgical cases had bilateral PLND. Two percent of RP patients (n = 17) had positive nodes vs none of the 16 RT patients who underwent PLND. The prostatectomies were completed in the 17 RP

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Klein and Kupelian Table 1 Distribution of Pretreatment and Treatment Parameters by Treatment Modality

Parameter Age <65 yr ≥65 yr Race African-American Caucasian Prior TURP No Yes Clinical T stage T1–T2A T2b–T2c iPSA level (ng/mL) ≤4 >4 to ≤10 >10 to ≤20 >20 Biopsy Gleason score ≤6 7 ≥8 Androgen deprivation (median duration 6 mo, range 3–6 mo) No Yes Total

All [no. (%)]

RT [no. (%)] RP [no. (%)]

p value <0.001

806 (48) 876 (52)

166 (26) 462 (74)

640 (61) 414 (39)

252 (15) 1430 (85)

148 (24) 480 (76)

104 (10) 950 (90)

1613 (96) 69 (4)

576 (92) 52 (8)

1037 (98) 17 (2)

1343 (80) 339 (20)

445 (71) 183 (29)

898 (85) 156 (15)

165 (10) 956 (57) 388 (23) 173 (10)

43 (7) 320 (51) 169 (27) 96 (15)

122 (12) 636 (60) 219 (21) 77 (7)

1170 (70) 392 (23) 120 (7)

391 (62) 176 (28) 61 (10)

779 (74) 216 (20) 59 (6)

1362 (81) 320 (19) 1682 (100)

484 (77) 144 (23) 628 (100)

0.002 878 (83) 176 (17) 1054 (100)

<0.001

<0.001

<0.001

<0.001

<0.001

Abbreviations: PSA, prostate-speciﬁc antigen; RP, radical prostatectomy; RT, radiotherapy; TURP, transurethral resection of the prostate. Reproduced with permission from ref. 28.

patients with microscopic lymph node involvement, no adjuvant AD was given, and all 17 cases were included in this series. Based on clinical stage, iPSA levels, biochemical Gleason score (bGS), and PLND findings in RP patients, we estimate that approx 4% of the RT patients would have had surgically detectable lymph node metastases. Table 1 summarizes the pretreatment clinical characteristics of the 1682 patients by treatment modality. The patients treated with RP were significantly younger and had more favorable tumor characteristics; there was also a higher proportion of Caucasians. RP was performed in the classical fashion as described by Walsh until 1995; subsequent RPs were performed by a modiﬁed lateral fascia technique (30). Megavoltage equipment was used in the delivery of radiation. The median total dose was 70.2 Gy (range: 68.0–78.0 Gy). A conformal technique was used in 321 cases (51% of RT cases). Doses ≥ 72 Gy were delivered in 307 cases (49% of RT cases). Follow-up information always included PSA levels; 11,678 follow-up PSA levels were available for analysis. The average number of follow-up PSA levels was 8.7 for

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Fig. 2. Kaplan-Meier estimates of biochemical relapse-free survival by treatment modality for all 1682 cases. Symbols represent censored events. Biochemical failure was deﬁned as PSA > 0.2 ng/mL for prostatectomy and the ASTRO deﬁnition (24) for radiotherapy. (Reproduced with permission from ref. 28.)

RT cases vs 5.9 for RP cases. The median follow-up time for all 1682 cases was 51 mo (range: 1–134 mo, mean: 54 mo). The median follow-time up for RP vs RT cases was 50.5 vs 51.0 mo, and the median follow-up times for RT patients receiving <72 Gy vs ≥72 Gy were 62 and 42 mo, respectively. The overall biochemical relapse-free survival (bRFS) for the entire cohort was 71% (95% CI 67–75%), using a deﬁnition of < 0.2 ng/mL for RP and the ASTRO deﬁnition for RT. Figure 2 compares bRFS by treatment modality for the entire cohort using the same deﬁnitions of biochemical failure. The 8-yr bRFS rates for RP vs RT were 72% (95% CI 68–77%) vs 70% (95% CI 64–75%), respectively. This difference was statistically signiﬁcant between the two treatment arms in favor of prostatectomy (p = 0.010). To control for the observed differences between treatments in patient selection factors (Table 1), Figs. 3 and 4 compare bRFS in groups stratiﬁed by pretreatment characteristics into low- and high-risk groups. These ﬁgures demonstrate that when differences in selection are controlled for, there is no difference in outcome by treatment modality. A multivariate analysis demonstrated that T stage, iPSA, bGS, year of therapy, and neoadjuvant AD were independent predictors of relapse, whereas age, race, prior transurethral RP (TURP), and treatment modality (RP vs external beam RT) were not. A striking difference in outcomes in the unfavorable group was apparent when comparing RT doses of 68–72 Gy (<72 Gy) with doses of 72.1–78 Gy (>72 Gy) (Fig. 5), with a signiﬁcant improvement in bRFS with higher RT doses.

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Fig. 3. Biochemical relapse-free survival for patients with favorable tumors (clinical stage T1–T2A, biopsy GS ≤ 6, and iPSA levels ≤ 10 ng/mL) by treatment modality. Biochemical failure was deﬁned as PSA > 0.2 ng/mL for prostatectomy and the ASTRO deﬁnition (24) for radiotherapy. (Reproduced with permission from ref. 28.)

The results were similar when deﬁning biochemical failure as achieving and maintaining a PSA ≤ 0.5 ng/mL for both RP and XRT (Fig. 6). A similar effect of dose was also noted. A head-to-head comparison of patients who did not receive neoadjuvant deprivation revealed no differences between those treated by RP vs RT using either deﬁnition of PSA failure (data not shown, published in ref. 28). What do these observations mean? Overall, the RP patients had signiﬁcantly higher bRFS rates compared with RT patients (Fig. 2). To a large extent, this is secondary to the more unfavorable nature of lesions treated with RT, as evidenced by the distribution of higher pretreatment stage, grade, and PSA (Table 1) and as conﬁrmed by the multivariate analysis, which indicated that treatment modality was not an independent predictor of outcome. However, this is also partially due to the worse outcome associated with standard-dose radiotherapy (<72 Gy) compared with surgery (Figs. 5 and 6). We believe that both of these observations account for the widespread perception of urologists that RP provided superior cancer control than RT in the pre-PSA era (31)—treating patients with more aggressive tumors with doses of RT <72 Gy (as was standard until recently) clearly is inferior to RP. These observations suggest that radiation doses < 72 Gy should now be considered inadequate to cure localized prostate cancers. Using the more stringent deﬁnition of reaching and maintaining a PSA level ≤ 0.5 ng/mL for RT cases did not change the ultimate conclusion that there were no differences in outcome between the two modalities that could not be accounted for by differences in case

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Fig. 4. Biochemical relapse-free survival for patients with unfavorable tumors (clinical stage T2b–T2c, or biopsy GS ≥ 7, or iPSA levels > 10 ng/mL) by treatment modality. Biochemical failure was deﬁned as PSA > 0.2 ng/mL for prostatectomy and the ASTRO deﬁnition 24 for radiotherapy. (Reproduced with permission from ref. 28.)

selection (Fig. 6). We have recently compared these results with those obtained by brachytherapy alone or in combination with external beam RT and again demonstrate similar bRFS for these modalities (Fig. 7) (32), ﬁnding conﬁrmed by a large (>5000 patient) multi-institutional analysis (33). The long natural history of localized prostate cancer makes it difﬁcult to determine from these data which therapy is best in men with life expectancies longer than 8–10 yr at diagnosis. In previous reports, we demonstrated that biochemical failure was not an independent predictor of mortality at 10 yr after either RP or RT (17,18), and others have demonstrated that the lead time for mortality after biochemical failure to death is longer than 10 yr after RP (19,20). Although age was not an independent predictor of outcome in this series, it is theoretically possible in men with long life expectancies at diagnosis that the late local recurrence rate might be higher after radiation (or other prostate-sparing treatments such as brachytherapy or cryotherapy) and that this will translate into more local complications or a higher mortality rate. This is certainly biologically plausible: even if all tumor present at the time of RT is eradicated, sublethal RT doses may lead to defective DNA repair in surviving normal cells, which could predispose to the development of true second tumors. These questions cannot be addressed without additional follow-up. At present, we use this information to counsel patients that the likelihood of “cure” of their prostate cancer is similar at 8 yr after initial therapy regardless of which modality is used and that there is a theoretical chance

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Fig. 5. Biochemical relapse-free survival for patients with unfavorable tumors by treatment modality and radiation dose. Biochemical failure was defined as PSA > 0.2 ng/mL for radical prostatectomy (RP) and the ASTRO definition 24 for radiotherapy (RT). (Reproduced with permission from ref. 28.)

that the local failure rate and therefore possibly the mortality rate will be higher in the long term with therapies that leave the prostate in situ. Because of these theoretical issues, our bias is toward counseling younger men to be treated by RP.

MORBIDITY A commonly held belief among radiation therapists is that the acute morbidity of external beam RT or brachytherapy is lower than that for RP. A review of recent trends in the perioperative management of RP patients suggests that this is not true. Beginning with an institution-wide length-of-stay project in 1992, we have shortened hospital stay progressively from 9 to 2 d, using a variety of preoperative, intraoperative, and postoperative strategies (34). Reducing length of stay to 2 d does not compromise functional outcomes, is associated with fewer complications, and is met with high levels of patient satisfaction (34,35). This experience has been duplicated by other groups in both the academic and community settings (36,37). Table 2 outlines our current perioperative

Fig. 6. Biochemical relapse-free survival (bRFS) using a nadir PSA value of ≤ 0.5 ng/mL for both radical prostatectomy (RP) and radiotherapy (RT) for all cases (A), for favorable cases (B), and for unfavorable cases (C). (Reproduced with permission from ref. 28.)

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Fig. 7. Comparative biochemical relapse-free survival rates for radical prostatectomy, external beam radiotherapy (EB), brachytherapy, and brachytherapy plus external beam radiotherapy.

regimen, and Table 3 shows a recent review (38) of acute complications in >300 consecutive RPs. Our current regimen is to permit full physical activity 3 wk after open retropubic RP, and many white-collar workers are able to return to work even sooner. These results indicate that the acute morbidity of open RP is acceptable and well tolerated. Laparoscopic approaches to RP hold promise for improving recovery time further. Continence as deﬁned by no need for protective pads is routinely achieved in approx 90% of patients in experienced hands, with 15% achieving immediate control (i.e., never wore a pad) and a median time to recovery of 6 wk (39,40). Late morbidity with RP is rare and is generally limited to vesical neck contractures or urethral strictures, which are typically cured by simple dilation or incision. With the advent of the newer external beam and modern brachytherapy techniques, the acute and late toxicity proﬁle associated with radiation to the prostate has changed but is still clinically signiﬁcant. With external beam RT, acute toxicity is limited to acute cystitis/urethritis and acute proctitis, and most patients (70–80%) will experience some degree of urinary or rectal symptomatology. Using the Radiation Therapy Oncology Group (RTOG) toxicity scale, grade 2 acute genitourinary toxicity has been documented in 30–50% of patients treated with conventional techniques and in 20–40% with conformal techniques. Grade 2 acute gastrointestinal toxicity has been docu-

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Table 2 Current Perioperative Routine for Patients Undergoing Open Retropubic Radical Prostatectomy Preoperatively Fleet’s enema the night before OR Admit to OR day of surgery Intraoperatively Epidural anesthesia only Infraumbilical, muscle-splitting incision Lymph node dissection optional in low-risk tumors 5% nonautologous transfusion Average operation time 120 min (skin to skin) Postoperatively Ambulate and po intake postoperative d 1 Patient-controlled epidural analgesia for the ﬁrst 24 h and then po ketorolac No systemic narcotics Drains removed at 48 h at time of discharge Foley catheter removed on postoperative d 7

Table 3 Acute Complications in 306 Consecutive Radical Prostatectomies Complication

%

Lymphatic/urine leak Catheter-related Wound Ileus Bleeding Acute myocardial infarction Miscellaneous Mortality Total

2.3 1.5 1.1 0.8 0.4 0.4 1.5 0.0 8.1

Reproduced with permission from ref. 38.

mented in 30–40% of patients treated with conventional and 15–25% of patients treated with conformal techniques (41–44). Severe acute toxicity (RTOG grade 3–4) is rare. All acute effects are transient and usually resolve within 1–2 mo after RT. Late toxicity was the limiting factor with dose escalation for conventional techniques, with rectal bleeding or mucosal damage being the most serious. However, the late toxicity proﬁle has been favorable for patients treated in the PSA era (45). The actuarial rate of grade 2 gastrointestinal or genitourinary toxicity is 10–15% and is dose-related. With conformal techniques, the rate of serious (grade 3–4) toxicity is extremely low, even with higher than standard doses (46–48). Signiﬁcant incontinence is rare after RT, although up to 30% of patients have reported urge incontinence. Most gastrointestinal or genitourinary episodes of late toxicity episodes occur within the ﬁrst 2 yr after RT. The acute toxicity of brachytherapy is also clinically signiﬁcant. Irritative voiding symptoms (urgency, frequency, burning, sense of incomplete emptying) are most

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prominent and may last 6–12 mo (49). Rectal symptoms are also common and follow a similar timecourse. Reports of late toxicity with brachytherapy are lacking because of the relatively small number of patients treated prior to the mid-1990s. Reported rates of potency after RP or RT vary widely and are related to patient age, comorbidities, experience of the surgeon or radiotherapist, and treatment technique. We have recently completed a retrospective cross-sectional questionnaire survey using a validated instrument in 1236 men who underwent RP or external RT at our institution between 1986 and 1996 (50). The study cohort included men with a mean age of 68.4 yr and mean follow-up of 4.8 yr and did not control for comorbidities or adjuvant therapies. Using a stringent criterion of achieving an International Index of Erectile Function (IIEF) score of ≥22 as a deﬁnition of potency, there was no difference in the reported rates of potency between those treated with RP vs external RT, a ﬁnding reported in several other similarly designed surveys in both the academic and community settings (51–53). Recent prospective reports on potency in large numbers of men undergoing brachytherapy suggest that up to 50% of men lose their potency as early as 1 yr after therapy (54,55). Because of the anatomic relationship of the neurovascular bundles to the prostate, it is apparent that any prostate-directed therapy can have similar effects on potency, and it seems reasonable to expect that combinations of these therapies (adjuvant RT after RP or combined external beam RT and brachytherapy) will have a cumulatively adverse effect. These observations suggest that the desire for preservation of potency should not be a major factor in a patient’s choice of therapy.

QUALITY OF LIFE Despite the advent of validated questionnaires, the perception of a patient’s quality of life (QOL) after therapy remains subjective. All urologists have seen patients who are not bothered by wearing one or two pads a day for stress incontinence after RP, as well as the occasional patient who wears no pads, leaks a few drops with abdominal straining, and yet is psychologically incapacitated by this. Deﬁning acceptable QOL after therapy is made more difﬁcult by the marked differences in patients’ and physicians’ perceptions of the severity of the same symptoms, as demonstrated in a postprostatectomy survey by Litwin et al. (58) (Fig. 8). Much of a patient’s perception of QOL after therapy is dictated by his and his family’s expectations generated from information from friends, relatives, support groups, industry-produced pamphlets, various websites, books written by physicians, books written by patients, marketing materials produced by industry and medical groups, and his physician. There is a wealth of health-related quality of life (HRQOL) literature comparing outcomes after all commonly used therapies for prostate cancer. Although it is possible to cite one or more studies that support a bias toward improved QOL with one’s favorite therapy, in our view the collected literature all points to the same realities: (1) all therapies have some toxicity; (2) all patients experience some treatment-related decrement in overall HRQOL during and after therapy, which generally returns to baseline after 1 yr; (3) the type of side effects experienced by patients is therapy-speciﬁc (Fig. 9); and (4) most patients would choose to undergo the same therapy again. We believe patients are best served when the pretreatment QOL discussion is framed in this manner, and patients are then permitted to “pick their own poison” based on whatever is important to their value system—for some this will be the avoidance of a particular kind of therapy (surgery vs radiation of some variety), a strong propensity toward a particular kind of

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Fig. 8. Differences in patient and treating physician perceptions in domain-speciﬁc quality of life assessment after radical prostatectomy. (Reproduced with permission from ref. 56.)

Fig. 9. Relative morbidity of commonly used therapies for localized prostate cancer. RP, radical prostatectomy; XRT, external beam radiotherapy; Brachy, brachytherapy; Sx, symptoms.

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therapy (“cut it out and it will be gone” is a commonly expressed sentiment), or the avoidance of a particular side effect (“I don’t want any chance of incontinence”). This approach is helpful to patients in avoiding cognitive dissonance over the choice of therapy when unexpected or unwanted outcomes occur.

SALVAGE OF FAILURES Because of the long natural history of prostate cancer, a discussion of salvage of treatment failures is relevant. We have previously discussed observations that the occurrence of biochemical failure after RP or external RT is not predictive of survival 10 years after therapy (17,18). A signiﬁcant difﬁculty in deciding whether to proceed with a second attempt at cure after primary treatment failure is limitations in the ability to deﬁne who has a true local recurrence. Standard imaging modalities (CT, magnetic resonance imaging, and bone scans) are not sensitive enough to exclude the possibility of microscopic metastases. First-generation anti-prostate speciﬁc membrane antigen (PSMA) antibody scans have also been disappointing in distinguishing local vs distant recurrence (57). Biopsy of an in situ prostate is fraught with sampling error, and even a positive biopsy of a prostate after RT or of the prostatic fossa after RP does not exclude metastatic disease (58). Rates of biochemical failure after salvage RP have varied signiﬁcantly depending on the experience of the institution and the selection criteria. The best reported results are 55% bRFS at 5 yr with very wide conﬁdence intervals (59). That series also suggested that patients with favorable postradiotherapy grade, stage, and PSA level are more likely to have organ-conﬁned disease, suggesting that early intervention at the ﬁrst sign of failure could improve the cure rate. This observation is tempered by another series in which these factors were not predictive of pathologic stage and by the observation from our own series that 75% of men undergoing salvage prostatectomy died of prostate cancer by 8 yr (60,61). Most series agree that the rates of potency and continence are not as good after salvage RP than the rates for nonirradiated cases, and there is a higher rate of anastomotic strictures. One study has also suggested that HRQOL is worse after salvage RP than salvage RT after RP (62). Early reports on the effect of salvage radiotherapy were very optimistic, with up to 70% of patients achieving an undetectable PSA after treatment. However, longer follow-up demonstrated that these responses are not durable in most patients (57). A recent series reported that only 24% of patients treated with salvage RT had an undetectable PSA at 5 yr. Although those with long PSA doubling times seemed to fare better, no pathologic factors (such as positive margins or extracapsular extension) predicted response to therapy (63). These results highlight the difﬁculty in distinguishing between local and systemic recurrence. There are no long-term data on the cumulative effects of combined RP and RT on continence, potency, bowel symptoms, or measures of HRQOL. In summary, salvage of failures after primary therapy with RP or RT is difﬁcult, with no clear advantage to either modality.

Second Malignancies One real but small disadvantage of external RT is the risk of second malignancies. Two large series have been published, and both demonstrate an increased risk of inﬁeld second malignancies of the bladder, rectum, and pelvic sarcomas (64,65). One of

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Fig. 10. Relative cost comparison between 125I transperineal brachytherapy and open retropubic radical prostatectomy. Office plan, dosimetric volume study performed as a separate procedure; O.R. plan, dosimetric volume study performed at the time of implant. (Reproduced with permission from ref. 65.)

these studies also demonstrated a higher risk of lung cancer even when smoking history was accounted for (64). Overall, the likelihood of a second malignancy for patients treated by RT is about 0.5% compared with RP. The risk of developing a second malignancy of the bladder or rectum is likely to decrease with more conformal RT techniques, which minimize the dose to those structures.

Cost Cost comparisons between various types of therapy for localized prostate cancer are difﬁcult because most reports are based on charges billed to the patient rather than actual costs. Charge-based data are difﬁcult to interpret because local market forces and institutional markups vary widely between geographic regions and even within hospital systems depending on market demand. A single study comparing the relative Medicare charges in a nationwide survey of RP, RT, and brachytherapy concluded that brachytherapy was cheapest, followed, in order, by RT and RP (66). It is generally believed that brachytherapy is cheaper than other forms of therapy because it can be performed as an outpatient procedure in a single sitting. An analysis of actual allocated costs (as opposed to charges) at our institution did demonstrate that the relative perioperative technical costs of 125I transperineal brachytherapy were lower than those associated with open retropubic RP. However, when the cost of the seeds was included, the total cost of brachytherapy was more than double that of RP (Fig. 10) (67). Five recently published series show that the relative cost of brachytherapy ranges from 0.97 to 1.85 times the cost of RP. Combination therapies (RP plus adjuvant RT, hormones plus brachytherapy, and so on) are more expensive than single-modality therapy (66).

Are There Unique Advantages to RP? A detailed pathologic analysis of an excised prostate is a demonstrable and unique advantage for RP over therapies that leave the prostate in situ. Despite trends in the use

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of extended biopsy techniques and pathologic stage migration, a substantial proportion of patients are still clinically understaged and undergraded based on DRE and prostate biopsy, and therefore complete pathologic sampling is more likely to yield the ability to predict outcomes on an individual basis. Pathologic stage thus provides the best information on the likelihood for cure and the need for adjuvant therapy. A widely held belief among urologists is that the late local failure rate after RT will be higher than for RP. As previously discussed, the fact that not all normal prostate epithelium is destroyed after RT makes the occurrence of a late second primary tumor after RT theoretically plausible. In our experience we have observed a higher clinical local failure rate 8 yr after RT only in men with tumors of Gleason sum ≥ 8 (12%, compared with 6% for RP) (68). This observation is limited because not all patients in either the RP or RT groups had biopsies performed, the biopsies that were performed were usually prompted by symptoms, and we have not observed any difference in survival. Until longer term data are available, the presumed elevated risk of late local recurrence (or second primary tumors) after RT remains theoretical.

How Should Patients Be Counseled? The issues of cancer control, morbidity, QOL, salvage of primary treatment failures, late effects, and cost should all be discussed with patients facing the decision of which therapy to choose for localized prostate cancer. We believe that the discussion of these issues vis-à-vis different therapies should be driven by data rather than by personal choice or economic considerations and that practitioners who have experience with all available therapies may give the most balanced view. When patients ask “What’s the best treatment?” they most often are asking which is most likely to be curative. Despite the limitations discussed, the available data suggest that biochemical failure rates and survival are similar for RP, RT, and brachytherapy for 8 yr after therapy and that in the absence of long-term survival data patients should choose a therapy with which they are most comfortable based on morbidity and QOL. For patients with favorable risk features (clinical stage T1 or T2a, PSA < 10 ng/mL, and biopsy Gleason sum ≤ 6), it seems likely that monotherapy with RP, RT of appropriate dose, or brachytherapy will provide equivalent rates of cure and long-term survival. For the youngest patients with the longest life expectancy, it seems prudent to recommend RP because of the theoretical risk of late local failure, but these patients should be counseled about the lack of long-term data on this issue. For patients with intermediate- or high-risk tumors, it is likely that combination therapy (RP plus adjuvant RT, hormones plus dose-escalated RT approaches using intensity-modulated RT or combined RT and brachytherapy, or other neoadjuvant or adjuvant therapies) will be needed to improve the relatively lower cure rate obtainable by monotherapy. Which of these combination therapies is best with respect to cure, morbidity, and QOL is as yet unanswered. Ultimately the “best” treatment choice is one made by an informed patient who is comfortable with and committed to whichever he chooses.

REFERENCES 1. Paulson DF, Lin GH, Hinshaw W, et al. Radical surgery versus radiotherapy for adenocarcinoma of the prostate. J Urol 1982;128:502–504. 2. Hanks GE. More on the Uro-Oncology Research Group report of radical surgery vs radiotherapy for adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 1988;14:1053–1054.

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3. Stamey T, Ferrari M, Schmid H. The value of serial prostate speciﬁc antigen determinations 5 years after radiotherapy: steeply increasing values characterize 80% of patients. J Urol 1993;150:1856–1859. 4. Zagars G, von Eschenbach A. Prognostic factors in prostate cancer: prostate speciﬁc antigen: an important marker for prostate cancer treated by external beam radiotherapy. Cancer 1993;72:538–548. 5. Zagars GK. Serum PSA as a tumor marker for patients undergoing deﬁnitive radiation therapy. Urol Clin North Am 1993;20:737–747. 6. Zagars GK. Prostate speciﬁc antigen as an outcome variable for T1 and T2 prostate cancer treated by radiation therapy. J Urol 1994;152:1786–1791. 7. Zietman AL, Shipley WU. Re: The value of serial prostate speciﬁc antigen determinations 5 years after radiotherapy: steeply increasing values characterize 80% of patients. J Urol 1994;152:1564–1565; discussion 1565–1566. 8. Leibman BD, Dillioglugil O, Scardino PT, et al. Prostate-speciﬁc antigen doubling times are similar in patients with recurrence after radical prostatectomy or radiotherapy: a novel analysis. J Clin Oncol 1998;16:2267–2271. 9. Fowler FJ Jr, McNaughton Collins M, Albertsen PC, et al. Comparison of recommendations by urologists and radiation oncologists for treatment of clinically localized prostate cancer. JAMA 2000;283:3217–3222. 10. Jhaveri FM, Klein EA, Kupelian PA, et al. Declining rates of extracapsular extension after radical prostatectomy: evidence for continued stage migration. J Clin Oncol 1999;17:3167–3172. 11. Han M, Partin AW, Piantadosi S, Epstein JI, Walsh PC. Era speciﬁc biochemical recurrence-free survival following radical prostatectomy for clinically localized prostate cancer. J Urol 2001;166:416–419. 12. Elder JS, Jewett HJ, Walsh PC. Radical perineal prostatectomy for clinical stage B2 carcinoma of the prostate. J Urol 1982;127:704–706. 13. Ragde H, Blasko JC, Grimm PD, et al. Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer 1997;80:442–453. 14. Polascik T, Pound CR, DeWeese TL, Walsh PC. Comparison of radical prostatectomy and iodine 125 interstitial radiotherapy for the treatment of clinically localized prostate cancer: a 7-year biochemical (PSA) progression analysis. Urology 1998;51:884–890. 15. Ramos CG, Carvalhal GF, Smith DS, Mager DE, Catalona WJ. Retrospective comparison of radical retropubic prostatectomy and 125 iodine brachytherapy for localized prostate cancer. J Urol 1999;161:1212–1215. 16. Svetec D, McCabe K, Peretsman S, et al. Sextant prostate biopsy is a poor surrogate endpoint for the evaluation of treatment efﬁcacy for localized prostate cancer. J Urol 1998;159:1606. 17. Jhaveri FM, Zippe CD, Klein EA, Kupelian PA. Biochemical failure does not predict overall survival after radical prostatectomy for localized prostate cancer: 10 year results. Urology 1999;54:884–890. 18. Kupelian PA, Buchsbaum JC, Patel C, et al. Impact of biochemical failure on overall survival after radiation therapy for localized prostate cancer in the PSA era. Int J Radiat Oncol Biol Phys 2002;52:704–711. 19. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999;281:1591–1597. 20. Iselin CE, Robertson JE, Paulson DF. Radical perineal prostatectomy: oncological outcome during a 20-year period. J Urol 1999;161:163–168. 21. Shah R, Bassily N, Wei J, et al. Benign prostatic glands at surgical margins of radical prostatectomy specimens: frequency and associated risk factors. Urology 2000;56:721–725. 22. Consensus statement: guidelines for PSA following radiation therapy. American Society for Therapeutic Radiology and Oncology Consensus Panel. Int J Radiat Oncol Biol Phys 1997;37:1035–1041. 23. Hanlon AL, Hanks GE. Scrutiny of the ASTRO consensus deﬁnition of biochemical failure in irradiated prostate cancer patients demonstrates its usefulness and robustness. American Society for Therapeutic Radiology and Oncology. Int J Radiat Oncol Biol Phys 2000;46:559–566. 24. Gretzer MB, Trock B, Han M, Walsh PC. A critical analysis of the interpretation of biochemical failure in surgically treated patients using the American Society for Therapeutic Radiation and Oncology criteria. AUA Meeting, 2002 (abstract #269). 25. Critz FA, Levinson K, Williams WH, Holladay D, Holladay C, Grifﬁn V. Prostate-speciﬁc antigen nadir of 0.5 ng/mL or less deﬁnes disease freedom for surgically staged men irradiated for prostate cancer. Urology 1997;49:668–672. 26. Hanks GE, et al. American Society of Therapeutic Radiation and Oncology Meeting, 2001 (abstract #203).

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27. Patel C, Elshaikh MA, Angermeier K, Ulchaker J, Klein EA, Chidel MA, Wilkinson DA, Reddy CA, Ciezki JP. Erratic PSA behavior (PSA bounce) following permanent 125I implantation of the prostate. (Submitted) 28. Kupelian PA, Elshaikh M, Reddy CA, Zippe C, Klein EA. Comparison of the efﬁcacy of local therapies for localized prostate cancer in the PSA era: a large single institution experience with radical prostatectomy and external beam radiotherapy. J Clin Oncol 2002;20:3376–3385. 29. Clark PE, Levin HS, Kupelian PA, Reddy C, Zippe CD, Klein EA. Intermediate-term outcome with radical prostatectomy for localized prostate cancer: The Cleveland Clinic Experience. Prostate J, 2001;3:118. 30. Klein EA, Kupelian P, Tuason L, Levin H. Initial dissection of the lateral fascia reduces the positive margin rate in radical prostatectomy. Urology 1998;51:766. 31. Menon M, Tewari A, Divine G, et al. Comparison of long-term survival in men with clinically localized prostate cancer managed conservatively, with deﬁnitive radiation or radical prostatectomy. J Urol 2001;165:151. 32. Kupelian PA, Khuntia D, Potters L, et al. Radical prostatectomy, external beam radiotherapy < 72 Gy, external beam radiotherapy ≥ 72 Gy, permanent seed implantation, or combined seeds/external beam radiotherapy for stage T1–T2 prostate cancer. Int J Radiat Oncol Biol Phys, 2004;58:25. 33. Vincini FA, Martinez A, Hanks G, Hanlon A, et al. An interinstitutional and interspecialty comparison of treatment outcome data for patients with prostate carcinoma based on predeﬁned prognostic categories and minimum follow-up. Cancer 2002;95:2126–2135. 34. Licht MC, Klein EA. Early hospital discharge after radical retropubic prostatectomy: impact on cost and complication rate. Urology 1994;44:700. 35. Klein EA, Licht MR. Reducing length of stay after radical prostatectomy. Semin Urol 1995;13:137. 36. Litwin MS, Smith RB, Thind A, Reccius N, Blanco-Yarosh M, deKernion JB. Cost-efﬁcient radical prostatectomy with a clinical care path. J Urol 1996;155:989–993. 37. Gaylis FD, Friedel WE, Armas OA. Radical retropubic prostatectomy outcomes at a community hospital. J Urol 1998;159:167–171. 38. Ng CS, Klein EA. Acute complications after radical retropubic prostatectomy. Prostate J 2000;2:22–26. 39. Klein EA. Early continence after radical prostatectomy. J Urol 1992;148:92. 40. Catalona WJ, Carvalhal GF, Mager DE, Smith DS. Potency, continence, and complication rates in 1,870 consecutive radical retropubic prostatectomies. J Urol 1999;162:433–437. 41. Pollack A, Zagars G, Starkshall G, et al. Conventional vs conformal radiotherapy for prostate cancer: preliminary results of dosimetry and acute toxicity. Int J Radiat Oncol Biol Phys 1996;34:555–564. 42. Teh B, Uhl B, Augspurger M, Grant W, et al. Intensity-modulated radiotherapy (IMRT) for localized prostate cancer: preliminary results of acute toxicity compared to conventional and six-ﬁeld conformal approach. Int J Radiat Oncol Biol Phys 1998;42(suppl 1):219. 43. Zelefsky M, Leibel SA, Kutcher GJ, et al. The feasibility of dose escalation with three-dimensional conformal radiotherapy in patients with prostatic carcinoma. Cancer J Sci Am 1995;1:142–146. 44. Lawton CA, Won M, Pilepich MV, et al. Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: analysis of RTOG studies 7506 and 7706. Int J Radiat Oncol Biol Phys 1991;21:935–939. 45. Shipley WU, Zietman AL, Hanks GE, et al. Treatment related sequelae following external beam radiation for prostate cancer: a review with an update in patients with stages T1 and T2 tumor. J Urol 1994;152:1799–1805. 46. Zelefsky MJ, Aschkenasy E, Kelsen S, Leibel SA. Tolerance and early outcome results of postprostatectomy three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 1997;39:327–333. 47. Sandler HM, McLaughlin PW, Ten Haken RK, et al. Three dimensional conformal radiotherapy for the treatment of prostate cancer: low risk of chronic rectal morbidity observed in a large series of patients. Int J Radiat Oncol Biol Phys 1995;33:797–801. 48. Schultheiss TE, Lee WR, Hunt MA, et al. Late GI and GU complications in the treatment of prostate cancer. Int J Radiat Oncol Biol Phys 1997;37:3–11. 49. Gelblum DY, Potters L, Ashley R, et al. Urinary morbidity following ultrasound-guided transperineal prostate seed implantation. Int J Radiat Oncol Biol Phys 1999;45:59–67. 50. Schover LR, Fouladi RT, Warneke CL, et al. Deﬁning sexual outcomes after treatment for localized prostate cancer. Cancer, in press. 51. Talcott JA, Rieker P, Clark JA, et al. Patient-reported symptoms after primary therapy for early prostate cancer: results of a prospective cohort study. J Clin Oncol 1998;16:275–283. 52. Potosky AL, Legler J, Albertsen PC, et al. Health outcomes after prostatectomy or radiotherapy for prostate cancer: results from the Prostate Cancer Outcomes Study. J Natl Cancer Inst 2000;92:1582–1592.

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53. Sanda MG, Dunn R, Wei JT, et al. HRQOL determinants of prostate cancer patient satisfaction after prostatectomy, external radiation or brachytherapy at referral and community practices. AUA Meeting, 2002 (abstract #626). 54. Ben-Josef E, Forman JD, Cher ML, Kaufman N, Frazier AJ. Erectile function following permanent prostate brachytherapy. AUA Meeting, 2002 (abstract #1558). 55. van der Hoeven J, Bevers RFM, Jeroen RA, van Moorselaar JRA, Battermann JJ, Boon TA. A prospective study of erectile function following transperineal I-125 seed implantation for localised prostate cancer. AUA Meeting, 2002 (abstract #1348). 56. Litwin MS, Lubeck DP, Henning JM, Carroll PR. Differences in urologist and patient assessments of health related quality of life in men with prostate cancer: results of the CaPSURE database. J Urol 1998;159:1988–1992. 57. Jhaveri FM, Klein EA. How to explore the patient with a rising PSA after radical prostatectomy: deﬁning local versus systemic failure. Semin Urol Oncol 1999;17:130–134. 58. Svetec D, McCabe K, Peretsman S, et al. Sextant prostate biopsy is a poor surrogate endpoint for the evaluation of treatment efﬁcacy for localized prostate cancer. J Urol 1998;159:1606. 59. Rogers E, Ohori M, Kassabian VS, Wheeler TM, Scardino PT. Salvage radical prostatectomy: outcome measured by serum prostate speciﬁc antigen levels. J Urol 1995;153:104–110. 60. Gheiler EL, Teﬁlli MV, Tiguert R, et al. Predictors for maximal outcome in patients undergoing salvage surgery for radio-recurrent prostate cancer. Urology 1998;51:789–795. 61. Pontes J, Montie JE, Klein EA, Huben R. Salvage surgery for radiation failure in prostate cancer. Cancer 1993;71:976. 62. Teﬁlli MV, Gheiler EL, Tiguert R, et al. Quality of life in patients undergoing salvage procedures for locally recurrent prostate cancer. J Surg Oncol 1998;69:156–161. 63. Leventis AK, Shariat SF, Kattan MW, Butler EB, Wheeler TM, Slawin KM. Prediction of response to salvage radiation therapy in patients with prostate cancer recurrence after radical prostatectomy. J Clin Oncol 2001;19:1030–1039. 64. Brenner DJ, Curtis RE, Hall EJ, Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery. Cancer 2000;88:398–406. 65. Neugut AI, Ahsan H, Robinson E, Ennis RD. Bladder carcinoma and other second malignancies after radiotherapy for prostate carcinoma. Cancer 1997;79:1600–1604. 66. Brandeis J, Pashos CL, Henning JM, Litwin MS. A nationwide charge comparison of the principal treatments for early stage prostate carcinoma. Cancer 2000;89:1792–1799. 67. Ciezki J, Angermeier K, Ulchaker J, Zippe C, Wilkinson A, Klein EA. Cost comparison of radical prostatectomy and transperineal brachytherapy for localized prostate cancer. Urology 2000;55:68–72. 68. Kupelian PA, Buchsbaum JC, Elshaikh M, Reddy CA, Zippe C, Klein EA. Factors affecting relapse rates after prostatectomy or radiotherapy in patients with biopsy Gleason score 8 or above: therapeutic implications. Cancer, 2002;95:2302–2307. 69. Kupelian PA, Buchsbaum JC, Elshaikh M, Reddy CA, Zippe C, Klein EA. Factors affecting recurrence rates after prostatectomy or radiotherapy in localized prostate carcinoma patients with biopsy Gleason score 8 or above. Cancer 2002;95:2302–2307.

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Counseling the Patient With Prostate Cancer The Radiation Oncologist’s Perspective

Anthony Zietman

INTRODUCTION Radiation oncologists, like urologists, often spend more time counseling patients with prostate cancer than treating them. Approximately half the radically treated prostate cancer patients in the United States will have some form of radiation as their primary therapy—but how do they make their choice and what are the contemporary recommendations of the radiation oncologist? Fowler et al. (1) performed a survey of over 1000 US radiation oncologists and urologists in 1998, with depressing results. They showed the truly “partisan” nature of our specialties; 93% of surgeons recommended surgery as primary therapy for early-stage prostate cancer, and 72% of radiation oncologists recommended radiation. I believe that sufficient data have now emerged to allow both sides to be more “reasonable” and to agree on recommendations. In 2002 an important randomized trial from Sweden was published in which 629 men with T1–2 prostate cancer were randomized to be managed either expectantly or with radical surgery (2). At 8 yr, there was a small reduction in metastasis-free survival (13% vs 27%) for the patients receiving surgery and a small reduction in the number requiring androgen deprivation, although no overall survival advantage was found. These cancers were not detected by prostate-specific antigen (PSA), and most men had palpable disease. Because of the lead-time bias introduced by PSA early detection, which may be as much as 7 yr, these 8-yr data translate to 15-yr data for patients diagnosed in the United States. It does prove that local treatment reduces the development of metastases and may ultimately, perhaps by the third post-treatment decade, translate into a detectable survival advantage. It also emphasizes that the most radical of therapies have only a small impact on this disease in the short and medium term. Thus, any advantage claimed for surgery over radiation must, at most, be very small.

From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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In counseling patients, radiation oncologists, who tend to see older patients, must look at the Swedish trial very carefully. There is no survival advantage to treatment over the ﬁrst decade, and so the patient’s other comorbid conditions must be carefully scrutinized. In our own series of 205 men treated in 1991–1992, only 52% were still alive in 2002, and very few of those who died did so because of prostate cancer (unpublished data). Can these patients then be said to have beneﬁted from treatment at all? I believe the answer is yes, as there are other endpoints by which we can measure beneﬁt other than disease-speciﬁc survival. First, there is freedom from local progression. Warner and Whitmore (3) reported that over 60% of men with clinical T2 disease will progress locally by 10 yr without treatment. Johannsen et al. (4) agreed but suggested that the proportion becoming symptomatic and requiring measures to deal with this problem (primarily transurethral resection of the prostate [TURP]) was only 35%. In our series of radiation-treated patients, clinical local progression for a comparable group of men had occurred in only 18%. A second nonsurvival beneﬁt from using radiation accrues if patients can be kept away from long-term androgen deprivation (AD) therapy with all its morbid consequences. Data from the Cancer Rehabilitation and Evaluation System (CaPSURE) database suggests that watchful waiting is currently a difﬁcult policy in the United States (5). The PSA inevitably rises, and even very small rises are sufﬁcient to trigger the “chicken switch.” The CaPSURE study shows that >80% of men will come to treatment (usually AD) by 8 yr. Our own series of 198 expectantly managed patients shows much the same, with 40% of patients having come to therapy by 5 yr if they have not died of some other cause (6). The median PSA rise to trigger therapy was only 2.7 ng/mL. It is interesting to note that 84% of patients, when asked, thought that their physician had initiated therapy, whereas only 27% of physicians felt they had. We have looked at the ability of external beam radiation as a primary therapy to keep patients away from AD. Only 31% of the men we treated in 1991–1992 needed AD by 2002. Freedom from castration may therefore be another tangible beneﬁt of treatment. This presumes, of course, that the morbidity of AD exceeds that of radiation. There are no good quality of life studies to show this, although our general clinical experience suggests that this is the case.

RADIATION IN EARLY-STAGE PROSTATE CANCER The conventional idea is that young men (<60 yr old) with early prostate cancer should have surgery, older men (>70 yr old) should have radiation, and those in between can take their pick. There is little doubt that surgery offers the young man certain advantages. Prognostic information is obtained at the time of surgery that can be used to predict the future and intelligently guide the use of adjuvant therapy. For those who “need to know,” surgery is a more appropriate treatment. Data exist to show that younger men experience a lower morbidity from surgery than older men and, in good hands, have a reasonable chance of retaining potency. Furthermore, surgery is not associated with any risk of late radiation-induced malignancy, although whether that is a signiﬁcant issue will be discussed later. In general, surgery has been recommended over radiation for younger men on the ground that it is more likely to cure the patient. Certainly several single-institution series have been published documenting high rates of disease control with the radical prostatectomy. Cure rates of 80% and higher are commonly quoted for early-stage disease. Here the data need closer scrutiny because the silent hand of selection may well

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be at work. The series from Johns Hopkins and Baylor are heavily weighted with men who have T1c lower grade tumors and PSA values well below 10 ng/mL, indeed, frequently below 4 ng/mL (7,8). Although relapse appears to be very infrequent for men with organ-conﬁned T1c disease, those who had higher PSAs or palpable disease continue to fail. In the Johns Hopkins series, which contains patients ≥15 yr after surgery, less than half of those with adverse features are ultimately cured. It must be noted that most surgical series are heavily skewed toward relatively short follow-up, and many of these late relapses have yet to be counted. Some series with long follow-up, such as those from UCLA or the Mayo Clinic, have shown much higher rates of failure by 10–15 yr than are now currently being quoted to patients (9,10). The argument is often given that these patients were treated early in or even before the PSA era and by outdated surgical techniques. All of this is indeed true, but these are concerns that could equally by raised by radiation oncologists as they seek to determine long-term outcome from their treatments. The radiation oncologists have been hampered by not having as good a marker of success or failure as the surgeons have in PSA. The American Society of Therapeutic Radiology and Oncology (ASTRO) deﬁnition of failure decided on in 1997 did put radiation oncologists on the same page and at least allowed comparisons between radiation series (11). Unfortunately, it has proved to have several intrinsic ﬂaws, which have undermined the value of conclusions reached. First, the deﬁnition relies on three successive PSA rises backdated to a midpoint between the nadir and the ﬁrst rise. This was done because the biologic event, the failure, is really occurring when the PSA ﬁrst goes up, even though it may take three or more rises to see it reliably. The hope was that this would make radiation and surgical series comparable. This has not really been the case because the backdating dilutes the weight of each failure event by bringing it back into an earlier time when the patient denominator is larger. This reduces overall failure rates and artiﬁcially ﬂattens the tail end of the Kaplan-Meier curve. In addition, the deﬁnition is highly sensitive to median follow-up, also a consequence of backdating. Less follow-up means less failure. Thus, radiation series cannot be compared with one another (let alone surgery) unless they have identical follow-up such as obtains in a randomized trial. An additional problem is that the deﬁnition cannot be reliably used in any situation in which the PSA may bounce for a benign reason, as small bounces may be falsely called failures. Bouncing occurs after brachytherapy in >40% of cases. It also occurs as a rebound after neoadjuvant AD 31% of the time. In 2002, over half of all patients were treated with either brachytherapy or AD. Any deﬁnition that cannot deal with over half the treated patients needs changing. New analyses have been performed on a pool of over 4000 patients (Dr. Howard Thames, personal communication), and over 60 alternative definitions have been tested. One deﬁnition seems to be less time-sensitive, capable of dealing with most small bounces (90% are <2 ng/mL), and also potentially useful for comparative studies with surgery. This requires a PSA rise of 2 ng/mL over the last nonrising value without backdating. Any therapeutic intervention occurring before a 2 ng/mL rise also counts as failure. Hopefully, this new deﬁnition, together with an emphasis on long and complete follow-up, will allow radiation oncologists to be more conﬁdent in their claims of success or failure with their techniques (Fig. 1). Radiation oncologists have been unable to present their patients with convincing long-term series for three major reasons. First, there has been confusion over a reliable

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Fig. 1. Outcome for a cohort of 205 men treated in 1991 and 1992 with conventional external beam radiation to a dose of 68 Gy. The median follow-up for all surviving patients in this cohort is 9.5 yr. Three different deﬁnitions of biochemical failure were used: 1, ASTRO 1—the standard ASTRO definition (see ref. 11); 2, ASTRO 2—the same without backdating; 3, 2-ng rise—any rise of greater than 2 ng/mL from the last low value (no backdating). When there is mature follow-up, as in this series, all deﬁnitions give comparable results.

endpoint. Second, the rapid evolution of therapy continuously outdates the therapy we used just a few years before. Finally, the age of patients treated by radiation is such that many die of other diseases or are lost to follow-up as they migrate in retirement or enter nursing homes. Although I may believe that contemporary radiation is as effective as surgery in eradicating small cancers, there are no long-term data to prove it. Younger patients sense this. I will review the evidence we have upon which claims of equality are based.

External Beam Radiation and Eradication of Cancer There are few series with mature long-term data, and those that exist document the results of outmoded and probably inferior techniques. At our institution we have followed a cohort of men treated in 1991–1992 and maximized their follow-up to a median of 9.5 yr for those still alive. At 10 yr 42–49% are free from a biochemical failure depending on the definition. At first glance this would appear to be lower than the 10-yr figure of 60–70% reported by the Johns Hopkins and Baylor groups, but this cohort did include mainly T2 disease and a high proportion of men with high-grade disease. The radiation dose delivered was low by contemporary standards, at only 68 Gy. The results are not, however, very different from the less selective UCLA and Mayo series previously mentioned. Thus, if there is an advantage to surgery, it seems to be small. Two comparative studies have been performed prospectively, one from UPenn/Brigham and Womens Hospitals and the other from the Cleveland Clinic

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(12,13). Both show that the failure rates when stratiﬁed by risk group are remarkably similar. The Cleveland Clinic series does emphasize that results were inferior when lower radiation doses were used (doses less than 72 Gy). This observation by the Cleveland Clinic group has subsequently been borne out in a randomized trial conducted at the M.D. Anderson Hospital. Patients with T1–3 tumors were randomized to either 70 Gy (conventional dose radiation) or 78 Gy (high dose). A substantial and signiﬁcant advantage has already emerged for the intermediate-risk patients receiving higher doses. We can, therefore, counsel patients that conventional dose radiation may be inferior to surgical removal of the prostate. High-dose radiation narrows the gap and may even obliterate the difference. We don’t yet have data to state that point deﬁnitively.

Brachytherapy and Eradication of Cancer If long-term data are thin for contemporary external beam radiation, it is thinner still for brachytherapy. Only one series has been reported with 10-yr follow-up, from the Seattle group that pioneered the technique (14,15). They have kept a close eye on their original cohort of patients treated in the late 1980s, as these are the most informative patients to study. They report two encouraging ﬁgures. First, the PSA values achieved and maintained by those remaining disease-free are extremely low (median 0.1). This certainly suggests that brachytherapy is an ablative therapy. Second, they report good 10-yr freedom from biochemical failure rates of 60% in the 1987–1988 cohort, rising to over 80% for the 1988–1989 cohort. The latter implies a learning curve or evolving techniques. The principal criticism of these data is that the cohort size is small (only 150) compared with the 1000s in surgical series, and thus it is insufﬁcient evidence upon which to assume parity. The second criticism is that the series was heavily skewed with Gleason 4 and 5 patients, i.e., very low grade, and with low initial PSA values. We are all awaiting the publication of mature series by other institutions to see whether these results can be matched. In my own series (unpublished data) I have 160 men who all have a minimum of 4.5 yr of follow-up; 77% of these have PSA values of <0.5 ng/mL and 59% have <0.2 ng/mL. These early data seem to support the Seattle ﬁgures, but only time will tell. Another concern arising from the earliest Seattle data is that those who received a combination of external beam radiation and brachytherapy, usually those with good prognostic factors, seemed to fare better than those who received radiation alone, implying that brachytherapy by itself was inadequate treatment. This is important as the principal advantage of brachytherapy over either prostatectomy or external beam is its speed and convenience. The authors, however, have shown that if their ﬁrst year (1987) data are excluded, then the advantage to the combination is lost and brachytherapy alone is sufﬁcient for most good-risk patients. It would thus appear that the external beam was compensating for inadequate early technique. In counseling the younger patient with prostate cancer, the same caveats therefore apply for brachytherapy as for contemporary conformal radiation. Although the data look good, they cannot yet be described as mature and need veriﬁcation. Although that is not sufﬁcient reason to deter a committed patient who wishes to avoid surgery, it does make this radiation oncologist very cautious in recommending radiation as the ﬁrst choice for very young men.

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MORBIDITY OF RADIATION External Beam The prospective study of Potosky et al. (16) clearly documents that there are advantages to external radiation over surgery in some quality of life domains. Using validated instruments, this group demonstrated significantly fewer urinary symptoms and less urinary bother. The likelihood of maintaining potency was also higher for the radiation group. Although irradiated patients did have more bowel symptoms and bother, these were at a lower level than the urinary problems. Talcott et al. (17), in a single-institution prospective study, showed similar results, although they documented that after a few years the potency advantage to radiation had been lost because of late impotence. Patients with pre-existing inﬂammatory bowel disease are well advised to avoid radiation because “ﬂares” may be triggered. Those with very large-volume glands also need to have their prostates shrunk by AD to minimize the volume of healthy bladder and rectum receiving high radiation. If a patient had a large prostate then he might choose surgery to avoid the morbidity of AD and also to have his benign prostatic hyperplasia dealt with at the same time. Randomized trials have shown that the use of contemporary conformal techniques reduces morbidity, particularly proctitis (18). They have also shown that radiation doses can now be safely escalated to increase the chance for cure without, apparently, increasing the risk of late morbidity (19). Here a word of caution needs to be expressed, as late effects may manifest very late. We have followed 42 men who received high-dose radiation (77 Gy) for a median of 13 yr. Although the risk of rectal bleeding peaks at 12% by 3 yr, the risk of late hematuria keeps on rising and by 13 yr stands at close to 50% (20).

Brachytherapy The morbidity of brachytherapy is poorly documented. It begins with an acute radiation prostatitis lasting for 1–2 mo although in some cases more. Lee et al. have shown that by 3 mo most men have an American Urological Association (AUA) symptom score similar to that prior to treatment (20a). Late urinary effects are very likely, but mature data are not yet available. During the acute prostatitis, those with large glands, high AUA symptom scores, and prominent intravesical median lobes are at considerable risk for acute retention (21). This is 4% for those with glands < 30 cc but 18% for those with glands larger than 50 cc. Again, the principle advantage of brachytherapy is its speed and convenience. If a man has pre-existing urinary problems that put him at high risk for retention, then this advantage will be lost and he should be counseled to seek a different treatment. Although the acute retention is usually temporary, in some it may be more long lasting. In this case both physician and patient feel a strong need to “do something.” If a TURP is then performed to relieve the obstruction, it is frequently, and for reasons ill understood, followed by superﬁcial urethral necrosis, sloughing, and incontinence, the latter being the most feared risk of the radical prostatectomy and something brachytherapy patients are often primarily seeking to avoid. The original “stampede” to brachytherapy in the mid-1990s was, to some degree, based on a presumption that the risks of impotence are low. They do appear to be lower than surgery in a cross-sectional study performed by Schellhammer’s group (22). They are probably not as low as originally hoped.

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LATE MALIGNANCIES Radiation-induced malignancies are a concern whenever radiation is given to patients with a long life expectancy. Studies in pediatric malignancies have shown that when a young child is given the combination of large-ﬁeld radiation and alkylating agent chemotherapy there is an increased risk of malignancy that becomes increasing evident with the passage of decades. Adult tissues do not seem to be as prone to this problem. Taghian et al. (23) have estimated that 1 in 200 women treated for breast cancer will develop a radiation-induced malignancy over the next 20 yr. The risk for prostate cancer may be similar, although the radiation ﬁelds are substantially smaller. Brenner et al. (24) have explored this in prostate cancer patients using the SEER database and found a comparable small but real additional risk of rectal and bladder cancer in patients who live longer than 10 yr after therapy. Although this risk is sufﬁciently low that it does not feature in the counseling of most patients, it might be an issue that men in their 40s or 50s should weigh.

COST ISSUES The ﬁrst report of a Swedish trial comparing radical prostatectomy with watchful waiting showed that only one life is saved for every 17 operations performed, making it a “low-yield” procedure (2). Although cost should not enter into the patient’s decision making, it is a concern of the responsible physician and the cost-conscious government and insurance companies. Litwin’s group (25) looked at HCFA and Medicare charges in the mid-1990s and made the point that brachytherapy was, at that time, the least expensive option; it probably remains so today. Efforts to reduce the hospital stay after radical prostatectomy have driven its cost down to competitive levels. External radiation is, on the other hand, becoming increasing complex, and the use of conformal and intensity-modulated techniques has pushed the cost up substantially. To the cost of any of these therapies can be added the price of AD if given in addition. The most expensive of all options is the combination of brachytherapy and external beam radiation. This combination can be justiﬁed in theory for higher risk disease, but there are no solid data supporting its routine use. The Radiation Therapy Oncology Group is about to launch a randomized trial comparing brachytherapy alone with the combination in intermediate-prognosis disease.

CONCLUSIONS The Swedish randomized trial shows us that the advantage to treatment is going to be limited for older men and will be greater for younger men. Younger men tend to elect for surgery for the good reasons listed in this discussion, but those who do not wish to take this route do not need to be made to feel that they are making a reckless decision and putting their life in peril. Contemporary radiation therapy with high-dose conformal external beam or brachytherapy seems to offer very competitive rates of tumor and symptom control. When counseling older men who are not surgical candidates, the debate has to revolve around whether or not they need radiation in the ﬁrst place. If they do, or feel like they do, then a full discussion of the unique merits and disadvantages of both external radiation and brachytherapy must be held. Each has advantages in different clinical situations, and neither has yet demonstrated superior cancer control.

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REFERENCES 1. Fowler FJ, Collins MN, Albertsen PC, Zietman AL, Elliot D, Barry MJ. A comparison of the treatment recommendations for men with clinically localized prostate cancer by urologists and radiation oncologists. JAMA 2000;283:3217–3222. 2. Holmberg L, Bill-Axelson A, Helgesen F, and the Scandinavian Prostatic Cancer Study Group. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 2002;347:781–789. 3. Warner J, Whitmore WF. Expectant management of clinically localized prostatic cancer. J Urol 1994;152:1761–1765. 4. Johansson J-E, Holmberg L, Johansson S, Bergstrom R, Adami H-O. Fifteen-year survival in prostate cancer. A prospective, population-based study in Sweden. JAMA 1997;277:467–471. 5. Koppie TM, Grossfeld GD, Miller D, et al. Patterns of treatment of patients with prostate cancer initially managed with surveillance: results from the CaPSURE database. J Urol 2000;164:81–88. 6. Zietman AL, Thakral HJ, Wilson L, Schellhammer PF. Conservative management of prostate cancer in the PSA era:watchful waiting or delayed therapy? J Urol 2001;166:1702–1706. 7. Pound CR, Partin AW, Epstein JI, Walsh PC. Prostate speciﬁc antigen after anatomic radical retropubic prostatectomy. Urol Clin North Am 1997;24:395–402. 8. Dillioglugil O, Leibman BD, Kattan MW, Seale-Hawkins C, Wheeler TM, Scardino PT. Hazard rates for progression after radical prostatectomy for clinically localized prostate cancer. Urology 1997;50:93–99. 9. Patel A, Dorey F, Franklin J, deKernion JB. Recurrence patterns after radical retropubic prostatectomy: clinical usefulness of prostate speciﬁc antigen doubling times and log slope prostate speciﬁc antigen. J Urol 1997;158:1441–1444. 10. Amling CL, Blute ML, Bergstralh EJ, et al. Long-term hazard of progression after radical prostatectomy for clinically localized prostate cancer: continued risk of biochemical failure after 5 years. J Urol 2000;164:101–105. 11. American Society for Therapeutic Radiology and Oncology consensus panel. Consensus statement: guidelines for PSA following radiotherapy. Int J Radiat Oncol Biol Phys 1997;37:1035–1041. 12. D’Amico AV, Chen MH, Oh-Ung J, et al. Changing prostate-speciﬁc antigen outcome after surgery or radiotherapy for localized prostate cancer during the prostate-speciﬁc antigen era. Int J Radiat Oncol Biol Phys 2002;54:436–441. 13. Kupelian P, Potters L, Ciezki J, Reddy C, Reuther A, Klein E. Radical prostatectomy, external beamradiotherapy <27Gy, external beam radiotherapy >72Gy, permanent seed implantation, or combined seeds/external beam radiotherapy for stage T1–2 prostate cancer. Int J Radiat Oncol Biol Phys 2002;54:38–43. 14. Ragde H, Elgamal AA, Snow PB, et al. Ten-year disease free survival after transperineal sonographyguided iodine-125 brachytherapy with or without 45-gray external beam irradiation in the treatment of patients with clinically localized, low to high gleason grade prostate carcinoma. Cancer 1998;83:989–1001. 15. Blasko JC, Grimm PD, Sylvester JE, Badiozamani KR, Hoak D, Cavanagh W. Palladium-103 brachytherapy from prostate carcinoma. Int J Radiat Oncol Biol Phys 2000;46:839–850. 16. Potosky AL, Legler J, Albertsen PC, et al. Health outcomes after prostatectomy or radiotherapy for prostate cancer: results from the Prostate Cancer Outcomes Study. J Natl Cancer Inst 2000;92:1582–1592. 17. Talcott JA, Clark JA, Stark PC, Mitchell SP. Long-term treatment complications of brachytherapy for early prostate cancer: a survey of patients previously treated. J Urol 2001;166:494–499. 18. Dearnaley DP, Khoo VS, Norman AR, et al. Comparison of radiation side effects of conformal and conventional radiotherapy in prostate cancer: a randomized trial. Lancet 1999;353:267–272. 19. Pollack A, Zagars GK, Smith LG, et al. Preliminary results of a randomized radiotherapy dose-escalation study comparing 70 Gy with 78 Gy for prostate cancer. J Clin Oncol 2000;18:3904–3911. 20. Gardner BG, Zietman AL, Shipley WU, Skowronski UE, McManus P. Late normal tissue sequelae in the second decade following high dose radiation therapy with combined photons and conformal protons for locally advanced prostate cancer. J Urol 2002;167:123–126. 20a.Lee WR, Hall MC, McQuellon RP, Case LD, McCullough DL. A prospective quality-of-life study in men with clinically localized prostate carcinoma treated with radical prostatectomy, external beam radiotherapy, or interstitial brachytherapy. Int J Radiat Oncol Biol Phys 2001;51(3):614–623. 21. Sacco DE, Daller M, Grocela JA, Babayan RK, Zietman AL. Corticosteroid use after prostate brachytherapy reduces the risk of acute urinary retention. Br J Urol 2003;91:345–349.

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22. Davis JW. Kuban DA. Lynch DF. Schellhammer PF. Quality of life after treatment for localized prostate cancer: differences based on treatment modality. J Urol 2001;166:947–952. 23. Taghian A, De Vathaire F, Terrie P, et al. Long term risk of sarcoma following radiation treatment for breast cancer. Int J Radiat Oncol Biol Phys 1991;21:361–367. 24. Brenner DJ, Curtis RE, Hall EJ, Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery. Cancer 2000;88:398–406. 25. Brandeis J, Pashos CL, Henning JM, Litwin MS. A nationwide charge comparison of the principal treatments for early stage prostate carcinoma. Cancer 2000;89:1792–1799.

25

Counseling Patients on Choice of Therapy The Medical Oncologist’s Perspective

Celestia S. Higano

INTRODUCTION When a patient seeks an option about the choice of therapy for primary management of prostate cancer, he has already heard the advice of the urologist and frequently the radiation oncologist as well. The patient views the medical oncologist as the “uninvolved” party who has “nothing to gain or lose” financially or otherwise from rendering an opinion. The following discussion will not reiterate relapse or survival data for specific treatment modalities per se, as this information has been well covered in previous chapters, rather, it will focus on aspects of counseling that a medical oncologist can draw on to help patients make decisions about treatment options for localized prostate cancer.

MEDICAL CONSIDERATIONS Review of the medical records will help establish the general health of the patient in terms of comorbidities and life expectancy. Clariﬁcation of details with respect to the extent and severity of any comorbidities may take place during the patient interview. This information is then factored in with the patient’s age, family history (for longevity or early death), and life expectancy. If a patient is not likely to live for more than 5–10 yr, this will inﬂuence the approach to counseling the patient with respect to treatment options (see Case 2). Some medical oncologists rely heavily on the use of nomograms to counsel patients. Although the currently available nomograms are predictive of local disease extent and prognosis, there is no nomogram at present that predicts survival. Nevertheless, many medical oncologists will recommend against surgery if the disease is likely to be outside of the prostate based on a nomogram. This algorithmic approach to counseling

From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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does not take into account the many individual patient considerations that should be addressed during a consultation. A patient should be asked to reiterate what he has been told to date, what he understands about treatment options, and toward what, if any, option he is leaning. In this manner, any misunderstanding or misinterpretation of information previously provided by other physicians, friends, family members, Internet, or other sources can be identiﬁed and addressed. This is particularly important with respect to expectations the patient has in terms of outcomes after treatment (see Case 1). The decision-making process is confusing for most patients who seek the treatment with the best cure rate with the least complications. Most patients do not realize that, despite the variety of treatment options, no one treatment has been shown to be superior to another in a randomized trial, nor, in fact, has any treatment been shown to affect survival. Given these facts, the importance of understanding the potential short- and longterm consequences of the different treatment modalities must be emphasized, and attention to quality of life issues must play a vital role in the decision-making process.

QUALITY OF LIFE ISSUES All the treatment options are associated with side effects that can affect quality of life. It is difﬁcult to predict, however, how an individual patient will respond to a given side effect. Although a given side effect may occur with a certain frequency after a speciﬁc treatment, studies have shown that after treatment, patients may report varying degrees of bother from the side effect. If a patient is not bothered despite suffering the side effect, the fact that the side effect occurred did not impact on the quality of life. A treatment decision based solely on the frequency of the side effect would not have been an informed one. Another concept that needs emphasis is that some side effects can change over time. Some will improve, and others will develop slowly over years; the quality of life may change as a result.

Urinary Incontinence Only a small percentage of patients report baseline urinary incontinence before therapy (1). Patients tend to regard incontinence as the most signiﬁcant potential side effect after radical prostatectomy. Although incontinence does occur with greater frequency after surgery, patients require further education about the nature and impact of incontinence. Incontinence is not an all-or-nothing phenomenon, and in fact, most patients are not totally incontinent (2). Most patients who report urinary leakage have stress incontinence and may or may not wear a small pad. Interestingly, patients seldom rate stress incontinence as a major source of bother after the surgery (3). Postoperative incontinence tends to improve during the ﬁrst year after surgery (1), and patients should be informed that pelvic ﬂoor exercises before and after surgery should be performed. Incontinence can also occur after either external beam radiation therapy (EBRT) or brachytherapy. After EBRT, a small number of men report leakage or dribbling of urine, and some wear a protective pad (1,4,5). As long-term follow-up becomes available for brachytherapy, it is now apparent that incontinence can develop over time in almost half of the patients (6). The nature of the incontinence is similar to that seen after EBRT. Men who were treated with combined EBRT and brachytherapy (as opposed to brachytherapy alone) or who had prior transurethral resection of the prostate (TURP) before brachytherapy appear to be at greater risk (5,7). Modiﬁed treat-

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ment techniques in brachytherapy and use of conformal EBRT are currently employed in many centers and appear promising with respect to minimizing incontinence, but these approaches will require further follow-up of long-term outcomes. Patients who have been treated with radiation occasionally require TURP to treat obstructive symptoms. If TURP is necessary, patients are at additional risk for incontinence (8–10).

Irritative Bladder and Bowel Symptoms Patients expect some acute urinary and bowel symptoms after either EBRT or brachytherapy, but they are often unprepared for the potential duration of toxicity. After brachytherapy, most patients experience some degree of urinary irritative and obstructive symptoms (11–14). Routine prophylactic (vs therapeutic) use of α-blockers before brachytherapy shortens time to reach baseline function as measured by the International Prostate Symptom Score (IPSS) (13). The incidence of dysuria peaks at 1 mo after implantation. Those who have dysuria had no signiﬁcant improvement in either frequency of dysuria or pain for approx 36 mo, but by 45 mo dysuria had resolved in most patients. In contrast, overall IPSS scores continue to improve over time from brachytherapy. EBRT can result in chronic irritative voiding symptoms (frequency, urgency, hesitancy, nocturia), causing patients signiﬁcant bother. Several studies have demonstrated that quality of life can be adversely affected by these problems (5,15–17). Some patients report altering activities of daily life secondary to these voiding symptoms (17). Acute bowel toxicity of the bladder and rectum is expected after EBRT or brachytherapy combined with EBRT. Long-term bowel dysfunction can also occur, although it is infrequent after brachytherapy alone. These symptoms consist of frequent diarrhea, passing mucous per rectum, rectal bleeding, and stool leakage (6,10,18). The incidence of these symptoms increases during the second and third years (19) and seems to stablize 4 yr after EBRT (20). Many patients consider bowel dysfunction a minor problem (18,21,22). Radical prostatectomy can also affect bowel function, although with much lower frequency than after radiation (23,24).

Sexual and Erectile Dysfunction The patient’s expectations for sexual functioning after any form of therapy must be addressed. It is not uncommon for patients to report some degree of erectile dysfunction (ED) prior to diagnosis (1). Like incontinence, ED is more common immediately after surgery than after radiation but can improve during the year following radical prostatectomy. Nonetheless, erections sufﬁcient for successful penetration are unusual (1). Efforts to preserve erectile function with nerve sparing or sural nerve grafting techniques have been somewhat disappointing (25,26). Although some patients maintain spontaneous erections, many require use of sildenaﬁl or other agents for successful intercourse (27). Patients perceive that nonsurgical approaches will preserve potency. Although potency is maintained in most patients (who are potent at the outset) 1 year after EBRT or brachytherapy, the potency rates diminish over time so that by 5 yr, up to half of the patients report difﬁculties with potency (6,23,28,29). Many patients with ED owing to any form of therapy can be helped with medical therapy or by insertion of a penile implant. Addition of couples counseling to medical therapy is actively being studied to determine whether outcomes are improved. Interestingly, although potency may be of paramount importance prior to therapy, many patients do not seem to be bothered by ED after the fact (15,30,31). Conversely, some men who

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Risk Low Intermediate High

10-yr PSA-free survival (%)

T stage

PSA

Gleason score

78–88 65–80 40

T1c, T2 and T2b or T3 or

≤10 and PSA >10, ≤20 or PSA >20 or

≤6 7 ≥8

maintain erectile function report signiﬁcant bother (15), possibly related to some of the issues discussed below. Other considerations regarding sexual functioning are often not discussed with patients before therapy. Ejaculation volume is either reduced or absent in most patients after any of the treatment modalities (32–34). This is apparent immediately after surgery but may take several years to develop after radiation approaches. In addition, some patients report decreased intensity of orgasm (32,34) or even pain with ejaculation. Occasionally men experience urinary incontinence with orgasm and hence avoid sexual contact altogether (34). There is still much research to be done in this area, and patients must be informed that all the treatments available for early-stage prostate cancer can signiﬁcantly impair sexual functioning and satisfaction. More effort must be made to assist motivated patients with treatment-induced sexual dysfunction.

CAVEATS RELATED TO RISK STRATA FROM THE MEDICAL ONCOLOGIST’S PERSPECTIVE Discussion of low-, intermediate-, and high-risk strata based on prostate-speciﬁc antigen (PSA) level, Gleason score, and clinical T stage (Table 1) (34a) can be useful to make several points relevant to the patient’s speciﬁc case. Regardless of risk category, not all patients are cured, nor do all patients relapse, owing to the tremendous heterogeneity of the disease. Rather than focusing on statistics, it is sometimes helpful to pose a patient’s situation in absolute terms of “best case” and “worse case” scenarios. This helps the patient go through a mental exercise that may help him prioritize quality of life issues and arrive at a treatment decision.

Low-Risk Disease In the setting of low-risk disease, long-term survival appears to be quite good regardless of the treatment modality. Therefore, an understanding of the differences in morbidity for each treatment option should play a signiﬁcant role in decision making.

Intermediate- or High-Risk Disease For patients with intermediate- or high-risk disease, the concept of potential neoadjuvant or adjuvant therapy, preferably on a clinical trial, should be introduced. Although there is signiﬁcant risk for relapse in this setting, the natural history of the disease may be changed by adding additional therapy. If the patient chooses to have surgery and does not wish to enroll on a neoadjuvant therapy trial, a follow-up appointment should be offered to review the pathology ﬁndings and postoperative PSA levels

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and to determine what additional therapy or protocol treatment might be appropriate. Patients should be made aware that there is growing evidence that monotherapy in the setting of intermediate- and high-risk disease is not probably not adequate (35).

ADVANTAGES AND DISADVANTAGES OF SPECIFIC TREATMENT OPTIONS Watchful Waiting Although watchful waiting is certainly an option for selected patients with low-risk disease or limited life expectancy, the speciﬁc criteria for selecting such patients remain undeﬁned. Certainly some low-risk patients (Gleason score ≤ 6, small-volume disease, and PSA near normal limits) appear to be reasonable candidates for this approach. Patients need to be informed that “small-volume” disease cannot always be diagnosed accurately. The obvious advantage to those who choose watchful waiting is that treatment, with its inherent morbidities, is delayed or avoided. Even so, many men with life expectancies under 10 yr still choose an active therapy (36). One of the disadvantages is that by waiting, the therapeutic window for cure with surgery or radiation may be missed. If the disease progresses and treatment is pursued, addition of hormonal therapy to surgery or radiation, (or EBRT to brachytherapy) may be indicated. The additive therapies also add to the toxicity of each deﬁnitive treatment. For those who choose watchful waiting, frequent testing and biopsies must be done, although there are no clear guidelines on the recommended frequency of PSA testing, the PSA threshold for rebiopsy of the prostate, and so forth. The psychological toll of watchful waiting for some patients is clearly not worthwhile (18).

Radical Prostatectomy Surgery provides a debulking of the tumor and hence, even when the patient is not cured, local recurrence is usually not an issue. This is discussed further below. Another advantage of radical prostatectomy is that the PSA level can be used almost immediately to monitor the status of the disease. Finally, pathologic staging permits better prediction of prognosis and may, if more advanced disease is deﬁned, indicate that additional therapy is warranted. Any surgical procedure such as a radical prostatectomy carries a very low but real risk of perioperative death or morbidity, and the requirement for administration of a general anesthetic contributes to both. Patients who are at poor risk to receive general anesthesia should consider other options. Time in the hospital varies but is usually less than 3 d. Patients leave the hospital with a urinary catheter that is often removed 1–2 wk later. Most patients can return to work 4–6 wk after surgery. The main concerns related to surgery are the possibility of incontinence and ED. These complications are discussed in detail above. Highly experienced surgeons have better outcomes than those who perform fewer radical prostatectomies (37,38).

External Beam Radiation Therapy and Brachytherapy External beam is given on an outpatient basis over 6–7 wk. No anesthetic is necessary, and many patients can continue to work throughout therapy. By contrast, brachytherapy requires anesthesia at most institutions, but it is a 1-d procedure. EBRT is not a good choice for patients with inﬂammatory bowel disease or vascular disorders such as ataxia telangiectasia. Some patients are not brachytherapy candidates because of the location of

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the prostate high beneath the pubic bone. Most of the time, a urinary catheter is not required for EBRT, and after brachytherapy most patients have the catheter removed on the same day as the procedure (39). In either case, pathologic staging information is not routinely obtained, making prediction for prognosis less accurate. After any form of radiation, PSA is not immediately useful for monitoring the disease. It may take up to 2–3 yr for the PSA to reach nadir, and the nadir may not reach the undetectable range, further clouding the status of the patient. Likewise, biopsy of the prostate within 2–3 yr of treatment can be difﬁcult to interpret because the histologic appearance of carcinoma in the biopsy may not represent viable cancer. After brachytherapy, the PSA bounce phenomenon can cause anxiety while it is being sorted out. Although incontinence or ED does not occur within the ﬁrst year after therapy, either can occur over time, as discussed previously. Patients who have larger prostates or intermediate/high-risk disease will require administration of hormonal therapy lasting months to years, depending on the situation, usually in conjunction with additional EBRT to the pelvis. Local recurrences after radiation, probably caused by difﬁculties of tumor targeting and inadequate dose delivery owing to the shifting position of the prostate, can be problematic over time. This will be discussed in more detail below.

SPECIFIC CIRCUMSTANCES AND BIASES The Patient With Signiﬁcant Voiding Symptoms at Diagnosis Although there does not seem to be any body of literature that addresses whether any treatment modality offers therapeutic superiority over another when patients present with signiﬁcant voiding symptoms owing to an enlarged prostate, medical oncologists have biases related to their experiences with such patients over time. Patients who relapse locally often give a history of signiﬁcant voiding symptoms and an enlarged prostate at diagnosis and have been treated with EBRT or brachytherapy. These patients can experience signiﬁcant “plumbing” problems and may have deep pelvic pain, hematuria, bladder outlet and/or ureteral obstruction, and rectal involvement with bowel obstruction. Although the denominator for this situation is unknown, the patient who presents to the medical oncologist under these circumstances is particularly challenging. More radiation to treat the local relapse is not feasible, and systemic therapies offer only transient, if any, relief of these problems. Palliative surgery is sometimes an option for a select few. Patients who present with voiding symptoms and enlarged prostates should be counseled that such complications might occur over time with nonsurgical approaches in the “worst case scenario” and should understand that another course of radiation is not an option. Modern (high-dose, conformal, intensity-modulated) radiation techniques in conjunction with hormonal therapy will hopefully make this problem obsolete in the future.

Addition of Hormonal Therapy to Radiation Patients with high-risk disease planning on brachytherapy and/or EBRT may not realize the implications of the additional hormonal therapy. If the patient has decided on proceeding with a radiation approach that includes long-term (≥1 yr) hormonal therapy, the myriad of effects listed in Table 2 should be outlined, and monitoring recommendations should be made. Short courses of androgen deprivation are probably of less concern.

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Table 2 Potential Side Effects of Androgen Deprivation Therapy Commonly mentioned Loss of libido Erectile dysfunction Hot ﬂashes Less commonly mentioned Physical changes Gynecomastia Weight gain Loss of muscle mass Loss of penile and testicular volume Loss of body hair Metabolic and physiologic changes Loss of bone mineral density Anemia Lipid changes Exacerbation of underlying hypertension or diabetes Physical, psychological, and cognitive symptoms Fatigue and lack of energy Emotional lability, depression Cognitive dysfunction Muscle aches and pains

If Radiation Fails, I Can Have Surgery… Patients often believe that if radiation fails, surgery can be performed at that time. Although salvage radical prostatectomy might be an option in some circumstances, it is a much more difﬁcult procedure after deﬁnitive radiation. Some surgeons will perform a cystoprostatectomy, and others will (when feasible) perform a radical prostatectomy, with a 50% chance of incontinence. This procedure is best performed by one of the small number of surgeons who have gained experience and expertise in this ﬁeld.

CASE STUDIES Case 1 A 64-yr-old trial attorney presents with a PSA of 5 ng/mL, T1c, Gleason score 6 prostate cancer. He initially saw his urologist for decreased urinary stream and frequency. His AUA symptoms score showed moderate obstructive symptoms. He understands (from the brother of a partner at the ﬁrm) that he can go right back to work if he has brachytherapy. This is a high priority to the patient. Furthermore, he is still potent and has been told that potency will be normal after brachytherapy but probably not after surgery. Finally, he feels strongly that he could not continue in his position as a trial attorney if he were to become incontinent. He is told that he has a “low-risk” tumor and therefore, on the surface, any of the treatment modalities are quite acceptable with respect to long-term survival. Although patients are ambulatory and more active sooner after brachytherapy than after a radical prostatectomy, the patient is advised that he may have signiﬁcant urinary frequency after brachytherapy that could last for 6–12 mo or more. He is told that he may be at a higher

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risk for irritative voiding symptoms because of his baseline AUA symptom score. He is asked to consider how such symptoms would impact on his work in the courtroom. As he gains insight into the incontinence and potency issues, he is able to come to the conclusion that his highest priority is the ability to return to work in the courtroom without constant interruption. He decides that the potential urinary frequency and urgency, even if temporary, is not acceptable and opts for surgery instead of brachytherapy.

Case 2 A 60-yr-old man with aortic insufficiency and a recent episode of congestive heart failure is president of a local insurance company. He presented with a PSA of 11 ng/mL, a palpable nodule on one side, and a Gleason score of 4 + 4. His brother was diagnosed with prostate cancer over 5 yr ago and was “cured” with a radical prostatectomy. His brother has had no problems with incontinence and uses sildenafil with success. The patient is convinced that he wants to have a radical prostatectomy. Because of his cardiac history, the urologist is reluctant and refers the patient to a radiation oncologist for further discussion. The patient is adamantly opposed to radiation because a friend who was treated 15 yr ago with EBRT has had chronic bowel problems ever since, forcing his retirement. Instead, he makes an appointment with a medical oncologist, hoping to be referred to another urologist who will go ahead with the surgery. The medical oncologist explains that the combination of aortic insufﬁciency and congestive heart failure is of great signiﬁcance in his decision making. He is a poor anesthesia candidate; therefore surgery and brachytherapy (in many institutions) are risky. The patient is not aware that his heart condition increases his anesthesia risk and, in fact, limits his longevity. He is told that it is unlikely that he will die of prostate cancer before he dies from valvular heart disease. The oncologist explains that radiation can result in bowel problems but they are not usually severe and that newer conformal techniques have signiﬁcantly decreased the risk of bowel injury. He is referred to a radiation oncologist who has the most modern equipment and techniques available.

CONCLUSIONS Many patients seek the advice of a medical oncologist regarding treatment options for localized prostate cancer. In the process of meeting with such patients, it is critical to identify and correct misconceptions or misunderstandings and to educate patients about disease characteristics and quality of life issues. The medical oncologist can help patients factor quality of life, comorbidities, patient priorities, and preferences into a complex equation. In the absence of randomized studies showing survival beneﬁt for any of the treatment options, emphasis must be placed on understanding that all the treatments have potentially bothersome side effects and that quality of life considerations should take priority in making treatment decisions. Medical oncologists who advise patients with localized prostate cancer have a responsibility to stay abreast of new treatment reﬁnements and ﬁndings in the evolving quality of life literature. The opportunity to advise patients in this difﬁcult time is a privilege that must not be taken lightly.

REFERENCES 1. Talcott JA, Rieker P, Clark JA, et al. Patient-reported symptoms after primary therapy for early prostate cancer: results of a prospective cohort study. J Clin Oncol 1998;16:275–283.

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2. Stanford J, Feng Z, Hamilton A, et al. Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the Prostate Cancer Outcomes Study. JAMA 2000;282:354–360. 3. Kao T, Cruess D, Garner D, et al. Multicenter patient self-reporting questionnaire on impotence, incontinence and stricture after radical prostatectomy. J Urol 2000;163:858–864. 4. Shrader-Bogen CL, Kjellberg JL, McPherson CP, et al. Quality of life and treatment outcomes: prostate carcinoma patients’ perspectives after prostatectomy or radiation therapy. Cancer 1997;79:1977–1986. 5. Litwin MS, Pasta DJ, Yu J, et al. Urinary function and bother after radical prostatectomy or radiation for prostate cancer: a longitudinal, multivariate quality of life analysis from the Cancer of the Prostate Strategic Urologic Research Endeavor. J Urol 2000;164:1973–1977. 6. Talcott JA, Clark JA, Stark PC, et al. Long-term treatment related complications of brachytherapy for early prostate cancer: a survey of patients previously treated. J Urol 2001;166:494–499. 7. Brandeis JM, Litwin MS, Burnison CM, Reiter RE: Quality of life outcomes after brachytherapy for early stage prostate cancer. J Urol 2000;163:851–857. 8. Hu K, Wallner K. Urinary incontinence in patients who have a TURP/TUIP following prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998;40:783–786. 9. Gelblum DY, Potters L, Ashley R, et al. Urinary morbidity following ultrasound-guided transperineal prostate see implantation. Int J Radiat Oncol Biol Phys 1999;45:59–67. 10. Joly F, Brune D, Couette JE, et al. Health-related quality of life and sequelae in patients treated with brachytherapy and external beam irradiation for localized prostate cancer. Ann Oncol 1998;9:751–757. 11. Merrick GS, Butler WM, Lief JH, et al. Temporal resolution of urinary morbidity following prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000;47:121–128. 12. Kang SK, Chou RH, Dodge RK, et al. Acute urinary toxicity following transperineal prostate brachytherapy using a modiﬁed Quimby loading method. Int J Radiat Oncol Biol Phys 2001;50:937–945. 13. Merrick GS, Butler WM, Wallner KE, et al. Prophylactic versus therapeutic alpha blockers following permanent prostate brachytherapy. Urology 2002;60:650–655. 14. Arterbery VE, Frazier A, Dalmia P, et al. Quality of life after permanent prostate implant. Semin Surg Oncol 1997;13:461–464. 15. Litwin MS, Hays RD, Fink A, et al. Quality-of-life outcomes in men treated for localized prostate cancer. JAMA 1995;273:129–135. 16. Caffo O, Fellin G, Graffer U, et al. Assessment of quality of life after radical radiotherapy for prostate cancer. Br J Urol 1996;78:557–563. 17. Franklin CI, Parker CA, Morton KM. Late effects of radiation therapy for prostate carcinoma: the patient’s perspective of bladder, bowel, and sexual morbidity. Australas Radiol 1998;42:58–65. 18. Frasson P, Damber J, Tomic R, Modig H, Nuberg G, Widmark A. Quality of life and symptoms in a randomized trial of radiotherapy versus deferred treatment of localized prostate cancer. Cancer 2001;92:3111–3119. 19. Pilepich MV, Perez CA, Walz BJ, et al. Complications of deﬁnitive radiotherapy for carcinoma of the prostate. Int J Radiat Oncol Biol Phys 1981;7:1341–1348. 20. Fransson P, Widmark A. Late side effects unchanged 4–8 years after radiotherapy for prostate carcinoma: a comparison with age-matched controls. Cancer 1999;85:678–688. 21. Widmark A, Fransson P, Tavelin B. Self-assessment questionnaire for evaluating urinary and intestinal late side effects after pelvic radiotherapy in patients with prostate cancer compared with an agematched control population. Cancer 1994;74:2520–2532. 22. Lim AJ, Brandon AH, Fiedler J, et al. Quality of life: radical prostatectomy versus radiation therapy for prostate cancer. J Urol 1995;154:1420–1425. 23. Potosky AL, Legler J, Albertsen PC, et al. Health outcomes after prostatectomy or radiotherapy for prostate cancer: results from the Prostate Cancer Outcomes Study. J Natl Cancer Inst 2000;92:1582–1592. 24. Bacon CG, Giovannucci E, Testa M, Kawachi I. The impact of cancer treatment on quality of life outcomes for patients with localized prostate cancer. J Urol 2001;166:1804–1810. 25. Catalona JW, Carvalhal GF, Mager DE, et al. Potency, continence and complication rates in 1870 consecutive radical retropubic prostatectomies. J Urol 1999;162:433–438. 26. McCammon KA, Kolm P, Main B, et al. Comparative quality of life analysis after radical prostatectomy or external beam radiation for localized prostate cancer. Urology 1999;54:509–516. 27. Chang DW, Wood CG, Kroll SS, Youseff AA, Babaian RJ. Cavernous nerve reconstruction to preserve erectile function following nerve sparing radical retropubic prostatectomy: a prospective study. Plast Reconstr Surg 2003;111:1174–1181.

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28. Mantz CA, Nautiyal J, Awan A, et al. Potency preservation following conformal radiotherapy for localized prostate cancer: impact of neadjuvant androgen blockade, treatment technique, and patient-related factors. Cancer J Sci Am 1999;5:230–236. 29. Merrick GS, Wallner KE, Butler WM. Management of sexual dysfunction after prostate brachytherapy. Oncology 2003;17:52–62. 30. Bates TS, Wright MP, Gillatt DA. Prevalence and impact of incontinence and impotence following total prostatectomy assessed anonymously by the ICS-male questionnaire. Eur Urol 1998;33:165–169. 31. Fowler FJ Jr, Barry MJ, Lu-Yao G, et al. Effect of radical prostatectomy from prostate cancer on patient quality of life: results from a Medicare survey. Urology 1995;45:1007–1013. 32. Helgason AR, Fredrikkson M, Adolfsson J, Steineck G. Decreased sexual capacity after external beam radiation for prostate cancer impairs quality of life. Int J Radiat Oncol Biol Phys 1995;32:33–39. 33. Emberton M, Neal DE, Black N, et al. The effect of prostatectomy on symptom severity and quality of life. Br J Urol 1996;77:233–247. 34. Koeman M, van Driel MF, Schultz WC, Mensink HJ. Orgasm after radical prostatectomy. Br J Urol 1996;77:861–864. 34a. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy or external beam radiation therapy for patients with clinical localized prostate carcinoma in the prostate speciﬁc antigen era. Cancer 2003;95:281–286. 35. D’Amico AV, Moul J, Carroll PR, Sun L, Lubeck D. Vital statistics following surgery or radiation for patients with clinically localized prostate cancer managed during the PSA era. Proc Am Soc Clin Oncol 2003;22:381. 36. Holmboe ES, Concato J. Treatment decisions for localized prostate cancer: asking men what’s important. J Gen Intern Med 2000;15:694–701. 37. Ellison LM, Heaney JA, Birkmeyer JD. The effect of hospital volume on mortality and resource use after radical prostatectomy. J Urol 2000;163:867–869. 38. Gleave ME, Goldenberg L, Chin JL, et al. Randomized comparative study of 3 vs 8 months of neoadjuvant hormonal therapy prior to radical prostatectomy: 3 year PSA recurrence rates. J Urol 2003;169(suppl 4):179. 39. Merrick GS, Butler WM, Lief JH, Dorsey AT. Temporal resolution of urinary morbidity following prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000;47:121–128.

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Emotional and Informational Support for the Patient Undergoing Radical Prostatectomy Dorothy A. Calabrese

INTRODUCTION Prostate cancer is the most common non-skin male malignancy diagnosed in the United States. The American Cancer Society estimated that 220,900 new cases of prostate cancer would be diagnosed in 2003 (33% of male cancers diagnosed) (1). In the United States, 80–90% of these prostate cancers will be diagnosed at a clinically localized stage, and approx 65% of these cases will be pathologically organ-conﬁned (2). This means that most newly diagnosed prostate cancer patients will have favorable survival outcomes following treatment. However, controversy exists regarding the best treatment for localized prostate cancer. Although each treatment option has the potential to cure the cancer, the options can have considerable impact on the patient’s quality of life. Having options regarding treatment is viewed by health care providers as a positive thing, but many men struggle to decide on the best treatment to cure the cancer while maintaining an acceptable quality of life. Getting accurate information about treatment options and the side effects of the options will help the person to make the decision that is right for him. Many men with localized prostate cancer will decide to have a radical prostatectomy. Whether this is done as an open procedure via a retropubic or perineal approach or laparoscopically, there are many issues with which the patient must deal. Education and support will help the patient navigate through the issues he will face before, during, and following surgery.

TIME OF DIAGNOSIS When a patient is diagnosed with prostate cancer, he and his family will experience a variety of emotions, anxieties, and stresses. Shock, fear, and feelings of helplessness and loss of control will be paramount at this time. The patient may worry about the From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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meaning of the cancer diagnosis in terms of his life span. He may also wonder about his future plans and dreams. Will he live to see his children grow up, graduate from college, get married? Will he live to see his grandchildren? What about all the things he and his signiﬁcant other had planned for the future? There are also fears about sexuality, masculinity, and self-esteem related to the cancer and the treatment. When the patient has localized prostate cancer, he can experience all these fears. He does, however, need to recognize that he has the potential to be cured of his cancer. He will learn about the treatment options available to him and that each of the treatment options for localized disease has the potential to affect his quality of life. Curing the cancer as well as having an acceptable quality of life is the ultimate goal. What deﬁnes an acceptable quality of life is different for each patient. Following his diagnosis, the patient needs to begin to understand the diagnosis and decide what the diagnosis means for him. He and his partner need to decide how they are going to face the challenges ahead of them. At this time, many couples identify survival as their primary concern (3). Since there is controversy in the medical arena regarding the best way to treat localized prostate cancer, it is certainly understandable that it is a struggle for many men to make a decision among the options available to them. For most men, the decision to treat their localized prostate cancer by surgery, brachytherapy, or external beam radiation therapy is not an easy one. Although options are good to have, the decision-making time can be very difﬁcult for the patient. Gathering information is a ﬁrst step that will help the patient through this process. He will need to make sense of the treatment options, the side effects, and what is the best option for him. He often receives advice (some helpful, some outdated) regarding effects of a treatment. Friends or relatives can be quite ﬁrm in their belief of what the patient should do. There is no one correct decision, rather, the person needs to make the correct decision for him. He needs to recognize that there are effects from each treatment option, and he should be honest with himself regarding what is important to him and what he is willing to put up with to reach that goal. Knowing this will help him make the best decision. To make the treatment decision, the person needs to become an educated consumer. Gone are the days when the doctor told the patient what to do (although for some patients, this would be the best option). The patient needs to be an active participant in his care. He can do this by learning as much as possible about his diagnosis. Gathering information will help him make a decision. He can talk to men who have been through various treatments for prostate cancer. Books found at the local library or book stores will give information about treatment options, side effects, questions to ask the physician, and additional resources to consult. The Internet has many sites that will also expose the person to this information. Not all books or web sites are equal. The person needs to ﬁnd resources that will give accurate, current information about treatment. The urologist and his ofﬁce staff can be a good resource for the person in this matter. They may also be helpful in helping the person to decide what he considers important quality of life issues and how to ﬁnd information about those issues. Although the mass media has done much to highlight the fact that prostate cancer is a prevalent problem in our society, much of the information has been sensationalized. This is not the best information for the patient to use, but it can lead the person to resources that may provide him with the information he is seeking. A meeting with a urologist is a crucial ﬁrst step. A second opinion to discuss treatment options will help the patient feel comfortable with his decision and help him to

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feel that he is doing the right thing. An intangible fact in the patient’s decision process is ﬁnding a physician that the patient likes and trusts. This urologist can then help the patient resolve any important issues that are still unresolved. How does the diagnosis of prostate cancer affect the spouse of the patient? Any diagnosis of cancer affects all members of the family. It especially affects the spouse. There are a variety of ways that spouses respond to the news of a prostate cancer diagnosis. The spouse will probably also experience fear, anxiety, helplessness, and uncertainty. Most spouses have planned a future with their husband, a plan that is now threatened. How the patient responds to the diagnosis affects the spouse. Some patients withdraw or retreat from normal life as they try to come to grips with their diagnosis. If this happens, it is certainly a difﬁcult time for the spouse. For the short term, as the patient is struggling to make sense about what is happening, the spouse may need to take over chores that have been in the domain of the husband. Or the patient may be unwilling (or unable) to discuss the diagnosis. Coping mechanisms that a patient and his wife used during difﬁcult situations in their life together will usually dictate how they will work through this stage of the diagnosis. Sometimes the wife may take a very active role and become the searcher, looking for information to help her husband understand the treatment options and side effects. Sometimes she may take a less active role, allowing her husband to do the research. She can then be the sounding board for her husband as he struggles to decide on a treatment. Unfortunately, some wives are so overwhelmed by this threat to their husband that they become another stressor for the patient. Most couples ultimately begin to absorb the reality of the situation, and they move into the decision-making stage. Whether the spouse is an active or a passive participant in the decision about treatment, an important role is one of support. The decision regarding the treatment of the cancer will affect her and her relationship with her husband. Both the patient and the spouse will have to live with the consequences (the side effects) of the decision. Often the treatment decision is described by the couple as a consensus decision, but they may have struggled to integrate two different opinions of how the cancer should be treated. Their life experiences will play a role in inﬂuencing the decision that is ultimately made. Their beliefs regarding cancer as a disease, feelings about curing the cancer, experiences with others who have had cancer treatment, and other life experiences will all play a part in the treatment decision. Some patients fear the actual surgery, whereas others may believe that radiation causes cancer. These fears and beliefs factor into the decision that the patient makes. Quality of life issues (incontinence and impotence) are often less important to the patients’ wives. Wives are usually more interested in curing the cancer and the far-reaching effect this would have on the future of the couple than either incontinence or impotence (4). Although the patient is also focused on curing the cancer and living a long life, he is also very aware that he will be the one who will live with the side effects of the treatment. He often feels that it is worth living with the side effects to have the cancer removed. He feels that the side effects can be managed. How and when to tell other family members or friends is an individual decision. Some patients wait to tell their children until they have made a decision. They do not want to bother or burden the family members. Others ask for input from their children during the decision-making process. Neither way is right nor wrong. How families function during other stressful times is often how they function following a cancer diagnosis. This can be an important time for the patient and his family. There can be a

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strengthening of the family bonds as the family deals with the devastating news of the cancer diagnosis.

WAITING FOR THE TREATMENT There isn’t much that is positive about a cancer diagnosis, but there is one good thing from a prostate cancer treatment perspective—the decision does not need to be made immediately nor does the treatment need to occur instantaneously. The person has time to gather information and to identify important issues regarding the treatment and side effects. He can take time to make the correct treatment decision for him. If the patient decides on surgery, there is usually a waiting period until the operation will take place. This waiting period can be weeks or months. Apprehension and distress often accompany this waiting time for the patient, his partner, and the family members (3). The common anxieties during this time relate to whether they are doing the correct thing and whether the cancer will spread while they are waiting for surgery. They also wonder whether the side effects of the surgery (incontinence and impotency) will occur and how they will cope with them if they do occur. A lot of “what ifs” are discussed. Overall, this time is one of returning to a routine or normal life for the patient and family. Although the cancer diagnosis is always present, it is on the back burner while the patient settles back into his life. The decision has been made. The research is done. There is no more reading or gathering of information. Now the patient and his family just need to wait until the decision becomes a reality. As the surgery date approaches, it is important to be sure that expectations regarding outcomes of surgery are realistic. The patient and his spouse may not have heard or assimilated potential information regarding the hospitalization or the side effects from treatment (postoperative incontinence and potency issues). If the patient or his partner seem unusually stressed, asking them what is worrying them allows the doctor or nurse to address these primary issues of concern. Repetition may be necessary at this time as well as other times following the diagnosis. Patients do not remember much of what they are being told regarding the surgery. What is routine for the health care team certainly is not routine for the patient and the family. They will often have many questions, ranging from blood donation (is it necessary? Should I get family members to donate blood also?) to where his family should park on the day of surgery. The patient’s life is out of control (or beyond his control), and this questioning can be a way of getting some control over an uncertain future. One way to supply information that may be helpful for the patient and the family is a written instruction sheet that describes the physician’s routine. They will be able to get answers for areas of concern from this information sheet, and they do not need to rely on their memory. This written information should include schedules of appointments, as well as the speciﬁc information regarding what they can expect during the preoperative phase, while in the hospital, as well as following their discharge from the hospital. Each physician has unique protocols, and this information is not available from any general book or Internet site. This information can help to allay some of the stress and anxiety for the patient. He has an idea of how things will proceed. At this time, the patient may again voice a variety of concerns. Although he is glad that the surgery will ﬁnally take place, he may begin to fear that he will not live through surgery or that he will not be able to manage the pain following the surgery. Often the patient will focus on very concrete things (such as what he should bring with him to the

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hospital) to help him maintain a sense of control about what is occurring in his life. Speciﬁc information about what to expect before, during, and following the surgery can help to reduce this psychological distress. This information may also impact on the degree of pain that the patient experiences, as well as improve the recovery time (3). In addition to written information, a member of the health care team should be available to address patient concerns, to help make the preoperative time a less anxious one.

AT THE TIME OF SURGERY The postoperative time has been identiﬁed as the most stressful time for men who elect to have surgery to treat their prostate cancer. Although information that explains what to expect can be helpful, it may not alleviate all the stress (5). Many patients receive an epidural anesthesia, so they are aware of their surroundings during surgery. This type of anesthesia facilitates early recovery from surgery, but the thought of being awake during surgery can cause a great deal of distress for the patient. The patient may fear that he will feel what is going on during the surgery, or that it (what he feels) will be very painful. The patient needs reassurance that additional medication to help sedate him will be used in addition to the epidural. This may help to relieve some of the anxiety. Immediately following the surgery, the patient may feel a sense of relief that he made it through the operation. Other immediate concerns follow surgery. Pain management, early ambulation (especially getting out of bed the ﬁrst time), and resumption of his diet are areas that concern the patient. Once he realizes that his pain is being managed, that the ﬁrst time out of bed was rough but bearable, and that his dietary intake is progressing, his thoughts turn to how he will manage when he is discharged from the hospital. A review of simple written instructions regarding management of the Foley catheter, pain control, and activities of daily living does a lot to alleviate the patient’s concerns. Knowing what to expect helps the patient gain some control over his world. Another important concern for the patient is whom he should call with questions if he is experiencing a problem following his discharge from the hospital. Stressing the importance of reporting any symptom or situations that do not seem normal may help identify problems before they become crises. Knowing that someone is available to answer questions provides a sense of relief or security for the patient and the patient’s family. Discussing expectations regarding diet progression, liquid intake, activity, showering, lifting, driving the car, and bowels can be time-consuming, but it does help to make the immediate postoperative time at home easier for the patient. Many patients have never had a Foley catheter before, and they can be intimidated by the care of the catheter. Examples of how to manage the catheter drainage bag at night (for example, hang it on a waste basket or the drawer of a bedside stand) will help the patient realize that he will be able to manage once he is discharged from the hospital. The patient’s spouse experiences a variety of feelings and emotions during this time. She may feel a sense of relief that the surgery is ﬁnally over. She may feel emotional and physical fatigue from the stress of the past few months. She may also feel anxiety about what will be happening in the next few weeks (for example, how her husband will do physically and psychologically following the surgery or how he will deal with the side effects of the surgery). She also will be the primary person to relay information to the family and friends. She may also be tired from needing to make trips to the hospital to visit with the patient and learn about his needs following discharge.

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TIME AT HOME FOLLOWING SURGERY Patients experience a variety of emotions when they return home following surgery. Usually they are glad to be home. They feel more comfortable in their own environment, but they may miss the security of having the nurse just an intercom call away. The instructions at discharge were very common sense . . . what could go wrong? The main anxieties are usually related to care of the catheter and fear that they will inadvertently do something and “undo” the surgery. They are anxious that something could go wrong and that they would not recognize the problem. Although written instructions with phone numbers given to the patient at discharge are very helpful, responding in a timely fashion to patient phone calls with answers to their concerns will also allay the anxiety that they are feeling during this time. The time at home is usually one of continued improvement, both physically and emotionally. The euphoria experienced immediately following the surgery and the anxieties that the patient experienced immediately upon returning home have subsided. As the patient continues to gain strength and resume self-care, he recognizes and appreciates the healing process. Issues and questions that occur are answered. His recovery is progressing as he was told it would. The spouse usually experiences a variety of emotions when she brings her husband home from the hospital. One of the ﬁrst emotions is relief. She is glad that the surgery is over and that her husband is doing well. She may experience anxiety since her husband has just had surgery, and she is not sure that they will be able to manage his care at home, especially the care of the Foley catheter. She may feel fatigue, both physically and mentally, owing to the stress of the cancer diagnosis and surgery. While her husband was hospitalized, the trips to the hospital were another stress. She wanted to be with her husband to assure herself that he was improving and doing the things he was supposed to do to improve, but it added another thing to her day. Once the home routine is established, the spouse relaxes into the new role. She is a caretaker, a helper, a coach (during times that the patient feels “down”), and a gatekeeper. She needs to keep well-meaning friends from exhausting the patient. During this recovery time, the focus of everything is on the patient and his recovery. Having friends that recognize and acknowledge how difﬁcult this time must have been for the spouse allows the wife to admit her fears and anxieties regarding the threat to her marriage.

REMOVAL OF THE STAPLES AND THE CATHETER The patient approaches the time to have the staples and the Foley catheter removed with mixed feelings. He is glad they will be out (signifying internal healing and a positive step in returning to normal). The patient is fearful that the catheter and staple removal will hurt. He may express anxiety regarding having to deal with the reality of incontinence following the removal of the catheter. There are also some fears regarding staple removal. Will his incision split open when he coughs? Will he have any urine control? How will he manage the incontinence? Prior to surgery these issues had been abstract concepts. Now he is facing the reality of the situation. Reassurance and explanation of every step during this process help the patient understand what will be happening during the appointment. The explanation should be incremental for men who are extremely anxious, since their ability to retain information is limited. Sometimes giving an overview of what will occur and talking the patient through the process as it is occurring will help decrease stress and anxiety.

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Teaching should occur following the removal of the staples and Foley catheter, since the patient is usually less apprehensive and will retain more of the information. Whether or not to have the patient’s partner present during the staple and Foley catheter removal and the instruction phase should be up to the patient. Some patients want their partner to be part of the process, and some men want to take control of this part of the process and do not want to involve their spouse. This is another difﬁcult time for the patient. Once the patient made his decision about surgery and the surgery was scheduled, he knew when the surgery would occur, how long he would be in the hospital, and how long the staples and catheter would be in place. Now the patient is told that there is no way to know how long he will leak urine. Discussing the way urine control usually returns and what he can or should do to help regain urine control are important. Providing information about products available to keep him dry during this time as well as where to purchase them will be invaluable to the patient during this phase of the postoperative recovery. Written information can also prove helpful, since the patient can review it at home when he is uncertain about what he heard and what he is experiencing. Occasionally a man will not remember he was told preoperatively that he will leak urine when the catheter is removed. He may have been very overwhelmed when he heard his diagnosis and during subsequent discussions with the urologist about the surgery. This can be a difficult time for both the patient and the person removing the catheter (MD, RN, or PA). Reinforcing what will occur following removal of the catheter regarding urine control (or lack of urine control) will take more time, but it is essential that the patient have an understanding of what he can expect at this point in his recovery. Lack of urine control following removal of the catheter can range from leaking a few drops of urine for a few days to leaking signiﬁcant urine for weeks to months. The uncertainty of this process is stressful for the patient. Preparing the person for the worse-case scenario (no or little urine control) may scare the patient, but he needs to know what can and may occur. If the situation is better than anticipated, the patient experiences a positive psychological boost. If he leaks signiﬁcant urine for weeks or months, he can be reminded that this is expected. Urination was more or less something that happened without thinking about it since the patient was about 2 or 3 yr of age. Following the removal of the Foley catheter, the patient tends to focus on the mechanics of urination. He notices that his stream is good, small, or nonexistent. He voids too often or not often enough. There is burning at the beginning, middle, or end of urination. There may be blood in the urine. All these things cause anxiety for the patient. The patient has been diagnosed with cancer—do these things have a meaning related to the cancer or are they effects of the surgery? Repeated explanation and reassurance may be necessary to help the patient through this part of the recovery. Knowing who to call with questions and concerns is again important for the patient. If he is uncertain whether his recovery is progressing the way it should, discussing his questions with a knowledgable member of the health care team will reassure him and allow him to recognize that he is making slow or steady improvement. If there is a problem (for example, a urinary tract infection), discussing what the patient is experiencing and what will be done helps alleviate the anxiety he may be feeling. If the pathology report is not available when the patient is scheduled to have his staples and Foley catheter removed, he may become anxious. The usual feeling is that

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there is something wrong (or not good news), and the urologist does not want to tell him. The pathology review in many organizations is a labor-intensive process to give the surgeon a variety of data regarding the prostate cancer (location, status of the lymph nodes, capsular extension, status of the seminal vesicles, and status of the surgical margins). Health care providers need to recognize how important this information is to the patient. Reassurance that he will be notiﬁed as soon as the report is available by the usual ofﬁce mechanism may help to alleviate some of the anxiety that is present. At this postoperative appointment, some men will ask about the resumption of intimacy with their partner. For many men, this question is asking about the resumption of intercourse. When can they try to have an erection, will it hurt, is there information to help them understand what to expect? Each physician has guidelines regarding resumption of sexual activity. Encourage the patient to follow those guidelines. However, remind the patient that it can take a year or longer to have a spontaneous erection and that there are other methods available to help with erections until then. Many men are unwilling to think about erections at this postoperative visit and prefer to deal with and to concentrate on urine control at this point in time. Sexual functioning and intimacy are future things to think about.

WHEN THE PATIENT LIVES ALONE There are many men who live alone and do not have the emotional and physical support of a spouse. The decision-making process will probably follow a similar pattern as for the patient with a spouse. Usually a close friend or relative can serve as a sounding board for the patient as he is working through the process of making a decision regarding treatment. Issues regarding incontinence and impotence are still present for these patients. The issue of incontinence is present for all men, and it may be more difﬁcult for the patient without a spouse. He will need to shop for incontinence supplies prior to the surgery or arrange to have a friend take him to the store following his catheter removal. He will also lose emotional support, since it is very difﬁcult to talk about such topics with friends and acquaintances. Many of these patients will call the ofﬁce prior to surgery and ask for suggestions on what can be done to manage in the postoperative recovery period. The patient often feels a great sense of relief when he realizes that he will be able to manage his care. Encourage him to have nonperishable food available for his meals until he is able to drive. Also, this is the time to accept offers from friends to help. It is helpful to identify friends or relatives that can assist him by going to the grocery to get perishable foods, drive him home from the hospital, and bring him to the postoperative appointment to get the staples and Foley catheter removal. It is also helpful to identify someone who can be called on in case there is a problem that needs immediate attention. Having this planned ahead of time can alleviate stress following the surgery.

POSTOPERATIVE OFFICE VISIT Patients who undergo a radical prostatectomy will return for a postoperative visit with the Urologist approx 6–8 wk following surgery (or per the ofﬁce routine). At this visit, the patient will be assessed regarding his general recovery from surgery and his urinary control. Any questions regarding the pathology report or any questions regarding future care will also be addressed. A baseline prostate-speciﬁc antigen (PSA) blood test will be drawn. The PSA is expected to be 0 and to remain there on subsequent

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checks because the patient does not have a prostate nor prostate cancer. This is a good time to explain to the patient that the PSA may not actually be a 0, but that it should be the lowest value of the assay since this is considered undetectable. Many patients want to see a 0, and they are distressed when they hear that the value is <0.1 or <0.03 ng/mL. A discussion about the expected laboratory value avoids unnecessary stress for the patient and his family when he gets the results. Discussion of urinary control is an important part of this ofﬁce visit. The patient may be distressed that control hasn’t returned as quickly as possible or to the extent he had hoped by this point in time. He may have frequency or urgency and considerable urinary leakage, especially with activity. Most patients don’t remember they have been told that it may take weeks to months to regain urine control. Reassurance on expectations about regaining urinary control may or may not help at this time. The patient is usually feeling well and is anxious to have urine control so that he can get on with his life and put the prostate surgical experience behind him. There is a small subset of patients who are extremely happy about their urination postoperatively. Men who have had signiﬁcant lower urinary tract symptoms owing to an enlarged prostate may actually have signiﬁcantly improved urination following a radical prostatectomy (6). Improved American Urological Association (AUA) symptom and symptom problem scores for those patients who previously had moderate or severe symptoms can favorably impact the quality of life of these patients. Patients who are experiencing stress incontinence can fall into several categories. There are men who are not extremely upset about leaking a few drops of urine with stress. They feel that they can deal with the occasional drops of urine that are released with certain movements—coughing, sneezing, laughing. They feel it is a small price to pay to have had their cancer removed. These men verbalize that urine control is “so much better” than they anticipated. Other men may not be happy with the fact that they are leaking drops of urine with activity; they know they have to be patient until their body heals further. They are optimistic that their urine control will return to normal in time. There is a third group of men who are very distressed with the fact that they are leaking any urine, no matter how small the amount. For this latter group, the postoperative recovery period is one of extreme unhappiness and distress. They admit that they were told that they would leak urine, but they believed that this would not happen to them. These patients are difﬁcult to work with because reassurance does not usually help. The only help they want is knowing when their urination will be normal, as well as actually getting complete control of urination back ASAP. The issue of impotence should be addressed at this postoperative appointment. Again, the patients had been told that impotence was something that would occur and that it could take a year or longer to regain spontaneous erections. For men with a favorable pathology who have regained urine control, their focus now is on the fact that they have not regained erections. Some patients elect to try an oral agent (such as Viagra®), but they often comment that using medication (or other methods) to gain an erection is not natural. A review male anatomy and surgical techniques may help the patient to understand why the impotence has occurred and why it will take time to see whether spontaneous erections will return. It may not make the patient happy, but at least he does have an understanding of why it has occurred. If the patient does not respond to Viagra, he may be unwilling to move to a different treatment method to have an erection. Information regarding the methods that are available should be given to the patient when he is ready. Many men have difﬁculty

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discussing the issue of impotence. Their perception is that they should not be concerned with such issues. They may say things like “I know this shouldn’t be important at my age” or “you must think that I’m a dirty old man to be thinking about this.” Reassuring the person that sexuality and intimacy are an important part of life may help the person to verbalize his frustration at not being able to have intercourse with his wife. Many men do not bring up the subject of erections. They may not be ready to deal with the subject or they may be of the era that does not discuss such topics. Asking the question allows the man to know that it is appropriate to discuss this important aspect of his relationship with his partner if and when he is ready. Erections are important to the patient’s sense of self, but they are not usually the basis of a good marriage or the ability to enjoy life. It may take a man a while to ﬁgure that out, but frank discussions between the husband and wife may help clarify this area. It is important that a man recognize that intercourse is an important part of life, yet an intimate sexual relationship does not depend entirely on the physical act of intercourse.

WHAT IF THE PATHOLOGY NEWS ISN’T GOOD? The reason that a patient selects a radical prostatectomy is to cure the prostate cancer. There are patients who will undergo the surgery, but their pathology is not favorable. They may have a positive surgical margin or cancer in the lymph nodes or seminal vesicles. They may need to undergo additional treatment. In addition to all the issues that patients have following surgery such as returning to their normal strength, incontinence, and impotence, these patients are now faced with the need for additional treatment. They will again experience a variety of fears, anxieties, and concerns. These may be similar to the ones they experienced at diagnosis, but now they have been through what was supposed to “cure” them of their cancer. The patients often want to start treatment as soon as possible, since they seem to have been living with the cancer diagnosis for what seems like forever. These patients may ask why they can’t start radiation therapy until they have good urine control or how will chemotherapy affect their healing process. They will again start the information process, to learn what they can expect. When the patient begins additional treatment for prostate cancer, a relationship with the new physician and staff needs to be established. Some of the patients may continue to call the urologist and staff with questions or concerns. These patients feel comfortable with the relationship with the team who got them through the original treatment. As the comfort level with the new team is established, the patient will build a new relationship to help him through the treatment. If the patient elects not to begin treatment at this time, a routine of surveillance needs to be established. The patient needs to realize the importance of following up with the physician to monitor his status. Changes in PSA blood tests or examinations will indicate that the patient needs to begin the adjuvant treatment.

ONGOING PATIENT ISSUES A percentage of patients will form strictures at the site of the anastamosis of the bladder neck and the urethra following a radical prostatectomy. These strictures are a result of healing, and it is impossible to predict in most cases when they will occur. Patients have been prepared for urinary incontinence, but now they are faced with the opposite problem. They have difﬁculty urinating and emptying their bladder, and they have a very weak stream. Dilation of the stricture may help the problem, but some men

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need repeated dilations or removal of the scar tissue in the operating room to correct this problem. These patients are again forced to live with and deal with uncertainty. Each patient responds differently to this problem; he should be instructed to monitor urination and report any signiﬁcant, persistent changes to try to avoid an emergency situation of retention. Occasionally a patient may have other unresolved issues that necessitate follow-up with the urologist. When urine control does not return to an acceptable level, the patient may need to consider a medication such as oxybutynin (Ditropan®) to relax the bladder and decrease urinary leakage. If that does not improve the situation, either a pelvic sling or a urinary sphincter is an option to consider. Having to consider additional surgical options may be difﬁcult, but these options will help the patient to attain a satisfactory quality of life in relation to urinary control. Another patient issue is lack of response to sildenaﬁl (Viagra). If the issue is important, patients will call to discuss other options that may be available. Medicated urethral system for erection (MUSE), vacuum devices, injection therapy, or combinations of these therapies are other options that should be considered. However, since each of these options involves more than taking a pill, patients often comment that all the treatment options for erectile dysfunction do not seem “natural.” The person’s motivation to resume intercourse determines whether they will try other options to achieve an erection. When and how often the patient is to be seen and evaluated and how often PSA levels need to be ascertained will depend on the pathology and the MD preference. This routine varies from physician to physician, and it should be communicated to the patient at his postoperative appointment. Patients often comment that they experience anxiety from the time the blood is drawn for the PSA assay until the time they hear the results. This anxiety can be less the further the patient is from treatment, but for some men, the anxiety remains high no matter how long ago the surgery was. They have lived through a cancer diagnosis, and they always have at the back of their mind that the cancer can recur. For a percentage of patients who have had a radical prostatectomy, the PSA may begin to rise at some point in time in the years following surgery. Although patients know this intellectually, they are devastated when it does occurs. They are again forced into an uncertain situation, one that requires facing the fact that the cancer has returned. The patient and his partner are again confronted with learning and deciding on further treatment that will alter their quality of life.

SUPPORT GROUPS A variety of support groups are available for the patient who has been diagnosed with prostate cancer. The mission of the group can range from supplying information to serving as a means of support, or it can be a combination of both. Although a support group can be beneﬁcial, many men will not attend. Men do not often share intimate areas of their lives with others, and they may fear having to share their fears and anxieties with a group of people they do not know. The real value of a support group may be hearing what men who have been through a variety of treatment options have experienced while going through the treatment. It also helps to recognize that while a man’s cancer is a unique experience for him, there are similarities that each prostate patient experiences. Receiving help and giving help to other men in a similar situation may give a sense of meaning to the man’s life.

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CONCLUSIONS The type of relationship that a patient forms with a urologist and his/her staff is important. He puts his trust in a doctor at a very vulnerable time in his life. The education, support, and help that he receives at this time can help the patient deal with the reality of cancer, cancer surgery, and the side effects that may occur. There are few things as rewarding as hearing from a patient that “this (the whole experience) wasn’t so bad . . . I dealt with it with your help and your support . . . I’ve moved on with my life.”

REFERENCES 1. Jemal A, Murray T, et al. Cancer statistics, 2003. CA: Cancer J Clin 2003;53:5–26. 2. Catalona WJ, Resnick MI, Williams RD. Treating early prostate cancer: difﬁcult decisions abound. Patient Care Nurs Pract 1999;Oct:18–37. 3. Gray RE, Fitch MI, Phillips C, Labrecque M, Klotz L. Presurgery experiences of prostate cancer patients and their spouses. Cancer Pract 1999;7:130–135. 4. O’Rourke ME. Decision making and prostate cancer treatment selection: a review. Semin Oncol Nurs 2001;17:108–117. 5. Davison BJ, Goldenberg SL, Gleave ME, Degner LF. Provisions of individualized information to men and their partners to facilitate treatment decision making in prostate cancer. Oncol Nurs Forum 2003;30:107–114. 6. Schwartz EJ, Lepor H. Radical retropubic prostatectomy reduces symptom scores and improves quality of life in men with moderate and severe lower urinary tract symptoms. J Urol 1999;161:1185–1188.

27

Prostate Cancer A Survivor’s View

Nathaniel K. Cooke

If you are a young 57-yr-old, in excellent health (deﬁned as running 3–4 miles a day, playing tennis three times a week, and weighing 150 pounds), to be told that you have prostate cancer and, on top of that, advanced prostate cancer, is very hard to accept. So, I didn’t accept it, at least for a while. My wife, Nancy, accepted it and thereby carried most of the burden for a long time. 1. It is my ﬁrm belief that the wife, or caregiver or signiﬁcant other is often overlooked and in need of support during a serious illness.

The prostate-speciﬁc antigen (PSA) test was quite new when I ﬁrst had one and even today raises controversy among some. When I went for my normal biannual physical and asked for the test, I was told that he, my doctor, only gave it to people 60 yr old or older. I insisted on having one and in the conference after the physical was told that he would have called for the test anyway because of the size and feel of my prostate. Quite a few of my acquaintances who have been diagnosed with prostate cancer said that it was only found as a result of the PSA test. A week after the physical, I called the doctor and was told that I had a PSA of level 25 ng/mL and that I should see a urologist. No explanation of the meaning of the reading, just go see a urologist. This was, by the way, the last time my doctor spoke to me on a professional basis. At this point, Nancy and I were blessed by the presence of our daughter-in-law, who is a physician. Although her ﬁeld is not urology, she was able to start gathering information for Nancy and me to study. This was of the utmost importance, because at that time the Internet was quite new and finding good, up-to-date information about prostate cancer was difﬁcult. She also came with us to see the urologist who ﬁrst handled my case and was with us through the whole ordeal after that. Everything went well during that ﬁrst visit. The urologist performed the biopsy and, on my way out, told me that even without the results from the pathologist, he was con-

From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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vinced that I had prostate cancer. We agreed that I would have a bone scan prior to getting the results of the biopsy in order to condense the time frame for conﬁrming his conviction. By this time, Nancy was beginning to be really afraid about what was going on, and even I was beginning to have some worries. She insisted on going with me for the bone scan, to the point of sitting near me and reading to me while the scan was in progress. In fact, apart from my ﬁrst physical, she was with me every step of the way. 2. I would recommend to all those going through prostate cancer, or any other lifethreatening disease, that the spouse, or caregiver or signiﬁcant other, attend all meetings with doctors and accompany the survivor to all tests. This is important for gathering information, the survivor not being ﬁt for remembering too much, and also giving the caregiver an important role in handling the disease.

Nancy and I went to lunch after the bone scan; when we arrived back home, we found our daughter-in-law had left a message that the results of the scan were negative. How she had found this out we never asked, but it was the ﬁrst positive piece of news we had received since that ﬁrst PSA test. Several days later, when I called the urologist’s ofﬁce for the results, I was told that they wouldn’t be available for another week. I don’t know what we would have done if the results were positive, and I think I understand the reason for withholding results. 3. It must be understood that waiting around for the results of critical tests is one of the most nerve-wracking periods that patients have to face. Sometimes I wonder if all doctors recognize this fact.

When we went back to see the urologist, our daughter-in-law went with us. We got the distinct impression that she was not welcome, mainly because she was knowledgable and aggressive and asked questions. We were told that the biopsy was positive, but when we asked for the Gleason score we were told that it wasn’t important. We were not given information as to the stage of the cancer. After this meeting, we all agreed that a second opinion was necessary, not to determine whether I really had cancer, but to find a urologist with whom we felt more comfortable. 4. I am sure that most doctors at major hospitals are fully capable of doing an excellent job. It is a patient’s right, and duty, to ﬁnd that doctor with whom he or she is most comfortable. It is equally important for the doctor to be comfortable with the patient.

When the dust had settled, we had found the urologist with whom we felt comfortable. He was able to tell us that, using the staging system of that time, I had a D1 cancer. He also told us that with a cancer this far advanced, the normal procedure would be external beam radiation and/or hormonal treatment. My approach while all this was going on was to tell friends, relatives, co-workers, and anyone else who would listen about my situation. I found that the support I got from these people was a very important part in what seems to have been an excellent result. I have talked with prostate cancer survivors who did not have this kind of support and found that they had a very difﬁcult time. There were no support groups, such as Man to Man or Us Too, in the Cleveland area at that time.

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At this time, my family became deeply involved in determining what therapy to select. After a lot of discussion, we decided that a radical prostatectomy was what we wanted. When we discussed this with our urologist, we were advised that under normal circumstances, if cancer was found in the lymph nodes the surgeon would sew me up and we would try another therapy. We stated that we wanted the surgery to proceed even with evidence of cancer in the lymph nodes. I think my urologist agreed to this because of my excellent health, relatively young age, and very aggressive, positive outlook. It was just as well we had this agreement. When the operation was performed, the cancer had spread to the bladder as well as the lymph nodes. It took quite a while to perform the operation, and I know Nancy was thoroughly shaken up when she heard the ﬁndings. Luckily, my son was in town and my daughter came the next day. 6. I have talked about support for the caregiver. Some of the best support Nancy received was having our daughter there to answer telephone calls and queries as to my health. That meant that Nancy could spend more time in the hospital with me and, when she got home, would be able to take her shoes off and relax.

One thing I remember most clearly was the evening of the operation when Nancy lay down beside me on the bed and hugged me. That was the support I needed most of all. Because of complications during surgery, I was in the hospital for 9 d. Although I remember feeling better every day, Nancy recalls a couple of days when I was deﬁnitely depressed. Not having been depressed during my lifetime, this was of great concern to her. Recuperation at home went smoothly, with many walks around local parks and problems with leaking catheters. I was back to work in 6 wk, and 8 wk after the operation we were off to the Galapagos Islands for a 2-wk jaunt. It was wonderful. I was put on Lupron and Eulixin immediately after the surgery, had a full course of conformal, external beam radiation 4 mo after the surgery, and a year later had an orchiectomy. This course of action was not in response to an increase in my PSA level but rather to try to prevent an increase. Whether it was all really necessary we will never know, but it seems to have worked. 7. Many survivors, when put on antiandrogen treatments, are not fully advised as to all the side effects that might be expected. In my case, the emotional swings were different from anything I had ever known, and we have anecdotal reports of depression and extremely upsetting hot ﬂashes.

The dynamics of having an advanced cancer as well as a thriving business career are hard to assess. There were a lot of changes going on at that time. I was a member of senior management and usually had a say in some of the important decisions, especially those that affected my area of expertise, manufacturing. It seemed to me that my opinion carried less and less weight as the months went by. I will admit to being a lot more emotional than I was before the operation, possibly as a result of hormonal treatments, but the feeling of being ignored or overlooked was hard to handle. I am convinced that people thought that I was going to die. The year following my diagnosis and treatments was, in fact, a superlative year for my management team, but none of that was reﬂected on me. After 2 yr of frustration turning into anger, I asked for and got an early retirement package that was quite beneﬁcial to me.

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The next 2 years were spent doing consulting and generally enjoying myself. I did attend some support group meetings, which led into the next phase of my life. One day, in the summer of 1996, I received a call from a social worker saying that the American Cancer Society was interested in starting a Man to Man Prostate Cancer Support Group in the Cleveland area and asking if I would be interested in setting it up. One thing led to another, and soon I was in Jackson, Mississippi, attending training to become a group facilitator. Little did I know at the time that this would include setting up the group, coordinating the operations, and thoroughly immersing myself in Man to Man for the next 7 years. It has been a wonderful experience! I thank the American Cancer Society for the opportunity to share in its efforts. Working with a member of the Society, I started contacting doctors, nurses, social workers, and survivors to help set up the program. This included sending letters out to professionals all around the Cleveland area to ask for input and advice. The response was overwhelming. In very short order I had an advisory board of 20 people that counseled me on how to approach the task. I not only received counsel from these people, they also were willing to give of their time to help make the program a success. 8. I must say here that the support I have received from the medical community of Cleveland is absolutely amazing. These people are all putting in long hours at their jobs and are still willing to give of their time and knowledge to help survivors in need. Thank you!

Our ﬁrst meeting, in January 1997, was held on a night when the wind chill factor was –36° and the snow was blowing parallel to the ground. Three survivors and an intrepid doctor were in attendance. Within 4 months, we had started another group on the other side of town. The following January, thanks to an excellent article in the local paper, we had to double the number of meetings to four. At this time, there are three groups meeting once a month. Let me talk about support groups for a few minutes (or paragraphs). Common knowledge says that men are not willing to get up and talk about themselves, their erectile problems, or their problems with incontinence. Given the right situation, it is my experience that it is often more difﬁcult to shut them up, even with women in the room. It did, however, take a while to reach that level of conﬁdence. Running a support group took a great deal of learning for me. Several people taught me a lot about how to run a support group meeting. I had run meetings in my former jobs, but there was a different slant to these. It took me a long time to realize that if I wanted frank answers from the participants, I would have to talk frankly about myself. One skill I had to learn was how to draw people out, so that both the speakers and others in the group could get a better understanding of the speakers’ problems. By remaining silent after they had ﬁnished talking or by asking a follow-up question, I was better able to achieve this. I had to learn as much as I could about prostate cancer, its treatments, and its side effects, to answer the basic questions often were asked of me. Here I was lucky, because by attending all monthly meetings and listening to the speakers, I did manage to increase my knowledge considerably. Certain doctors have taken it upon themselves to treat these meetings as teaching opportunities. These people were and are greatly admired by the participants. The goals and objectives of the Man to Man Prostate Cancer Support Group are:

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Program Goals • Patient education—to provide accurate information about diagnosis and treatment options for prostate cancer. • Support—to provide support, encouragement, and solutions to common problems associated with prostate cancer. • Awareness—to promote awareness of prostate cancer as a major health concern for all men.

Program Objectives • To bring together prostate cancer patients, physicians, and other health care professionals. • To provide a forum for men to learn about diagnosis and treatment options through presentations, written materials, and videos. • To create a consistent meeting environment that encourages men and their wives to discuss their concerns openly and honestly and to share solutions to common problems. • To provide opportunities to promote a greater public understanding of prostate cancer, particularly the need for early detection and treatment.

I assume that these goals are similar to those of other prostate cancer support groups. In most cases, one of the hardest decisions a newly diagnosed survivor has to make is what to do. This used to be easier than it is now because in most cases, the urologist would recommend the treatment and the survivor would accept that decision. Commonly, surgeons suggested surgery and radiologists recommended radiology. Things have changed. Much to the chagrin of many survivors, the good doctors will explain the options and side effects and tell the survivor to make a decision. When survivors come to me questioning this approach, I agree that it seems strange that the urologist, having been paid all that money, would leave the decision to the survivor, but I also tell them that it is the correct approach. Although the urologist should learn as much as possible about the survivor’s feelings, the survivor should learn as much as possible about the options and make the decision based on his and his family’s priorities. When I receive a call from a newly diagnosed survivor, I listen as much as I can. I ﬁnd out his age, PSA level, and Gleason score. (Many have not been told by their urologist, or they have been told and they didn’t hear.) As much as possible I try to assure him that the end of the world has not yet arrived and that in most cases he has the time to make that decision that best meets his needs. I do describe the various options and side effects but stress that I cannot and will not tell him what to do. Because of my history, I can tell them the side effects of most options, but I urge him to come to the meetings in order to hear other people’s experiences. This is, I think, one of the main advantages of the support groups. We have had several survivors come to three meetings a month for 2 mo to hear speakers on different topics and to hear other survivors talk about themselves. Quite often, the meetings will be followed up by telephone calls requesting more information. We also suggest second opinions, not to conﬁrm the cancer but to get more input on the options. From the meetings and discussions they ﬁnd the decision-making process easier. The support groups meet the requirements for patient education and support. We can, of course, only educate and support those who attend the meetings. Trying to get more people involved, especially during the decision-making phase, is still a problem. We seem to be attracting more people as the word gets out. This is thanks in part to the doctors who suggest to their patients that support groups are a positive approach to

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handling cancer. Others are referred by the American Cancer Society, and some come as a result of advertisements in the local press. Through the American Cancer Society, we have outreach programs to talk about early detection for prostate, breast, and colorectal cancers. Judging by the results locally, we still have a long way to go. In other parts of this volume I’m sure that the high incidence rate and death rate among African Americans has been discussed. It is a major problem, especially in Cleveland, which has a large African-American population. So far, we have met with limited success in reaching out to this community, but we see new opportunities and will do our best to take advantage of them, Over the years since my prostate cancer was diagnosed I have been very fortunate to meet survivors and their families who have faced this disease with courage and good humor. They have been willing to share their stories with any who are interested to hear them. They have been in the hospital to be with the wife or caregiver when a new survivor has gone in for treatment. Some have helped in the running of the support groups and in training other people to help in this way. One gets to love these people very quickly. I have got to know many professionals in the medical profession who, as stated earlier, have been ready and willing to spend time after a busy work day or on Saturdays and Sundays to help these survivors and their families. My admiration knows no bounds for these people, and I hope to know and work with them for many years ahead. I have also worked closely with members of the American Cancer Society. Their zeal and dedication to the prevention, early detection, and coping with all cancers is amazing. I thank them all for allowing me to help. Over the years, I have been given the opportunity to exercise skills I knew I had and to develop skills that were new to me. I am sure that I am a more caring individual then I was before this all started. Over the last 11 years, my wife and I have been closer than we were before the diagnosis. All this has been a great gift to me, as have the 11 cancer-free years since my diagnosis. I must add that without the constant support of my wife Nancy, I doubt that any of this could have happened. In his book HEAD FIRST; The Biology of Hope and the Healing Power of the Human Spirit, Norman Cousins wrote: Life is the ultimate prize and it takes on ultimate value when suddenly we discover how tentative and fragile it can be. The essential art of living is to recognize and savor its preciousness when it is free of imminent threat or jeopardy. Amen

28

Prostate Cancer A Spouse’s View

Nancy L. Cooke

When my husband Nat’s cancer was diagnosed in 1991, the prostate-speciﬁc antigen (PSA) test was new, the Internet was new, there were no prostate cancer support groups, and I had no idea about how to access a medical library. But I did have the strong feeling that I had to educate myself as well as I could about this disease, partly as a way of not being an emotional wreck, and also because it might make a difference in the health and long life of my partner of 33 yr. On the plus side, our local library had a decent book that described staging and explained the Gleason score. Much more important, we are lucky enough to have a daughter-in-law who is a physician and who was living in Cleveland at that time. She became our guide, advocate, and interpreter, an invaluable help through this stressful period. She attended appointments with us, talked to her urologist friends, read up on prostate cancer herself, and called family conferences at which we all helped Nat decide what to do. One of the important lessons we learned from her was that we had to feel comfortable, conﬁdent, and trusting of whatever physician we were dealing with; furthermore, it was a good idea to get several physician opinions, and it was incumbent on us to make a choice of the best treatment and then the best doctor to serve our needs. I think most patients today are aware of this empowerment, but we had neither of us ever really been sick, and we were reluctant to take charge in that way. Thus, Nat having decided on surgery, we found the doctor who suited us and who would listen to us. It helped enormously that he had a nurse who was always available, as time went on, to answer questions, give practical advice, and be a warm, concerned, and friendly presence. Nat’s hospitalization was longer than most, but his recuperation was speedy, and all the while we felt well supported, both by the professionals and by our family and friends. The support of our son, his wife, and our daughter felt like a cocoon in which I was safely wrapped to get through this ordeal. A curious situation with which I had to deal while Nat was still in the hospital, his cancer having been staged at D1, was the way in which his company’s nurse responded From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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to this news: she advised me not to let powers in the company know the seriousness of Nat’s illness. Nat said “no” to that idea, so the word was out. In the end, she may have been justiﬁed, as I do think Nat had a harder time dealing with the power structure after he went back to work; he eventually chose early retirement over working under unhappy conditions. That choice also has something to say about cancer survival: what once seemed terribly important no longer seems to matter. You choose your ﬁghts, and the one against cancer trumps a lot of the day-to-day problems that once seemed so signiﬁcant. Nat went on to have radiation treatments, which he dealt with on his own; I attended his ﬁrst appointments, felt comfortable with the doctor, and having met with the nutritionist, tried to do my part in making sure his diet was appropriate for whatever side effects Nat might suffer. He came through this well, and we entered the period we’re still happy to live in: a remission of Nat’s cancer. We always experience some anxiety over Nat’s semiannual PSA tests, but so far, so good. About a year after Nat’s surgery, we attended a support meeting for cancer survivors (all kinds of cancer, not just prostate) and their families at a local hospital. There were some very sick people there, and we learned a lot about how people cope and also about how difﬁcult waging this war can be. I suddenly realized I’d been through this whole experience without acknowledging the reality of cancer in our lives, how scary and upsetting and emotionally draining it is. It was a distressing and emotional experience, but, support groups being what they are, I came away the stronger for it. The ongoing awareness of mortality that cancer survival highlights certainly hit both of us, in lots of ways. I think we were extremely fortunate that it brought us closer together: somehow, we were going to beat this disease as best we could, and do it hand in hand. I think knowing that our sex life, as we’d known it, was history, was something that we shared regret and nostalgia over, but not sorrow—we had too many good times to savor. This sense of carpe diem has changed our priorities in lots of ways; we are more attentive to family and dear friends and less concerned with external commitments. For example, as a violinist, I had for years given or participated in solo recitals, which are part of being a musician, but which take a tremendous amount of time in preparation and, more important, personal concentration on one’s own needs. Nat had always been supportive of these events in practical and also emotional ways, but still, they were occasions focused on me. After Nat’s cancer, my desire and need to do these programs disappeared; life is more relaxed, and I have no regrets, but there is that difference. When Nat was asked to start a Man to Man support group in Cleveland, I thought it was a great idea and much needed, but since I was and am still working, I didn’t see my own role as having much impact. However, since Nat encouraged the participation of wives, it didn’t take long before I found many women who needed to talk, ask questions, or receive support of one kind or another at these meetings. One of my goals has been to try to provide for men and women going through this experience the equivalent of my daughter-in-law’s presence: how to be their own advocates; how to deal with the medical world without feeling like second-class citizens (or traitors if they change doctors); how to access and understand material that often seems to be written in a foreign language; how to prioritize questions to ask professionals; how to weigh treatment options; and, above all, how to evaluate options vis-à-vis quality of life and life itself. Some important but more work-a-day tips for patients and their wives have been:

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• • • • • •

Making sure they have a list of questions to ask before an appointment. Making sure they understand the answers. Getting a doctor or nurse to write down difﬁcult terms or medical descriptions. Taking notes or taping interviews if possible. Being aware that access to medical records is a patient’s right. Making sure that they have copies of any important reports or information they might want to present to another professional. • Making sure they have something to read or occupy themselves with during the inevitable long waits that go with medical encounters these days.

For the women whom I’ve come to know at meetings, and for those I speak to on the phone, there are some common concerns: • How can I convince him he’s still a man and I still love him even if he’s impotent? • How can I convince him he’d better choose a treatment, any treatment, rather than spend months on the fence? • He doesn’t want to talk to anyone about it, what can I do? • I’ve been being so strong for him, but I’m having a hard time. • I don’t know what I’d do without him; we haven’t ever talked about death or made plans.

None of these concerns has an easy answer, and all a facilitator can do is listen, relate a similar experience, urge better communication between husband and wife, and/or recommend professional counsel. One of the things I’ve learned from Nat over the past several years as I’ve watched and listened to him do this kind of work is the importance of being a more or less impartial sounding board; he really listens, and people really appreciate that. (Sometimes this takes hours!) Some ongoing concerns: 1. The sensitivity of the medical system to each individual. A good example is the waiting period patients experience before getting test results. Although there may be no solution to this problem, the waiting period can be agony for patients and their families, and at least sometimes this agony could be avoided by a quick phone call from the doctor or someone on his staff. Another example is the vast difference in outlook between the doctor who diagnoses cancer daily and the patient for whom this diagnosis at ﬁrst seems like a death sentence. One has to hope for a sensitivity on the part of the physician at this moment, however busy he/she may be and no matter how many times the diagnosis has been made. 2. For the patient and his family, the importance of understanding that each person’s experience with this disease is unique and that decisions about treatment must be made based on an individual’s situation, not because a friend or relative chose a particular course. Another concern about patient understanding is the bottom line issue. For example, I have heard patients relate that they chose radiation because it wouldn’t interfere with work schedules. Although time away from work is a concern, it makes me crazy to think that someone doesn’t put long-term survival at the top of the priority list and then ﬁgure out the logistics. Choose radiation because it is the best for you, not because it’s convenient! Likewise, choose long life over sex, if it comes to an either/or, which in most cases it doesn’t. 3. Another concern is about those who may or may not become prostate cancer patients, but who balk at a blood test and a digital exam. Often these are persons who are not comfortable in any medical situation, and it’s difﬁcult to know how to change that, except to offer more free screenings in settings that are not overwhelming.

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4. Finally, a concern about the support group and recurrent cancer: We now have a fair number of members who are facing this challenge, and I do think it has been addressed well, with programs devoted to chemo, palliative care, and so on. But when a patient is beginning to suffer lots of bone pain or whatever, he stops coming to support meetings and we often lose track, unless a family member calls. This is of course a matter of patient choice, but I would like us to be sure to be there for anyone we know who is dying.

From time to time the various Man to Man groups have entertained motions to exclude wives from either a sensitive session (say, about impotence or incontinence) or just a general meeting once in a while. The vote, by men and their wives, has consistently been a resounding “no” to exclusion. I say hurrah for inclusion and for being in this complex but fascinating business together.

III

ADVANCED DISEASE

29

Management of PSA Recurrence After Deﬁnitive Therapy for Prostate Cancer Ilia S. Zeltser, Richard K. Valicenti, and Leonard G. Gomella

INTRODUCTION The ﬁeld of prostate cancer has witnessed dramatic improvements in the management of localized prostate cancer over the last 20 yr. It is thought that stage migration, probably because of screening efforts, combined with improvements in treatment modalities, is largely responsible for these outcomes. The initiation of prostate-speciﬁc antigen (PSA) screening has led not only to earlier detection of prostate cancer but also to detection at a lower stage of disease (1). Many more patients are now candidates for a deﬁnitive local therapy. However, there are patients with localized prostate cancer treated with curative intent who will have either rising PSA levels or clinical progression and who will require a secondary intervention (2). It is estimated that approx 134,000 patients receive localized disease treatment annually, and of those as many as 50,000 may experience PSA recurrence (3). Biochemical failure is defined as a detectable PSA level after deﬁnitive local therapy without clinical evidence of local or distal recurrence and is the most common pattern of disease progression. However, there is a subset of patients with biochemical recurrence after radical prostatectomy who on long-term follow-up do not exhibit PSA or clinical progression (4). Shinghal et al. (4) identiﬁed 14 patients (8.8% of biochemical recurrences) with a detectable PSA level after radical prostatectomy, yet without clinical or PSA progression at a mean follow-up of 10.3 yr. They described a benign clinical course in these patients, obviating the need for adjuvant therapy. PSA-only recurrence may precede clinical recurrence by 3–5 yr and may require secondary treatment (5). The analysis of patients in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database revealed a 21.7% rate of secondary cancer treatment within a mean of 3 yr after deﬁnitive local therapy (6). After adjustment From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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for differences in follow-up and in demographic and clinical characteristics, the lowest rates of secondary treatment were seen in the radical prostatectomy group, followed by radiotherapy (34% higher) and cryotherapy (88% higher). The type of secondary treatment varied between the groups as well. Whereas the cryosurgery and radical prostatectomy groups received two or three types of secondary treatment, most patients in the radiation group were treated with some form of androgen deprivation therapy, if a secondary treatment was required. The management of biochemical recurrence and the timing and type of secondary therapy after PSA failure following definitive local therapy remain controversial. In this chapter we review definitions of PSA recurrence after primary local therapy for prostate cancer and discuss the timing, available options, and results of adjuvant interventions.

DEFINING PSA RECURRENCE Serial PSA measurements provide the most reliable method of detecting tumor recurrence, since cancer progression rarely occurs without PSA elevation. Time to PSA nadir after primary treatment depends on the type of therapy used. After brachytherapy, the time interval to achieve PSA nadir may be as long as 2 or 3 yr, and up to 35% of patients may experience PSA “bounce” at 12–24 mo (7). Following primary cryoablation, a nadir is usually achieved after a gradual PSA decline for about 6–12 mo. Issues concerning PSA recurrence following surgery and radiation therapy are addressed in detail in this chapter. The commonly used Currently used PSA assays are unable to detect PSA levels <0.1 ng/mL; thus most clinicians use these assays in routine clinical care. The PSA level should become <0.1 ng/mL at 3–4 wk after radical prostatectomy; this allows for clearing of PSA from the serum. A detectable PSA level beyond 4 wk postoperatively suggests residual or unrecognized micrometastatic disease. However, a speciﬁc PSA threshold to deﬁne failure after radical prostatectomy is unclear, and no consensus value exists. Moul et al. (8) deﬁned PSA failure after prostatectomy by two PSA measurements of ≥0.2 ng/mL, or a single measurement of ≥0.5 ng/mL. Two values of ≥0.4 ng/mL were reported as failure by Kattan et al. (9). Amling et al. (10) used multiple PSA cut points to deﬁne biochemical progression after radical prostatectomy. PSA progression-free rate after radical prostatectomy was determined using several PSA cut points, including 0.2, 0.3, 0.4, and 0.5 ng/mL or greater. Although signiﬁcant number of patients with PSA levels < 0.4 ng/mL did not progress, >70% of patients with PSA of ≥0.4 ng/mL revealed PSA progression, and 80% either progressed or required treatment. Therefore, this PSA level may be a good choice to deﬁne PSA failure, since a large number of patients with this PSA value will exhibit biochemical progression. Development of ultrasensitive PSA assays allows lower detection thresholds, to 0.01–0.04 ng/mL (11). These new assays may lead to detection of recurrence after radical prostatectomy 6 mo to 2.3 yr earlier than conventional assays (10,12). Some suggested that PSA produced by periurethral glands may produce a false-positive result when ultrasensitive assays are used. However, 61–83% of the serum samples from patients who had undergone a radical cystoprostatectomy with or without urethrectomy had a serum PSA of 0.00 ng/mL when analyzed by three different ultrasensitive PSA assays (13). Therefore, a measured value after prostatectomy by an

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ultrasensitive assay may reflect PSA produced by residual benign or malignant prostate tissue, rather than periurethral glands. Overall, since the evidence is currently lacking that earlier therapy is superior to therapy administered after detection of PSA recurrence by conventional PSA assays (i.e., >0.1 or 0.2 ng/mL), clinical utility of ultrasensitive assays is uncertain. Reverse transcriptase polymerase chain reaction (RT-PCR) to detect circulating PSA-producing cells by amplifying PSA mRNA was initially developed clinically at Thomas Jefferson University. This extremely sensitive method has been used to predict potential surgical failures prior to radical prostatectomy and also to define failures postoperatively (14). The significance of this assay is not fully established in clinical practice. In September 1996, The American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Panel issued guidelines for PSA following after radiation therapy (15). They recommended that PSA recurrence after radiotherapy be deﬁned as three consecutive increases in PSA above whatever nadir is achieved, with follow-up every 3 or 4 mo for the ﬁrst 2 yr and for 6 mo thereafter. The use of three rather than two, consecutive rises in PSA reduces the risk of falsely diagnosing biochemical failure when two consecutive PSA values show one or two rises followed by a decline and a subsequent failure to rise. The date of failure is deﬁned as the midpoint between postirradiation PSA nadir and the first of three consecutive increases. PSA nadir is also considered to be a strong prognostic variable similar to pretreatment PSA, but no absolute level was considered valid for separating successful from unsuccessful radiation therapy treatments. It is important to note that a limitation of the ASTRO deﬁnition is that it does not take into account the time to PSA increase or its magnitude. When applying the ASTRO deﬁnition of biochemical failure to practical application, Kestin et al. (16) reported a 73% sensitivity, 76% speciﬁcity, and 75% overall accuracy in predicting clinical failure. Their data suggested that an overall increase in PSA to 3 ng/mL above the post-treatment nadir yielded the highest accuracy (87%) in predicting clinical failure. Shipley et al. (17) assessed rates of freedom from biochemical failure using the ASTRO criteria in 1765 men treated by external beam radiotherapy. The PSA failure-free rates at 5 and 7 yr after treatment for patients presenting with PSA < 10 ng/mL were 77.8 and 72.9%, respectively. PSA nadir was seen as a strong prognostic factor. When analyzing patients who achieved post-treatment nadirs of ≤0.5, 0.6–0.9, 1.0–1.9, and ≥2.0, the 5-yr PSA failure-free survival rates were 83, 68, 56, and 28%, respectively. The way “freedom from prostate cancer” is deﬁned in the literature can signiﬁcantly affect the interpretation of all prostate cancer treatment outcomes. Direct comparison of biochemical failure rates after radiotherapy and radical prostatectomy is difﬁcult, if not impossible, because the progression-free rate is highly dependent on the PSA cut point used (18,19). Gretzer et al. (19) demonstrated an apparent improvement in probability of being free of disease from 68 to 90% when applying the ASTRO criteria to a series of patients treated with radical prostatectomy. Other investigators showed a similar effect when the application of the ASTRO deﬁnition enhanced the PSA failure-free survival from 59 to 78% at 10 yr (20). Critz (18) observed a signiﬁcant difference in the disease-free survival rates calculated by a PSA cutoff of 0.2 ng/mL and the ASTRO consensus deﬁnition in the same group of men. He concluded that comparing diseasefree survival rates of various treatments may be misleading unless calculations are performed using a standard deﬁnition of disease failure.

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PREDICTING PSA PROGRESSION Multiple clinical and molecular predictors have been used to identify those patients who are at high risk of PSA progression after deﬁnitive therapy for prostate cancer. Tumor volume, DNA ploidy, Gleason score 4/5, cancer volume, extracapsular extension, margin status, preoperative PSA level, race, angiogenesis, and malignant cytologic washings have all been shown to inﬂuence the risk of progression (19–30,33). With the advent of new immunohistochemical techniques, several molecular biomarkers of PSA progression have been described (31–38). The cell cycle proteins p27kip1 and Ki-67, the tumor-suppressor gene p53, the cell adhesion protein CD44, and the proto-oncogene bcl-2 have all been shown to have an independent prognostic value in the prediction of clinical recurrence, and therefore may help distinguish patients who will beneﬁt from adjuvant therapy. Using clinical parameters, Partin et al. (39) developed an equation to predict the likelihood of progression. Gleason sum and margin status were utilized to calculate the relative risk of recurrence (Rr), which categorized the postprostatectomy patients into three groups (low, intermediate and high) (39). Rr = (0.061 × PSAST) + (0.54 × postoperative Gleason score) + (1.87 × specimen conﬁned)

Bauer et al. (40) combined clinical and molecular biomarkers to create a model for calculation of a relative risk of recurrence. They analyzed age, race, preoperative PSA, postoperative Gleason score, pathologic stage, and nuclear grade, as well as expression of p53, Bcl-2, and Ki-67 in 132 patients who underwent radical prostatectomy (40). PSA, race, p53, Bcl2, Gleason score, and nuclear grade were used in the model. Rr = exp [90.70 × race] + [0.79 × PSA (4.1–10)] = [1.34 × PSA (>10)] + [0.91 × organ conﬁnement] + [0.65 × p53 (1.2+)] + [1.45 × p53 (3,4 +)] + [0.70 × Bcl-2]

Organ-conﬁned disease is designated as 0 and non-organ-conﬁned disease as 1. Race is designated as 1 for African Americans and 0 for Caucasians. If p53 and Bcl-2 were expressed, the variables were designated as 1, and if no expression was seen, they were deﬁned as 0. Partin et al. (41) combined three presurgical clinical variables—PSA level, clinical stage, and Gleason score—in logistic regression analysis to predict pathologic stage in 800 patients treated for localized prostate cancer at Johns Hopkins Hospital. Nomograms were generated to help clinicians in therapeutic decision making. Later, these were updated using clinical and pathologic data from 4133 men treated surgically at three different institutions (42). In validation analysis, 72.4% of the time the nomograms correctly predicted the probability of a pathologic stage to within 10%. Unfortunately, the ﬁnal pathologic stage may not be the best endpoint since some patients with organ-conﬁned disease will develop a recurrence, and those with extracapsular extension can remain disease-free (43). Kattan et al. (44), utilizing postprostatectomy PSA level as the endpoint of treatment efﬁcacy, developed a model that predicts 7-yr treatment failure among men with localized prostate cancer treated with radical prostatectomy. The model has also been validated using clinical data from 6754 patients from multiple international institutions, and most predictions showed high concordance with actual observations (45).

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To increase the prognostic accuracy of nomograms in prediction of disease recurrence, Kattan et al. (46) combined postoperative information with the preoperative variables. In addition to preoperative PSA level and Gleason score, they analyzed prostatic capsular invasion, surgical margin status, seminal vesicle invasion, and lymph node status. Using a validation sample, a good accuracy was demonstrated with the sample area under the receiver operating characteristic curve of 0.89. Furthermore, the nomograms were validated by analysis of clinical and pathologic data from 2908 patients treated by a radical prostatectomy at multiple centers (47). A high level of predicted accuracy was observed, with the overall area under the receiver operating characteristic curve of 0.80. Han et al. (48) created a prediction model, based on analysis of pre- and postoperative variables in 2091 men treated with radical prostatectomy for clinically localized carcinoma of the prostate. The model integrates a downward stage migration and an improved surgical outcome over time (secondary to early detection in the PSA era) and provides biochemical recurrence-free survival probability. However, the authors acknowledged that the nomograms developed would need further validation from other institutions, since the patient population represented mostly White men treated by a single surgeon. Predictive nomograms were also developed for patients treated with external beam radiation and brachytherapy (49–51). D’Amico et al. (51) used pretreatment PSA, biopsy Gleason score, and American Joint Commission on Cancer clinical stage in 1654 patients treated with radiation therapy or radical prostatectomy to develop a nomogram predicting the time to post-therapy PSA failure (51). In a nomogram predicting the probability of remaining free from biochemical recurrence for 5 yr after three-dimensional conformal radiotherapy, Kattan et al. (49) studied the clinical parameters of 1042 men with prostate cancer. PSA failure was deﬁned by ASTRO criteria. Clinical stage, Gleason score, pretreatment PSA level, whether neoadjuvant androgen deprivation was administered, and delivered radiation dose were considered. When the predictive accuracy of the model was statistically tested, it discriminated signiﬁcantly better than chance. Later, pretreatment nomogram for predicting the probability of remaining recurrence-free for 5 yr after brachytherapy was created (50). Patients who received neoadjuvant hormonal therapy were excluded from analysis. Failure was defined as any administration of post-treatment androgen deprivation, clinical relapse, or three PSA elevations. Validation of the model revealed a concordance index of 0.61–0.64, which is lower than indices for surgery and external beam radiotherapy nomograms. Overall, these nomograms are useful but not perfect, especially in view of continued risk of biochemical failure after 5 yr following local therapy (52). They are helpful to physicians and patients in making reasonable decisions about treatment and in identifying patients at high risk of recurrence who may beneﬁt from established adjuvant therapies or to identify those patients who should be registered on clinical trials.

PATIENT EVALUATION FOR PSA RECURRENCE Deﬁning the site of cancer recurrence after local therapy is important in the selection of appropriate therapeutic intervention, because patients with local recurrence only can be cured by secondary localized treatment. PSA kinetics after primary local therapy have been used to distinguish men with local recurrence from those with distant spread, as noted previously by Pound and associates (53). Partin et al. (54) demonstrated that

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PSA elevation within 2 yr after radical prostatectomy was associated with distant recurrence. Also, 94% of men with local recurrence had PSA velocity of < 0.75 ng/mL/yr at 1 yr after prostatectomy, compared with only 46% of patients who went on to develop metastatic disease. Other investigators also showed signiﬁcant difference in PSA doubling time in patients with local recurrence and those developing distant disease (55). Although PSA velocity did not appear to be predictive in deﬁning local recurrence in men treated with external beam radiotherapy, PSA doubling time of <1 yr was predictive of distant recurrence (56). Rapidly rising PSA after primary local therapy is highly suggestive of distant metastases. Digital rectal examination (DRE) has been shown to be unreliable in evaluation of patients for local recurrence, since more than 50% of men with biopsy-proven local recurrence have an unremarkable examination (57). However, serial examinations may be more accurate than a single one (58). Foster’s group (59) compared DRE with transrectal ultrasonography in 43 patients with persistently elevated PSA levels and negative bone scan. Ninety-ﬁve percent of patients with biopsy-proven cancer recurrence had positive transrectal ultrasonography, whereas DRE was able to detect cancer in 45% of men. The authors concluded that a combination of PSA and transrectal ultrasound is more effective than DRE alone to detect local cancer recurrence. The sonographic features associated with local tumor recurrence after primary cancer treatment have been well characterized. Sonographic visualization of a hypoechoic mass in a prostatic bed, especially posterior or posterolateral to the anastamosis, and loss of integrity of the retroanastomotic fat plane correlate strongly with the ﬁnding of recurrent or residual tumor following radical prostatectomy (60,61). Local recurrences after radiation therapy are seen as hypoechoic lesions in the periphery of the gland, which usually appears hyperechoic with distorted tissue planes (62). The role of transrectal ultrasound-guided (TRUS) biopsy in detection of local recurrence is controversial. Connolly et al. (63) performed 156 US-guided prostatic fossa biopsies in 114 men with elevated PSA and negative bone scan after radical prostatectomy. Biopsy proved local recurrence in 53.5% of cases, and 66% of men had recurrence at the anastomotic site. TRUS appeared to be >90% sensitive but was not speciﬁc. The authors concluded that TRUS is a useful adjunct to PSA and DRE in detection of local recurrence. However, Koppie et al. (64) showed that positive anastomotic biopsy did not predict an improved outcome after radiotherapy following radical prostatectomy. In their series, 33 and 34 patients received radiotherapy for biochemical failure and biopsy-proven local recurrence, respectively. The 3-yr recurrence-free survival in patients treated for biochemical failure was 49%, compared with 39% in men treated for a positive biopsy. Only preradiation PSA of ≥1 ng/mL and seminal vesicle invasion were signiﬁcant independent predictors of biochemical failure. Although the anastomotic biopsy was associated with a longer time to salvage radiotherapy, the delay did not inﬂuence the disease-free outcome. Thus, anastomotic biopsy may not be necessary for detection of local recurrence in surgically treated patients. The utility of ultrasound-guided biopsy after primary radiotherapy to detect local recurrence is also unclear. Cheng et al. (65) acknowledged that the pathologic interpretation of postirradiation needle biopsies is a diagnostic challenge, especially in quantiﬁcation of radiation effect. They evaluated needle biopsy specimens in 29 men with cancer recurrence after radiation, who later underwent salvage prostatectomy. The Gleason score was underestimated in 35% of cases and overestimated in 14%. There was also a major discrepancy in degree of radiation effect between prostatectomy spec-

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imens and biopsies. Svetec et al. (66) created a model to study prostate biopsy as an indicator of treatment response for therapies in which the prostate gland remains in situ. Prostate glands of 90 patients undergoing radical prostatectomy underwent sextant biopsies immediately after removal of the gland. In 45.6% of cases a false-negative biopsy result was observed. The authors concluded that their results challenge the diagnostic accuracy of needle biopsies after therapies that leave the prostate gland in situ. Since cryosurgery results in the destruction in the internal architecture of the prostate, the TRUS ﬁndings are very difﬁcult to interpret (67). Parivar et al. (67) found that the internal prostatic anatomy was completely destroyed, with loss of zonal discrimination and formation of a thick capsule surrounding the prostate. Of the eight hypoechoic lesions that the authors identiﬁed on TRUS after cryosurgery, only three proved to be cancer. They found that TRUS was poor in differentiation between residual carcinoma and necrosis following cryosurgical ablation. Overall, post-treatment biopsies may be considered in patients treated with radiation and cryotherapy when salvage procedures are contemplated, as stated in the ASTRO consensus panel recommendations (68). Many patients undergo computed tomography/magnetic resonance imaging (CT/MRI) imaging and a bone scan after PSA progression following local therapy. However, the sensitivity of these studies in detecting recurrence is low. CT characteristics of prostatic fossa following radical prostatectomy have been characterized. In one study, a soft tissue density was seen in the resected bed of seminal vesicles in 88% of patients, and a transversely oriented, soft tissue density bar between the bladder base and rectum appeared in 53% of cases (69). Both of these structures can be confused with local tumor recurrence. It is not surprising, therefore, that even in a very careful CT examination, understaging can occur in as high as 41% of cases (70). Older et al. (71) measured tissue volumes in the prostatic fossa and evaluated 13 CT scans from patients with local recurrence following radical prostatectomy for the presence of six potentially discriminating criteria and also assessed their sensitivity. The sensitivities of ﬁnding asymmetric residual seminal vesicles, fat inﬁltration around seminal vesicles, inﬁltration of perirectal fat, and indistinct margins of the levator ani in the prediction of cancer recurrence were 0.68, 0.67, 0.60, and 0.50, respectively. Thus, CT scanning is not an effective technique for detecting recurrent prostate malignancy. MRI can provide excellent anatomic detail in detection of local recurrence, especially when an endorectal coil is used (72–74). Compared with adjacent muscle, the recurrent nodules appear isointense on T1-weighted images, and hyperintense on T2-weighted images and enhance with gadolinium administration. Silverman and Krebs (74) reported a 100% sensitivity and a 100% speciﬁcity in conﬁrming local recurrence of prostate cancer after radical prostatectomy. Recently, MRI imaging evolved to magnetic resonance spectroscopic imaging (MRSI), a noninvasive method of detecting small molecular markers (the metabolites of choline and citrate) within the cytosol and extracellular spaces of the prostate; it is performed in conjunction with high-resolution anatomic imaging (75). MRSI has a potential to provide a direct measure of the presence and spatial extent of prostate cancer after therapy, as well as a measure of the timecourse of response. The accuracy, sensitivity, and speciﬁcity of MRSI diagnosis of tumor localization have been reported to be as high as 84.2, 81.3, and 100%, respectively (76). Furthermore, the MRSI external surface coil provides the same detection accuracy as the endorectal surface coil, thus eliminating patient discomfort (77). However, further studies are needed to evaluate the role of MRSI in detection of localized recurrence.

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Bone scans in patients with rising PSA after failure of local therapy are rarely positive. Patients with newly diagnosed prostate cancer and serum PSA of < 10 have less than a 2% chance of having a positive bone scan (78). In patients with PSA failure after radical prostatectomy, the probability of a positive bone scintigram is < 5% until PSA levels increase to 40–45 ng/mL, and the trigger PSA level was the single best predictor of the bone scan result in a multivariate analysis (78). In a study by Kane and associates (79), 127 men with PSA progression had a bone scan. Of the scans, 12 (9.4%) were positive. The patients with true-positive bone scans had an average PSA at the time of the of 61.3 ± 71.2 ng/mL. The PSA velocity, calculated from the PSA levels determined immediately before the radiographic studies, averaged 22.1 ± 24.7 ng/mL/mo. Only two patients with a positive bone scan had a PSA velocity of < 0.5 ng/mL/mo. This suggests a limited yield for bone scan, especially with low PSA levels in the setting of PSA recurrence (79). Positron emission tomography (PET) using radiotracer 1-fluoro-2-deoxyglucose (FDG) may be used to detect local recurrence and lymph node metastases in patients with biochemical failure after primary local therapy (80,81). Since a high rate of glycolysis is characteristic of malignant tumor cells, FDG PET can detect tumor foci of multiple histologic types including prostate cancer. However, local recurrence in the prostate may be difficult to visualize, because the bladder will usually reveal intense FDG activity (filtered FDG is not reabsorbed by the nephron) and may obscure the lesion. Picchio et al. (81) detected local recurrence and distal metastases in 50% of patients using [11C]choline PET scanning and concluded that it is superior to FDG PET. Further investigation is needed to define the role of PET scanning in prostate cancer imaging. The conjugated monoclonal antibody cytogen 356 (ProstaScint) has been used in the detection and localization of prostate cancer recurrence (82). The antibody is a murine immunoglobulin produced by fusion of murine myeloma cells with the spleen cells of mice. The antibody is linked to a 111Indium isotope tracer, which then can be localized when patients are scanned using the single-photon emission computed tomography technique. ProstaScint (In-111-capromab pendetide) does not have crossover sensitivity to other tissue and thus is useful in early detection of recurrent prostate cancer after deﬁnitive therapy. Sodee et al. (83) found scintigraphic evidence of cancer recurrence in the prostatic bed of 14 patients with rising PSA after radical prostatectomy. Elgamal et al. (84) performed 136 scans in 100 patients with biochemical recurrence following a deﬁnitive prostate cancer treatment. Patients had an average PSA of 55.9 ng/mL; local recurrence alone was identiﬁed in 42.6% of patients and lymph node metastases in 48.5%. The sensitivity of ProstaScint scan was 91%, if biochemical failure is deﬁned as the gold standard of cancer recurrence. However if biopsy is used as the standard of disease recurrence, the sensitivity decreases to 89%. ProstaScint scans appeared to have a minimal role in identiﬁcation of bone metastases, with a sensitivity of only 57%, if a bone scan is used as the gold standard. At lower PSA levels (0.1–1.0 ng/mL), Petronis et al. (85) showed that ProstaScint scan was positive in 60% of cases and positive overall in 70.6 % of men with postprostatectomy recurrence. However, only 22% of cases showed an isolated recurrence in the prostatic fossa. Furthermore, the incidence of a false-negative scan of the prostatic fossa has been reported to be as high as 19%. The ability of ProstaScint imaging to predict response to salvage radiotherapy in men who failed primary surgical treatment was assessed by Kahn et al. (86). They followed PSA levels in 32 men with prostate cancer who had failed radical prostatectomy

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and had undergone a full-body In-111- capromab pendetide scan at 13 mo after the men received salvage radiotherapy. Seventy percent of men with no activity outside of the prostatic fossa achieved a complete response to salvage radiation, compared with 22% of men with a positive scan outside the prostatic fossa and pelvis (p = 0.0225). No other variables in their analysis showed a signiﬁcant association with the complete response rate. In summary, ProstaScint imaging may be useful in detection of local recurrence after primary therapy for prostate cancer; however, it is not as sensitive in diagnosis of bony metastasis. Further studies are needed to evaluate the ability of ProstaScint scanning to predict response to salvage therapies.

WHEN TO TREAT PSA RECURRENCE Timing of treatment for PSA-only recurrence after deﬁnitive local therapy remains controversial. Before 1999, the natural history of PSA recurrence had not been extensively studied. Then Pound et al. (53) published their data on 1997 men who had undergone a radical prostatectomy at Johns Hopkins Hospital from April of 1982 to April 1997. Using various prognostic factors, the authors created algorithms for prediction of metastasis-free survival. The mean follow-up was 5.3 yr (range: 0.5–15 yr), and 17% (344 patients) have been followed up for ≥10 yr. Of these, 315 men (15%) demonstrated biochemical recurrence, including 304 men who received no treatment until the development of documented metastases. Of 304 men, 34% have developed clinical metastases. The median actuarial time to development of metastases following PSA recurrence was 8 yr. The actuarial median time to death after development of metastatic disease was slightly less than 5 yr. The overall 10- and 15-yr metastasis-free survival rates were 87 and 82%, respectively, with 10- and 15-yr cancer speciﬁc survival rates of 94 and 91%, respectively. PSA recurrence of ≤2 yr, Gleason score >8, and PSA doubling time of < 10 mo were associated with decreased metastasis-free survival. This important study demonstrated that of the patients diagnosed with PSA elevation, many remained free of metastases for an extended period after initial PSA recurrence while treated with observation only. However, there are factors that limit applications of the study to the general patient population. The algorithms may not be relevant to patients treated with radiation, and all the patients represented selected referrals to one institution known for their expertise in radical prostatectomy. Furthermore, the mean followup was only 5.3 yr, and only 17% of men were followed for 10 yr, with only 5% developing metastatic disease. The data against deferred treatment after biochemical recurrence come from the two studies comparing immediate vs delayed hormonal therapy after cancer progression (87,88). In a Medical Research Council (MRC) Trial in the UK, 938 men with locally advanced or asymptomatic metastatic prostate cancer were randomized either to immediate treatment (orchiectomy or gonadotropin-releasing hormone analog) or to deferred androgen ablation until an indication occurred. Patients on deferred treatment progressed more rapidly to M1 disease and had earlier onset of metastatic pain. Also, the death rate in those with M0 disease in the immediate therapy group was 54%, compared with 70% in the deferred hormonal treatment arm. Pathologic fractures, spinal cord compression, ureteral obstruction, and development of extraskeletal metastasis were twice as common in the deferred arm. Cancer-speciﬁc survival was lower in the deferred hormonal therapy group, especially in patients with M0 disease. Although the results point to the beneﬁts of earlier treatment, a direct application to patients with

534

Zeltser, Valicenti, and Gomella Table 1 Potential Approaches to PSA Recurrence Following Deﬁnitive Local Therapy

Radical prostatectomy: observation, salvage radiation, salvage radiation plus hormonal therapy, hormonal therapy, investigational (e.g., chemohormonal, vaccine, novel compounds, others) External beam radiation therapy: observation, salvage prostatectomy, cryotherapy, cryotherapy with hormonal therapy, hormonal therapy, investigational (e.g., salvage brachytherapy, vaccines, high-intensity focused ultrasound, others) Brachytherapy: observation, salvage radical prostatectomy, hormonal therapy, other investigational approaches Cryotherapy (as primary therapy): observation, salvage radical prostatectomy, hormonal therapy, other investigational approachess

PSA-only recurrence is difﬁcult, because men with M0 cancer usually have more advanced disease than patients with PSA-only recurrence. Messing et al. (88) reported the results of a Southwest Oncology Group (SWOG) trial (7808) that randomized 98 men with stage D1 prostate cancer and treated by radical prostatectomy and pelvic lymphadenectomy to receive immediate antiandrogen therapy with either goserelin or bilateral orchiectomy, or to be followed until disease progression. Serum PSA was available after prostatectomy in 93 of 98 men. PSA levels were undetectable in 80% of these patients. After a median follow-up of 7 yr, survival was signiﬁcantly better in men treated with immediate antiandrogen therapy, and of 18 men who died in the observation group, 16 died of prostate cancer and the other 2 had distal metastases. The cancer-speciﬁc death rate in the immediate treatment arm was 4.3% compared with 30.8% in the deferred arm. Recurrence-free survival was signiﬁcantly better in the immediate therapy group than in the observation group (p < 0.001). The results favor early hormonal therapy in D1 disease; however, the same beneﬁts in men with PSA-only recurrence are unclear. Further investigation with prospective randomized trials is needed to establish the proper timing for initiation of secondary therapy.

MANAGEMENT OF PSA RECURRENCE AFTER RADICAL PROSTATECTOMY The issues concerning observation are addressed in the previous section. Hormonal therapy for PSA recurrence following radical prostatectomy is addressed later in the chapter. See Table 1 for a summary of approaches.

Adjuvant Radiotherapy Radiation therapy can be used in both an adjuvant fashion and as a salvage treatment in surgically treated men with prostate cancer. Adjuvant radiotherapy has been studied in men with high risk of PSA recurrence secondary to adverse tumor characteristics following radical prostatectomy. However, the beneﬁt of adjuvant radiotherapy in these men is yet to be established in a randomized prospective study. Our group assessed the efﬁcacy of early adjuvant radiation therapy for men with pT3N0 prostate cancer treated with radical prostatectomy (89). Men treated with adjuvant radiation 3–6 mo following radical prostatectomy were compared with matched

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Table 2 Results of Selected Recent Studies of Immediate Adjuvant Postoperative Radiation Therapy Study by primary author

Year

No. of patients

5-yr recurrence-free survival rate (%)

Kalapurakal Choo Petrovich Mayer Peschel et al.

2002 2002 2002 2002 2000

76 73 423 29 13

60 88 69 85.2 85 (3-yr)

controls, who were just observed. The patients were matched according to preoperative PSA (<10 vs >10 ng/mL), Gleason score (<7 vs ≥7), seminal vesicle invasion, and surgical margin status. Our median follow-up was 41 mo. A matched-pair risk ratio for cumulative risk of PSA relapse (increase > 0.2 ng/mL) was determined An 88% reduction in the risk of PSA recurrence associated with adjuvant radiation was observed. The 5-yr freedom from PSA relapse rate for patients undergoing adjuvant radiation was 89%, compared with 55% in men undergoing radical prostatectomy alone. Other recent studies reported improvement in PSA recurrence-free survival rates in patients with pathologic T3 prostate cancer treated by radiation in the adjuvant fashion following radical prostatectomy (Table 2). A clear survival benefit in patients with a high-risk prostate cancer treated with radical prostatectomy and adjuvant radiotherapy is yet to be demonstrated. The result of the SWOG study 8794, which randomized patients with stage C disease to adjuvant radiation vs observation, should clearly define the utility of this approach (www. SWOG.org). The difficulty in treating patients with biochemical recurrence after radical prostatectomy with salvage radiotherapy lies in not knowing whether the cancer recurrence is located in the radiation field or whether distant micrometastases are present. Overall, 30–70% of patients undergoing salvage radiotherapy, with total doses of 60–70 Gy, will reach an undetectable PSA level. The result can be durable, and PSA can remain undetectable or at least stable in the next 2–5 yr, thus offering a chance of cure in 50% (90). De la Taille et al. (91) identified predictive factors for success of salvage radiotherapy in 52 patients radiated for PSA recurrence after radical prostatectomy. On a univariate analysis, an age < 65 yr, Gleason score ≥ 8, stage pT3, a detectable nadir PSA after RT, and the absence of hormonal therapy were associated with a lower biochemical progression-free survival, yet only the nadir PSA after radiotherapy and Gleason score remained independent predictive factors on multivariate analysis. Recently, predictors of biochemical outcome after salvage conformal radiotherapy following radical prostatectomy were identified in a larger group of patients (92). One hundred and fifteen patients with rising PSA after radical prostatectomy received salvage three-dimensional conformal radiotherapy alone or with neoadjuvant androgen deprivation. The authors evaluated tumor-related and treatment-related predictors of PSA failure with a medium follow-up of 42 mo. Absence of extracapsular extension, negative/close margins, and seminal vesicle invasion were used to identify a cohort of patients with a favorable outcome after salvage radiotherapy alone or after salvage radiotherapy and androgen deprivation. All three risk factors were given equal weight in the analysis. Among the patients treated with radiotherapy alone (n = 70), the 4-yr

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PSA recurrence-free survival was 77% for those with zero risk factors and 20% for those who had one or more risk factors. In patients treated with both neoadjuvant androgen deprivation and salvage radiotherapy, the 4-yr PSA recurrence-free survival rate was 91% for those without risk factors and 43% for those who had one or more risk factors. PSA was not an independent predictor of biochemical outcome after salvage radiotherapy in the radiation-only group. Multivariate analysis limited to 70 patients treated with radiation alone revealed that negative margins, absence of extracapsular extension, and presence of seminal vesicle invasion were independent predictors of PSA failure after radiotherapy. Interestingly, neoadjuvant androgen deprivation did not improve a 4-yr PSA failure-free rate in patients with positive margins, extracapsular extension, and no seminal vesicle invasion. However, neoadjuvant androgen deprivation did improve PSA recurrencefree survival when one or more of these risk factors were absent. Cadeddu et al. (93) reported disappointing results when they examined 82 men who underwent salvage radiotherapy for PSA failure or local recurrence after radical prostatectomy. The patients were followed for at least 2 yr. The 5-yr PSA recurrence-free rate after radiation was 10%, and only 21% (87 of 82) of the patients maintained an undetectable PSA for at least 2 yr. None of the patients with Gleason score ≥ 8, positive seminal vesicles, or positive lymph nodes had undetectable PSA for ≥2 yr following radiation, and only 1 of 16 patients with PSA recurrence within 1 yr of RRP was disease-free at 2 yr. As the interval to PSA recurrence increased, the likelihood of responding to radiotherapy increased to 44% if initial recurrence was detected at ≥5 yr after prostatectomy. The initiating PSA did not predict response to therapy, nevertheless PSA for those responding to radiotherapy was 1.7 ng/mL, compared with 3.1 ng/mL in those who had PSA recurrence. Other groups reported varying rates of recurrence-free survival in patients treated with salvage radiotherapy (Table 3). One reason for this discrepancy in results may lie in the radiation dose used and the PSA levels at which the treatment was initiated. The total radiation dose used by Caddeadu and associates (93) and the mean PSA level when salvage radiation was initiated could have partially explained the adverse results. We have evaluated the significance of preradiation PSA on dose response in patients treated with adjuvant and salvage radiotherapy after radical prostatectomy (94). In the Jefferson series, 86 consecutive patients with pT3N0 prostate cancer underwent postoperative irradiation with doses ranging from 55.8 to 70.2 Gy (median 64.8 Gy). The median follow-up time was 32 mo from time of irradiation. For the 52 patients with an undetectable preradiotherapy PSA level, the 3-yr biochemical no evidence of disease (bNED) rate was 91% for patients irradiated to ≥61.5 Gy and 57% for those irradiated to lower doses (p = 0.01). For the 21 patients with preradiotherapy PSA levels of >0.2 and ≤2.0 ng/mL, the 3-yr bNED rate was 79% for patients irradiated to ≥64.8 Gy and 33% for those irradiated to a lower dose (p = 0.02). The preradiotherapy PSA level was the most significant predictor of improved bNED survival (p < 0.01), and actuarial analysis or radiation dose grouped with preradiotherapy PSA levels found higher radiation dose to be significant (p < 0.05). Many other investigators reported similar results with respect to radiation success with a lower PSA level and a higher total radiation dose to the prostate bed (95–98). Overall, to achieve maximum success, the initiating PSA should be <2.0 ng/mL, and the treatment dose should be at least 60–70 Gy. The ASTRO consensus statement recommends delivery of at least 64 Gy of radiotherapy before the PSA level is >1.5 ng/mL (99).

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Table 3 Results of Selected Reports of Salvage Radiation Therapy for PSA Recurrence Following Radical Prostatectomy Study by primary author

No. of patients

Mean follow-up (yr)

Progression-free survival (%) and modifying data

Zelefsky (106)

42

2

Valicenti (94)

21

2.7

Nudell (95)

68

3

Garg (96)

66

3

McCarthy (146)

37

3

Do (147) Morris (148) Schild (145) Catton (149)

60 48 27 59

3 3 3 5

Crane (150)

41

5

Cadeddu (151) Medini (152) Syndikus (153)

82 40 26

5 >5 10

74 if PSA < 1.0 ng/mL 71 if PSA > 1.0 ng/mL 79 if RT > 64.8 Gy 57 if RT < 64.8 Gy 60 if PSA < 1 ng/mL 25 if PSA > 1 ng/mL 78 if PSA < 2 ng/mL 31 if PSA > 2ng/mL 70 if rising PSA 30 if persistent PSA 50 47.5 48 30 if PSA < 2.0 ng/mL 5 if PSA > 2.0 ng/mL 48 if PSA < 2.7 ng/mL 0 if PSA > 2.7 ng/mL 10 27 54

Data from ref. 104.

Although prospective randomized data comparing adjuvant and salvage radiotherapy are lacking, there are multiple retrospective reports showing higher recurrence-free survival in patients treated in an adjuvant fashion. Vicini et al. (98) found a significant difference in 5-yr biochemical control rates in 61 men treated with adjuvant (n = 38) and salvage (n = 23) radiation after radical prostatectomy. Patients treated with adjuvant radiotherapy achieved a 67% biochemical control rates compared with 16% in the salvage group. Nudell et al. (95) demonstrated that adjuvant radiotherapy was an independent predictor of durable response to radiation after radical prostatectomy. However, in their analysis patients receiving therapeutic radiotherapy with a low serum PSA (<1 ng/mL) had equivalent outcomes to those receiving immediate radiotherapy. Thus, in the presence of minimal disease (as seen by detectable, but very low PSA) salvage radiotherapy was as effective as adjuvant radiotherapy. Similarly, McCarthy et al. (101) showed no difference between patients who received adjuvant and those receiving therapeutic radiotherapy when those who received therapeutic radiotherapy had an initially undetectable PSA after surgery. Also, Peschel et al. (102) compared adjuvant vs salvage radiotherapy in 66 consecutive patients with high-risk prostate cancer treated with radical prostatectomy. Patients treated with adjuvant RT had a statistically improved biochemical control, but not disease-free survival (91% vs 73%, p = 0.09). We adopted a policy of recommending adjuvant radiotherapy after radical prostatectomy in patients with a high risk of PSA recurrence (Gleason score ≥ 8, high-volume disease, stage T2c

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or higher, and positive margins). We irradiate with a dose of 65–70 Gy to achieve a maximum therapeutic effect. Should hormones be added to adjuvant radiation therapy to improve outcomes? The role of androgen deprivation in patients receiving adjuvant and salvage radiotherapy after radical prostatectomy will be further deﬁned when RTOG completes its two ongoing randomized trials (RTOG P-0011 and RTOG 96-01). The details of these trials are available at RTOG.org and are reviewed elsewhere (103). RTOG 96-01 combines postoperative radiation therapy with oral Casodex (150 mg) vs a placebo, and RTOG 0011 compares adjuvant radiation therapy alone with adjuvant radiation plus androgen blockage to a group of high-risk patients with a >50% risk of PSA progression. In the absence of the anxiously awaited prospective data, is there any support for the combined adjuvant and radiation approach? In a retrospective analysis by Corn et al., patients in RTOG 8531 who received postop radiotherapy alone were compared with men who also received hormone therapy with the postop radiotherapy. In this analysis, there was a slight improvement in long-term disease control based on PSA, but no clear beneﬁt on local control or overall survival (reviewed in ref. 104). Another issue concerning postoperative radiation concerns the potential for morbidity. The introduction of three-dimensional conformal radiotherapy (3D-CRT) has minimized the potential morbidity associated with postoperative radiation. Severe (grades 3 and 4) gastrointestinal (GI) complications are now rare, and the rate of urinary stricture formation has decreased to 5–10% (105). Zelefsky et al. (106) evaluated complications of 3D-CRT following radical prostatectomy. Ninety-three percent had minimal to no (grade 0–1) acute genitourinary (GU) toxicity, and only 7% experienced grade 2 symptoms. Low late morbidity was seen as well. The 2-yr actuarial risks of grade 2 or higher late GI and GU toxicity were 5% and 9%, respectively. The 2-yr actuarial risk of transient aggravation of stress incontinence was 19%, but in 66% of these patients, the radiation-induced symptoms resolved to baseline during the ﬁrst year after completion of radiotherapy. However, it is difﬁcult to estimate the true incidence of late radiationinduced symptoms from this study, since the follow-up was too short. Katz et al. (92) reported good tolerance to 3D-CRT in 115 patients followed for 42 mo after salvage radiotherapy. Approximately 23% of patients had no acute urinary toxicity, whereas 53 and 21% had grade 1 and 2 toxicity, respectively; 3% experienced grade 3 toxicity, and one patient discontinued treatment after dilation of a bladder neck contracture. In this study, 47 and 16% of patients had grade 1 and 2 Gl toxicity, respectively. The 4-yr actuarial rates of late grade 2 and 3 GU toxicity were 9 and 10%, respectively. Among patients with grade 2 late GU toxicity, 67% had hematuria with conﬁrmed radiation cystitis. The 4-yr actuarial risk of late grade 2 Gl toxicity was 12% and consisted of moderate radiation proctitis. Among the 53 patients who were completely continent before radiation, 17% developed long-term stress urinary incontinence, but only 2% required pads. For the 25 patients requiring pads before radiotherapy, 12% improved their continence. In a prospective randomized trial, Van Cangh et al. (107) analyzed the potential inﬂuence of adjuvant radiation on postprostatectomy continence. One hundred patients were randomized to receive adjuvant radiation (n = 48) and to be followed expectantly (n = 52). The mean follow-up was 24 mo. The irradiated patients received 60 Gy of external radiotherapy with 18-MV photon beams between 12 and 16 wk postoperatively. No signiﬁcant difference in urinary continence was observed. Seventy-seven percent of the patients in the irradiated group and 83% in the surveillance group were

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totally dry. The absence of major incontinence complications in these series may be attributed to the moderate dose of total radiation and inadequate follow-up.

MANAGEMENT OF PSA RECURRENCE AFTER RADIATION THERAPY Observation is addressed above in the section, When To Treat PSA Recurrence? Hormonal therapy will be addressed below.

Salvage Radical Prostatectomy Although salvage radical prostatectomy has been shown to result in a long-term disease-free survival (108,109), it did not ﬁnd widespread application because of a significant associated morbidity. To limit complications of this difﬁcult procedure and to maximize its beneﬁt, a careful patient selection is required. Several investigators evaluated the role of preoperative serum PSA as a predictor of success of salvage surgery (110–112). Rogers et al. (113) reported that all 9 patients undergoing salvage prostatectomy with preoperative serum PSA of ≥10 ng/mL or had invasion of the seminal vesicles and lymph node metastasis, compared with 9 of 11 patients with PSA < 10 ng/mL, who had organ-conﬁned disease. Gheiler et al. (110) attempted to identify the predictors of maximum outcome in patients undergoing salvage surgery following radiation failure. They retrospectively reviewed the results of salvage prostatectomy and cystoprostatectomy in 40 patients with PSA recurrence following radiation. Preradiation clinical stage and pathologically organ-conﬁned disease were found to be statistically signiﬁcant predictors of diseasefree survival. Seminal vesicle invasion and positive lymph nodes were the worst pathologic prognostic factors. Although the preoperative clinical staging was not a predictor of disease-free survival, a trend toward a better survival in patients with preoperative clinically localized disease was seen in the analysis of subgroups of patients based on a preoperative PSA cutoff of 10 ng/mL. Of the patients with a preoperative PSA ≥ 10 ng/mL, 73.7% had biochemical recurrence compared with 31.6% of patients with PSA ≤ 10 ng/mL. Of note, cystoprostatectomy had only a 30% biochemical disease-free rate, which was probably owing to more advanced disease in this group, necessitating anterior exenteration in the ﬁrst place. In fact, radical cystoprostatectomy was selected in patients with extensive local recurrence, urinary incontinence, hemorrhagic cystitis, or concomitant bladder cancer. Overall, 75% of patients experienced no complications related to their salvage surgery, and 50% were completely continent. Of the patients undergoing radical prostatectomy, 16.7% had early postoperative complications, which included a deep venous thrombosis, a vesicorectal ﬁstula, a ureteral ﬁstula, epididymitis, and prolonged ileus. Other investigators reported similar complications. Shekarriz and associates (114) report a 12.5% incidence of bladder neck contracture and a 50% incidence of urinary incontinence. In their experience, rectal injuries during salvage radical prostatectomy resulted from attempts to dissect the prostate bluntly off the rectum through a fibrotic and often obliterated plane. They emphasized sharp dissection between the prostate and the rectum and placement of a diverting colostomy in cases of significant rectal lacerations. The incidence of rectal injuries has been reported to be as high as 19% (115) in early series; however, over the years its frequency has decreased signiﬁcantly, and recent reviews found it to be as low as 0–3% (110,116). Almost all patients experience

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erectile dysfunction following salvage radical prostatectomy or cystoprostatectomy, necessitating further therapy. The role of salvage radical prostatectomy in patients with locally recurrent prostate cancer following 125I brachytherapy was examined by Brenner et al. (117). They performed salvage prostatectomy in 10 patients with locally recurrent disease 77 mo after the seed implantation. When relapse occurred, all men had palpable prostatic nodules that were conﬁrmed to be cancer. Three of the 10 patients had organ-conﬁned residual prostate cancer, whereas the other 7 patients had extraprostatic disease, including 4 men with positive surgical margins. After a mean follow-up of 30 mo, seven patients had rising PSA levels consistent with locally persistent and/or metastatic disease, and two of them developed clinically evident bone metastasis. Two men with organ-conﬁned disease and one with extracapsular tumor extension had no evidence of persistent local or metastatic disease at 31–50 mo following surgery. Based on their experience, the authors did not advocate a widespread use of salvage prostatectomy in this setting. Further work is needed to deﬁne the role of surgery in patients with locally persistent or recurrent prostate cancer following brachytherapy via the new transperineal template technique. It appears that ideal patients selected for salvage radical prostatectomy should have a clinically organ-confined disease, low PSA (< 10 ng/mL), and excellent performance status. All potential complications of the procedure should be discussed with patients in advance, emphasizing possible postoperative incontinence, bladder neck contracture, and erectile dysfunction. Patients should also be well informed on the possibility of a radical cystoprostatectomy with urinary diversion and placement of a diverting colostomy in cases of rectal injury and should give consent for these procedures preoperatively.

Salvage Cryotherapy Cryosurgical ablation of the prostate represents another method of salvage therapy for patients with PSA recurrence after radiation therapy. In recent years, technologic advances in cryosurgery allowed for a more rapid and more controlled freezing, by which a real-time monitoring of the ice ball formation with ultrasound and temperature sensors enhances the accuracy of tissue destruction, prevents freezing of the adjacent organs, and therefore limits the morbidity of the procedure. Smaller needles and ice balls have also enhanced safety. The utilization of continuous urethral warming has decreased urethral sloughing and postoperative obstruction. The mechanism by which cryosurgical tissue destruction occurs is not well understood; however, both the freeze and the thaw processes are integral for cell death (118). Centers of excellence, which have a large clinical experience with cryoablation of the prostate, have reported a good cancer control with this salvage treatment. At Columbia University, 38 patients with biochemical recurrence (PSA > 0.3 ng/mL) following radiation therapy underwent salvage cryosurgery (119). All patients received neoadjuvant androgen deprivation for 3 mo prior to cryotherapy. A urethral warming system was used in all patients. Biochemical recurrence-free survival was 86% at 1 yr and 74% at 2 yr. Their complications included rectal pain in 39.5% of patients, urinary tract infection in 2.6%, scrotal edema in 10.5%, hematuria in 7.9%, and incontinence in 7.9%. A very low rate of incontinence in these patients may be owing to continuous urethral warming during freezing cycles. Of note, no patient developed urethral sloughing or urinary retention. Although the cancer recurrence rate is low in this series, it is

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difﬁcult to estimate whether cryosurgery ablated all the prostatic tissue, since no postcryosurgery prostate biopsies were done. In fact, when Pisters et al. (120) examined radical prostatectomy specimens after cryoablation in seven patients with clinical stage T3 disease, they found that all seven patients had focal areas of viable normal prostate glands and three of seven had residual prostate cancer in the surgical specimen. However, only one patient had a positive surgical margin and biochemical failure at a mean follow-up of 22.6 mo, thus demonstrating that in a subset of patients, cryotherapy can result in complete destruction of the tumor and therefore can provide cure. At the M.D. Anderson Cancer Center, Izawa et al. (121) treated 131 men with biopsy-proven local recurrence following deﬁnitive radiotherapy with salvage cryoablation. The authors attempted to identify the pretreatment factors impacting on the disease-free and disease-speciﬁc survival. Androgen-independent local recurrence and preradiation clinical stage were found to impact on survival. The overall 5-yr survival rate for the entire cohort was 73%, with a 5-yr disease-free survival rate of 40%. Importantly, the 5-yr disease-free survival for patients treated with radiation and hormone therapy was 22% compared with 48% in men who received radiation only prior to cryoablation. This statistically signiﬁcant difference in disease-free survival demonstrates that the subset of patients with androgen-independent tumors will fare poorly after salvage cryotherapy. The 5-yr disease-free survival for patients with clinical stage T1 and T2 prior to radiation was 90%, whereas for men with T3–T4 disease, it was only 69%, indicating that tumors that are locally advanced prior to initial radiotherapy will not be well controlled with salvage cryoablation. Since the subset of patients cured by salvage cryotherapy is limited and the morbidity of cryoablation is signiﬁcant, patient selection for this intervention is critical. Clinical parameters predicting treatment success with salvage cryotherapy have been identiﬁed. Pisters et al. (122) found that precryotherapy PSA and Gleason score predict response to salvage cryosurgery. They found a signiﬁcant difference in 2-yr disease-free survival in patients with precryotherapy PSA < 10 ng/mL, compared with those with PSA > 10 ng/mL (74% vs 28%). For patients with a recurrent tumor Gleason score < 8, the disease-free survival was 58%, whereas for men with Gleason score ≥ 9, it was 29% (p < 0.004). Chin et al. (123) conﬁrmed these ﬁndings. They found that PSA > 10 ng/mL before cryoablation, Gleason score ≥ 8, and stage T3/T4 disease predicted an unfavorable biochemical outcome. A PSA nadir > 0.5 ng/mL following salvage cryotherapy was shown to be associated with increasing post-treatment PSA and positive biopsies (124). Overall, the best candidates for salvage radiotherapy are the patients with T1/T2 disease prior to radiation, Gleason score ≤ 8, and low pretreatment PSA. Despite the improvements, the morbidity of salvage cryotherapy can be signiﬁcant. With a median follow-up of 27 mo, Cespedes et al. (125) reported a 46% rate of incontinence and a 54% rate of signiﬁcant obstruction or retention in 28 patients undergoing salvage cryotherapy with an alternative urethral warmer device. Incontinence, however, resolved in almost 50% of patients with a follow-up of longer than 1 yr. In a different review from the same institution, patient-reported complications included incontinence in 73%, impotence in 72%, obstructive symptoms in 67%, severe perineal pain in 18%, and passage of debris in the urine in 22% (126). When health-related quality of life was measured in 112 patients undergoing salvage cryotherapy, a majority reported side effects resulting in a signiﬁcant morbidity (127). Seventy-two percent had some degree of incontinence, 85% became impotent after cryotherapy, and 26% had moderate to signiﬁcant perineal pain. Treatment without a urethral warming device was highly

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associated with urinary incontinence, perineal pain, urethral sloughing, and American Urological Associations symptom score of >20. Overall satisfaction with salvage cryoablation was 33%. In view of the potential for complications, patients must be well informed prior to deciding to undergo salvage cryotherapy. A less invasive approach to cryotherapy is now being utilized. The new ultrathin cryoprobes are placed transperineally through a 17-gage brachytherapy template. It is hoped that this technique will allow for a better cancer control with less complications. Zisman et al. (128) performed 71 primary cryoablations, 12 salvage procedures, and 2 repeated cryoablations utilizing the aforementioned approach. No ﬁstulous or major complications were observed, and only 8.3% of patients had minor complications. Prospective randomized studies are needed to assess the long-term efﬁcacy and complications of this treatment.

Salvage Brachytherapy Contemporary brachytherapy for prostate cancer now uses biplane ultrasound and ﬂuoroscopy to guide the placement of radioactive seeds in a speciﬁc pattern, which allows for a higher radiation dose to be delivered to the tumor while sparing the surrounding tissues. Grado et al. (129) assessed the effectiveness and morbidity of salvage brachytherapy in patients with biopsy-proven, locally recurrent prostate cancer following radiotherapy. Fourty-nine men underwent interactive transperineal ﬂuoroscopicguided and biplane US-guided brachytherapy with either iodine 125 or palladium 103 and were followed for a median of 64 mo. Disease-speciﬁc survival rates at 3 and 5 yr were 89 and 79%, and biochemical recurrence-free survival rates at 3 and 5 yr were 48 and 34%, respectively. Post-treatment PSA nadir was found to be a signiﬁcant predictor of PSA recurrence-free survival. A surprising ﬁnding of this review was a relatively low rate of complications. Although acute urinary symptoms such as frequency, urgency, hesitancy, and nocturia were seen commonly during the ﬁrst 3 mo after brachytherapy, only 14% of patients required a post-treatment transurethral resection of the prostate (TURP). 4% of patients developed rectal ulcers, with one patient requiring a colostomy, and 4% had gross hematuria. Incontinence developed in 6% of patients but was seen only in patients requiring a TURP, which compares favorably with other salvage modalities. It will be interesting to see whether this morbidity proﬁle is highly operator-dependent. Further study is warranted.

MANAGEMENT OF PSA RECURRENCE AFTER CRYOTHERAPY Cryotherapy is approved as a primary therapy for prostate cancer. A recent study from Bahn et al. (130) showed acceptable cancer control rates with transperineal cryotherapy. The 7-yr biochemical recurrence-free survival rates (ASTRO deﬁnition) for patients with low-, medium-, and high-risk prostate cancers were 92, 89, and 89%, respectively. The rate of positive biopsy following primary cryotherapy was 13%. Koppie et al. (131) reported higher cancer recurrence rates in 176 patients undergoing cryotherapy for clinically localized prostate cancer. Nadir PSA was undetectable in 49% of patients at 3 yr after cryoablation, and 38% of patients had a positive biopsy. Low-risk patients fared signiﬁcantly better than high-risk patients, with a 3-yr biochemical recurrence-free survival rate of 69% compared with 45% in the high-risk group. Undetectable PSA nadir and a pretreatment PSA of ≤10 ng/mL were associated with a favorable outcome following cryotherapy.

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Treatment options for patients who fail primary cryotherapy are not well documented. Bahn et al. (130) reported repeat cryoablation on 32 patients who had a positive biopsy after primary cryotherapy. For these patients, the rates of biochemical recurrence-free survival at 63 mo after repeat freezing were 68, 72, and 91% using a deﬁnition of failure of 0.5 ng/mL, 1 ng/mL, and ASTRO criteria, respectively. McDonough et al. (132) treated six patients with biopsy-proven local recurrence after cryosurgery with 66 Gy of external beam radiation therapy. Sixty-six percent of patients were rendered disease-free, and two patients developed biochemical failure as deﬁned by ASTRO criteria. No patient developed distal metastasis at a median followup of 34 mo. Complications included proctitis in two patients. Grampas et al. (133) performed a salvage radical prostatectomy in six patients 3–10 mo after failing prostate cryosurgery. They reported the presence of marked scarring and adhesions after cryotherapy but were able to avoid injury to the rectum, ureters, or other surrounding structures. The most significant postoperative complications were temporary incontinence and impotence. Future studies are needed to define cancer control and complications of these various treatment modalities for PSA failure after cryotherapy.

ANDROGEN DEPRIVATION THERAPY FOR PSA RECURRENCE Hormonal therapy remains a standard intervention for any patient treated for PSA recurrence following deﬁnitive local therapy. In the absence of deﬁned trials, as noted above, the MRC and ECOG studies of hormonal therapy for patients with D1 and D2 disease provide some guidance. These studies showed a survival beneﬁt in men who receive early hormones vs those initially observed. It is unknown whether the ﬁndings of these studies can be applied to patients with PSA-only recurrence. Furthermore, there is no consensus either on the PSA level at which to start androgen ablation or on the type of hormonal therapy that would provide a maximum beneﬁt to these men. Multiple options for androgen ablation are available to patients with metastatic prostate cancer. They include monotherapy with orchiectomy, luteinizing hormone releasing hormone (LHRH) agonist, or antiandrogen (ﬂutamide, bicalutamide, and nilutamide), as well as combination therapies with an LHRH agonist plus an antiandrogen and orchiectomy plus an antiandrogen. There is considerable debate on whether the combination therapies provide survival advantage over monotherapy treatments. In a meta-analysis of randomized, controlled trials, Caubet et al. (134) compared combination therapies with nonsteroidal antiandrogen plus an LHRH agonist or orchiectomy vs treatment with LHRH or orchiectomy alone. They demonstrated a survival benefit as well as a significant increase in time to progression with the combination therapy. However, other large studies and meta-analyses failed to show the same benefit (135,136). Eisenberger et al. (135) randomized 1387 patients with metastatic prostate cancer to treatment with bilateral orchiectomy and flutamide vs orchiectomy and placebo. There was no significant difference between the two groups in overall survival. Also, flutamide was not associated with enhanced benefit in patients with minimal disease. Similarly, members of the Prostate Cancer Trialists’ Collaborative Group, in a meta-analysis of 22 randomized trials, compared conventional castration with castration plus prolonged use of an antiandrogen such as flutamide, cyproterone acetate, or nilutamide (136). With a medium follow-up of 40 mo, no survival benefit of combination therapy

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was demonstrated. Other investigators, however, showed a small survival benefit for combination therapy in men with minimal metastatic disease (137). It is unknown whether the same benefit will be seen in patients with PSA-only recurrence. Since conventional androgen deprivation can be associated with side effects, especially for younger patients, new methods of hormonal therapy such as intermittent hormonal therapy and alternative oral therapies such as ﬁnasteride and antiandrogen have been explored. Tunn et al. (138) presented the ﬁrst prospective randomized trial comparing intermittent and continuous androgen deprivation in patients with PSA relapse following radical prostatectomy. Patients were treated with a 3-mo depot of leuprolide acetate and received ﬂare-up prophylaxis with cyproterone acetate. They were randomized to receive either intermittent (n = 82) or continuous (n = 68) androgen deprivation after 6 mo of treatment under the condition that PSA levels decreased to 0.5 ng/mL. In the intermittent group, the treatment was stopped and recommended again when PSA levels rose to >3 ng/mL. Mean follow-up was 24 mo and monthly PSA and testosterone levels were determined in all patients. The mean off-treatment times in cycles 1 and 2 were 62 and 51%, respectively. The median PSA levels decreased to 0.3 ng/mL during the treatment period of 6 mo. The median testosterone value in the intermittent group at baseline was 3.9 ng/mL and decreased to 0.3 ng/mL during treatment. In the off-treatment periods, the testosterone levels recovered to 3.2 ng/mL in 90% of patients. No statistically signiﬁcant difference was seen in time to progression between the treatment arms. Although the study demonstrates a potential beneﬁt of intermittent androgen ablation for patients with PSA relapse after local therapy, more randomized controlled trials are needed to assess the long-term efﬁcacy of this newer approach. Finasteride has been used alone and in combination with oral antiandrogens to limit androgen deprivation side effects in patients requiring hormonal therapy for prostate cancer. Andriole et al. (139) evaluated the role of ﬁnasteride in serum PSA and recurrence rates in patients with detectable PSA levels after radical prostatectomy. Patients receiving ﬁnasteride had a delayed increase in serum PSA compared with the placebo arm, but ﬁnasteride did not prevent PSA recurrence. Also, fewer recurrences were observed in ﬁnasteride group, but the difference was not statistically signiﬁcant. When ﬁnasteride was used in combination with oral antiandrogen—ﬂutamide—the combination therapy was shown to be effective and well tolerated in men with biochemical recurrence following surgical treatment (140–142). The ﬁnasteride-ﬂutamide combination therapy may be beneﬁcial in reduction of the common side effects of hormonal therapy such as anemia, loss of muscle mass, and hot ﬂashes, as well as in preservation of potency in younger patients, since these agents do not decrease the serum testosterone level. Another potential beneﬁt of this treatment may be the delay in progression to hormone-resistant prostate cancer. However, there is no evidence that oral antiandrogens alone or in combination with ﬁnasteride prolong survival, and again, randomized prospective trials with longer follow-up are needed. Adjuvant chemotherapy represents a promising development in the treatment of locally advanced and metastatic prostate cancer. Recently, a survival advantage has been demonstrated using adjuvant mitoxantrone in patients with locally advanced prostate cancer (143). Ninety-six patients with T3 or T4 disease diagnosed by CT or DRE, or metastatic stage M1 were entered into a stratiﬁed, randomized, single-institution study of hormonal therapy with an LHRH agonist and ﬂutamide, with or without four cycles of adjuvant mitoxantrone. Responses were determined by CT ﬁndings and PSA levels. Although more patients who were treated with chemotherapy had an objective tumor

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response, with 55% achieving a complete or partial response, the difference between the arms was not statistically signiﬁcant. However, in the subset analysis there was a signiﬁcant beneﬁt from adjuvant chemotherapy to patients without documented metastasis (95% vs 53%). There was no survival beneﬁt in the group receiving chemotherapy; however on the subset analysis, patients without metastatic disease and treated with mitoxantrone demonstrated a signiﬁcantly increased survival (80 vs 36 mo). In patients with metastases, there was no signiﬁcant survival beneﬁt with mitoxantrone. More evidence for the role of adjuvant chemotherapy should be provided by the SWOG trial 9921, (www.SWOG.org) investigating a combination of adjuvant chemotherapy and adjuvant hormonal therapy in patients with high-risk prostate cancer. Patients are randomized to a combined mitoxantrone plus prednisone with bicalutamide plus goserelin acetate arm or to a bicalutamide plus goserelin acetate arm. The study will evaluate the survival rates and quantitative and qualitative toxicity in the two arms.

New Modalities As scientiﬁc advances continue, new technologies are being applied to PSA recurrences. New modalities such as radiofrequency ablation and high-intensity focused ultrasound may prove to be another method of cancer control in many patients with localized prostate cancer who fail radiation. Vaccine strategies and new types of antibody, radioisotope, and molecular therapeutics are also in early study for PSA recurrences (144).

CONCLUSIONS Many patients may undergo PSA-only recurrence after initial local therapy for prostate cancer with or without evidence of clinical recurrence or progression. Management of these patients is challenging and continues to evolve in the PSA era. Initiatives to identify high-risk patients at risk for progression and to offer them neoadjuvant and adjuvant therapies continue to be investigated by several large clinical trials (103). For the patients with rising PSA following any local curative therapy, there are no large prospective clinical trials to provide the deﬁnitive management strategy. The best recommendation to the treating physician at present is to assess the risk of each patient who has PSA progression following deﬁnitive therapy for the potential complications and risk of death owing to prostate cancer. It is reasonable to offer men with PSA progression some form of therapy if the potential risks, beneﬁts, and uncertainties are understood by both the physician and the patient.

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104. Valicenti RK, Gomella LG, Perez CA. Radiation therapy after radical prostatectomy: a review of the issues and options. Semin Radiat Oncol 2003;13:130–140. 105. Amscher MS. Adjuvant radiotherapy following radical prostatectomy is more effective and less toxic than salvage radiotherapy for a rising prostate speciﬁc antigen. Int J Radiat Oncol Biol Phys 2001;96:91–93. 106. Zelefsky M, Aschkenasy E, Kelsen S, et al. Tolerance and early outcome results of postprostatectomy three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 1997;39:327–333. 107. Van Cangh PJ, Richard F, Lorge F, et al. Adjuvant radiation therapy does not cause urinary incontinence after radical prostatectomy: results of a prospective randomized trial. J Urol 1998;159:164–166. 108. Corral DA, Pisters LL, von Eschenbach AC. Treatment options for localized recurrence of prostate cancer following radiation therapy. Urol Clin North Am 1996;23:677–684. 109. Moul JW, Paulson DF. The role of radical surgery in the management of radiation recurrent and large volume prostate cancer. Cancer 1991;68:1265–1271. 110. Gheiler EL, Teﬁlli MV, Tiguert R, et al. Predictors for maximal outcome in patient undergoing salvage surgery for radio-recurrenct prostate cancer. Urology 1998;51:789–795. 111. Lerner SE, Blute ML, Zincke H. Critical evaluation of salvage surgery for radio-recurrent/resistant prostate cancer. J Urol 1995;154:1103–1109. 112. Garzotto M, Wajsman Z. Androgen deprivation with salvage surgery for radiorecurrent prostate cancer: results at 5-year follow-up. J Urol 1998;159:950–955. 113. Rogers E, Ohori M, Kassabian VS, et al. Salvage radical prostatectomy: outcome measured by serum PSA levels. J Urol 1995;153:104–110. 114. Shekarriz B, Upadhyay J, Pontes JE. Salvage radical prostatectomy. Urol Clin North Am 2001;28:543–555. 115. Neerhut GJ, Wheeler T, Cantini M, et al. Salvage radical prostatectomy for radiorecurrent adenocarcinoma of the prostate. J Urol 1988;140:544–549. 116. Cheng L, Sebo TJ, Slezak J, et al. Predictors of survival for prostate carcinoma patients treated with salvage radical prostatectomy after radiation therapy. Cancer 1998;83:2164–2171. 117. Brenner PC, Russo P, Wood DP, et al. Salvage radical prostatectomy in the management of locally recurrent prostate cancer after 1251 implantation. Br J Urol 1995;75:44–47. 118. Woolley ML, Schulsinger DA, Durand DB, et al. Effect of freezing parameters (freeze cycle and thaw process) on tissue destruction following renal cryoablation. J Endourol 2002;16:519–522. 119. Ghafar MA, Johnson CW, De La Taille A, et al. Salvage cryotherapy using an argon based system for locally recurrent prostate cancer after radiation therapy: the Columbia experience. J Urol 2001;166:1333–1338. 120. Pisters LL, Dinney CPN, Pettaway CA, et al. A feasibility study of cryotherapy followed by radical prostatectomy for locally advanced prostate cancer. J Urol 1999;163:509–514. 121. Izawa JI, Madsen LT, Scott SM, et al. Salvage cryotherapy fro recurrent prostate cancerafter radiotherapy: variables affecting patient outcome. J Clin Oncol 2002;20:2664–2671. 122. Pisters LL, Perrotte P, Scott SM, et al. Patient selection for salvage cryotherapy for locally recurrent prostate cancer after radiation therapy. J Clin Oncol 1999;17:2514–2520. 123. Chin JL, Paulter SE, Mouraviev V, et al. Results of salvage cryoablation of the prostate after radiation: identifying predictors of treatment failure and complications. J Urol 2001;165:1937–1942. 124. Greene GF, Pisters LL, Scott SM, et al. Predictive value of prostate speciﬁc antigen nadir after salvage cryotherapy. J Urol 1998;160:86–90. 125. Cespedes RD, Pisters LL, von Eschenbach AC, et al. Long-term followup of incontinence and obstruction after salvage cryosurgical ablation of the prostate: results in 143 patients. J Urol 1997;157:237–240. 126. Pisters LL, von Eschenbach AC, Scott SM, et al. The efﬁcacy and complications of salvage cryotherapy of the prostate. J Urol 1997;157:921–925. 127. Perrotte P, Litwin M, McGuire EJ, et al. Quality of life after salvage cryotherapy: the impact of treatment parameters. J Urol 1999;162:398–402. 128. Zisman A, Pantuck AJ, Cohen JK, et al. Prostate cryoablation using direct transperineal placement of ultrathin probes through a 17-gauge brachytherapy template-technique and preliminary results. Urology 2001;58:988–993. 129. Grado LG, Collins JM, Kriegshouser JS, et al. Salvage brachytherapy for localized prostate cancer after radiotherapy failure. Urology 1999;53:2–10. 130. Bahn DK, Lee F, Badalament R, et al. Targeted cryoablation of the prostate: 7-year outcomes in the primary treatment of prostate cancer. Urology 2002;60(suppl 2A):3–11.

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131. Koppie TM, Shinohara K, Grossfeld GD, et al. The efﬁcacy of cryosurgical ablation of prostate cancer: The University of California, San Francisco experience. J Urol 1999;162:427–432. 132. McDonough MJ, Feldmeier JJ, Parsai I, et al. Salvage external beam radiotherapy for clinical failure after cryosurgery for prostate cancer. Int J Radiat Oncol Biol Phys 2001;51:624–627. 133. Grampas SA, Miller GJ, Crawford ED. Salvage radical prostatectomy after failed transperineal cryotherapy: histologic ﬁndings from prostate whole-mount specimens correlated with intraoperative transrectal ultrasound images. Urology 1995;45:936–941. 134. Caubet J-F, Tosteson TD, Dong EW, et al. Maximum androgen blockade in advanced prostate cancer: a meta-analysis of published randomized controlled trials using nonsteroidal antiandrogens. Urology 1997;49:71–78. 135. Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without ﬂutamide for metastatic prostate cancer. N Engl J Med 1998;339:1036–1042. 136. Prostate Cancer Trialists Collaborative Group: Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomized trials with 3283 deaths in 5710 patients. Lancet 1995;346:265–269. 137. Denis LJ, Carnelro de Moura JL, Bono A, et al. Goserelin acetate and ﬂutamide vs bilateral orchiectomy: a phase III EORTC trial (30853). Urology 1993;42:119–129. 138. Tunn UF, Eckart O, Offenback DE, et al. Can intermittent androgen deprivation be an alternative to continuous androgen withdrawal in patients with PSA-relapse? First results of the randomized prospective trial. J Urol 2003;169, abstract 1481. 139. Andriole G, Lieber M, Smith J, et al. Treatment with ﬁnasteride following radical prostatectomy for prostate cancer. Urology 1995;45:491–497. 140. Fleshner NE, Trachtenberg J. Combination ﬁnasteride and ﬂutamide in advanced carcinoma of the prostate: effective therapy with minimal side effects. J Urol 1995;154:1642–1646. 141. Turner L, Mackenzie S, Zaida A, et al. Androgen deprivation therapy using ﬁnasteride and low dose ﬂutamide to treat PSA failure following therapy for clinically localized adenocarcinoma of the prostate. J Urol 1999;161(suppl), abstract 1151. 142. Harding P, Moul JW, McLeod DG, et al. Combination ﬂutamide and ﬁnasteride in PSA-only recurrence after prior local prostate cancer therapy. J Urol 1998;159(suppl), abstract 491. 143. Wang J, Halford A, Rigg R, et al. Adjuvant mitoxantrone chemotherapy in advanced prostate cancer. BJU Int 2000;86:675–680. 144. Syed S, Petrylak DP, Thompson IM. Management of high-risk localized prostate cancer: the integration of local and systemic therapy approaches. Urol Oncol 2003;21:235–243. 145. Schild Se, Buskirk SJ, Robinow JS, et al. The results of radiotherapy for isolated elevation of serum PSA levels following radical prostatectomy. Int J Radiat Oncol Biol Phys 1992;23:141–145. 146. McCarthy J, Catalona W, Hudson M. Effect of radiation therapy on detectable serum prostate speciﬁc antigen levels following radical prostatectomy: early versus delayed treatment. J Urol 1994;151:1575–1578. 147. Do T, Parker R, Do C, et al. Salvage radiotherapy for biochemical and clinical failures following radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys 1997;38:731–736. 148. Morris M, Dallow K, Zietman A, et al. Adjuvant and salvage irradiation following radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys 1997;38:731–736. 149. Catton C, Gospodarowicz M, Warde P, et al. Adjuvant and salvage radiation therapy after radical prostatectomy for adenocarcinoma of the prostate. Radiother Oncol 2001;59:51–60. 150. Crane C, Rich T, Read P, et al. Preirradiation PSA predicts biochemical disease-free survival in patients treated with postprostatectomy external beam irradiation. Int J Radiat Oncol Biol Phys 1997;39(3):681–686. 151. Cadeddu J, Partin A, DeWeese T, et al. Long-term results of radiation therapy for prostate cancer recurrence following radical prostatectomy. J Urol 1998;159:173–177. 152. Medini E, Medini I, Reddy P, et al. Delayed/salvage radiation therapy in patients with elevated prostate speciﬁc antigen levels after radical prostatectomy. Cancer 1996;78:1254–1259. 153. Syndikus I, Pickles T, Kostashuk E, et al. Postoperative radiotherapy for stage pT3 carcinoma of the prostate: improved local control. J Urol 1996;155:1983–1986.

30

When to Refer a Patient With Prostate Cancer to a Medical Oncologist The Earlier the Better

Jeanne Smoot and Nancy A. Dawson

INTRODUCTION Historically, the medical oncologist has been involved in the care of prostate cancer patients at the end of their lives; however, with newer chemotherapy interventions, clinical trials, more options, and increased involvement of patients in their medical care, the role of the medical oncologist should be revisited. A survey of the practice of British urologists clearly demonstrates the problem. “In clinical practice, 82% of urologists have close links with oncology, available through joint clinics or on-site referral. However, <5% refer patients to an oncologist before the development of hormone refractory disease. At relapse, only 53% of urologists referred their patients to oncologists or palliative-care clinicians. A wide variety of hormonal treatments were offered at relapse; only 24% of urologists treated their patients by antiandrogen withdrawal or introduction, which is currently, the most effective second-line treatment for recurrent prostate cancer” (1). With involvement from the day of diagnosis, the medical oncologist can assist in the coordination of treatments and the appropriate application of interventions. The assumption of the authors of this chapter is that it is never too early to refer a patient to a medical oncologist.

LOCALIZED LOW-RISK DISEASE: MIDDLE GROUND It is generally recognized in the urologic oncology community that a controversy exists in the management of localized prostate cancer. In the investigation by Moore et al. (2) of this issue, they found that 95% of surveyed urologic oncology specialists were aware of this controversy; however, data representing a bias to use their own treatment modality were discovered. Moore et al. (3) also report that patients are rarely informed of alternative treatment option and even if they are, they lack the background information to make an informed choice between options. From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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In a published telephone survey of 1000 patients with prostate cancer and 200 urologists who provided care for men with prostate cancer, there was a signiﬁcant disparity between what the urologist felt he or she had communicated and what the patient recalled being told (4). Nearly 100% of the urologists reported that they always discussed important considerations such as options for no therapy, patient preference, and changes in sexual function; however, only 20% of the patients recalled a similar discussion. Furthermore, 20% of patients felt they had not discussed treatment options with their physician, whereas only 1% of the urologists said that treatment options were not discussed. Most physician treatment decisions are based on personal experience, education, literature review, and discussion among peers. However, judgments regarding toxicities and potential beneﬁts of alternate treatments are made despite their direct experience being limited to one modality (2). Many studies have been performed on the evaluation of patient preferences in the decision making process; however, few have evaluated the actual process of decision making. O’Rourke (5) completed such a project in which she found that the lack of a multidisciplinary approach with prostate cancer patients compromised their access to information about options. Most patients were presented with three possibilities: prostatectomy, radiation, and their perception of “doing nothing.” O’Rourke found that those surveyed did not experience a review of each option with an unbiased current perspective of the potential risks and beneﬁts and an accurate prognosis. Only one went on to receive a second opinion from a different urologist. None went on to speak to a radiation oncologist or medical oncologist. She found that most decisions were based on a lifetime’s accumulation of attitudes, experiences, and their social context, with the urologist’s recommendation one of the strongest inﬂuences on decision making. A patient referral to a medical oncologist would complete the team, facilitate the educational process, and provide balance to the options offered. Moore et al.’s (3) survey results also included the medical oncologist. The preference of the surveyed medical oncologists for management of their own localized prostate cancer was divided between surgery and radiation therapy. In contrast, there was a very strong preference by surgeons and radiation oncologists to desire treatment with their own modality (3). We conclude that the medical oncologist is a valuable “middle-ground” consultant in the evaluation of current appropriate treatment options offered to patients.

LOCALIZED HIGH-RISK DISEASE: THE MULTIMODALITY APPROACH IS CRITICAL Over the last 10–15 yr, the clinical presentation of prostate cancer has changed significantly in the United States, with most men now presenting with clinically localized disease (T1, T2) (6). Despite this change, it has been found that 40–50% of men undergoing curative-intent prostatectomy will actually have disease beyond the prostate gland and be at high risk for treatment failure (7). It has also been found that among men with a normal digital rectal examination and a prostate-speciﬁc antigen (PSA) elevation (T1c), 30–50% will be found to have extraprostatic extension (7). Although prostatectomy is considered curative in most men with disease conﬁned to the prostate, there is clearly a need for additional approaches in men identiﬁed as high risk for recurrence. Methods to identify patients at increased risk for spread of the cancer outside the prostate have been developed by several investigators, allowing estimates for risk of

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recurrence using established tables or nomograms (8–10). One simple categorization developed by D’Amico et al. (9), based on a population of 1872 men treated with radiation or surgery for localized disease, identiﬁed high-risk patients as those with any of the following: (1) pretreatment biopsy Gleason score ≥ 8, (2) serum PSA > 20 ng/mL; or (3) clinical T2c disease. Effective local therapies of prostatectomy and external beam radiation are often not sufﬁcient for those with high-risk disease (10). The use of combination treatment approaches seems to provide the best potential chances for decreasing recurrence rates. It has been demonstrated that the use of total androgen suppression (TAS) before prostatectomy may decrease the incidence of positive surgical margins; however, it has not been shown to decrease subsequent failures (11). TAS, used in various combinations with radiation therapy, has been found to provide improved local control, disease-free survival, and possibly overall survival compared with radiation alone (12). Despite this ﬁnding, many men with high-risk prostate cancer continue to fail. The role of adjuvant radiation therapy for those with positive surgical margins has yet to be determined. The Southwest Oncology Group (SWOG) trial 8794 addressed this issue. Although the trial has been closed for several years, the pending results are not to be reported until 2004. For locally advanced prostate cancer (T2c, T3–4) local control and long-term survival with radiation therapy remains unsatisfactory, with 30–60% local relapse and 55–65% mortality occurring 10 yr after radiation therapy in these groups of patients (13). The recent use of hormonal therapy in combination with radiation appears to provide better local control and, more importantly, improved overall survival (13). What is available that can enhance the effectiveness of current therapies? The presence of androgen-dependent and androgen-independent prostate cancer cells from the moment of diagnosis may account for the reason many high-risk men continue to fail. Further emergence of additional androgen-independent cells complicates matters with disease progression. Such a concept suggests the design of early treatment regimes aimed at both populations of tumor cells (14). Clinical trials that add chemotherapy to target the androgen-independent cells have been a focus of numerous completed and ongoing studies. A multidisciplinary treatment team, formed from the time of diagnosis and consisting of the urologist, the medical oncologist, and the radiation oncologist, can together recommend the most suitable treatment options for each individual patient and situation.

Adjuvant and Neoadjuvant Chemohormonal Therapy Attacking androgen-independent cells with chemotherapy and androgen-sensitive cell with traditional TAS is the goal of several current studies. The idea of combination therapies using chemotherapy, plus hormone therapy with either radiation or surgery, has been accepted in concept, and formal exploration of this approach is currently being undertaken by the Radiation Therapy Oncology Group (RTOG) in clinical trial R9902 and the Intergroup SWOG trial 9921/Cancer and Leukemia Group B (CALGB) trial 99904. CALGB 99904/SWOG 9921 is a phase III trial randomizing men with high-risk prostate cancer who have undergone radical prostatectomy to adjuvant androgen deprivation for 24 mo vs mitaxantrone and prednisone for 6 cycles plus similar androgen deprivation. This protocol has had difﬁculty in accrual at least partly because of the failure of urologists to refer these patients to see a medical oncologist. The advent of chemotherapy used in this manner once again reafﬁrms the necessity of a multidisciplinary team approach in the management of prostate cancer at all stages.

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Currently, RTOG also has a phase III clinical study (9902) for locally advanced high-risk patients. A comparison is made of concomitant androgen suppression with radiation therapy followed by androgen suppression for a total of 24 mo vs the same treatment regime plus chemotherapy consisting of paclitaxel, estramustine, and etoposide following the radiotherapy. These ongoing trials emphasize the cooperation of the multiple disciplinary groups for successful management of prostate cancer patients. Investigators have also focused on neoadjuvant chemohormonal therapy prior to either prostatectomy or radiation in an attempt to again improve curability of men with high-risk locally advanced disease (15,16). These trials have demonstrated that this approach is quite feasible and is not associated with additional severe toxicity. These pilot studies have led to a phase III trial of radical prostatectomy vs six cycles of estramustine and docetaxel followed by surgery (CALGB 90203) that is expected to begin in mid-2004. This study has a primary endpoint of 5-yr biochemical disease recurrence rate with a secondary important endpoint of health-related quality of life. Again, these integrated therapeutic strategies assume a multidisciplinary team approach from the time of initial diagnosis. CHEMOHORMONAL THERAPY AS A PRIMARY APPROACH WITHOUT RADIATION OR SURGERY Wang et al. (17) reported a higher signiﬁcant objective response and median survival in locally advanced prostate cancer patients treated with hormonal therapy and adjuvant mitaxantrone. He compared the use of a luteinizing hormone-releasing hormone (LHRH) agonist and ﬂutamide with or without four cycles of adjuvant mitaxantrone in men with both localized and metastatic prostate cancer. The patients with localized disease who received adjuvant chemotherapy had a signiﬁcantly higher response rate and a >3-yr improved survival rate than those treated without chemotherapy. Although the study was small, it suggests that earlier use of chemotherapy may result in improved overall outcomes. In contrast, in men with metastatic disease, there was no signiﬁcant difference in overall survival with chemotherapy. These ﬁndings suggest that the greatest beneﬁt of chemotherapy may be in early-stage disease, similar to what has already been proved in breast and colon cancer.

PSA-ONLY AND METASTATIC HORMONE-SENSITIVE DISEASE: CHEMOTHERAPY COMEBACK In the United States, currently more than 53,000 men per year experience a PSA-only recurrence after undergoing deﬁnitive local therapy for local/locally advanced prostate cancer (10). This represents approx a 40% failure rate (10). Standard approaches have included observation only until symptoms appear or androgen deprivation therapy alone. Speculations have been made that once a patient develops hormone resistance, he has already developed chemotherapy resistance. This conclusion has led investigators to explore the use of chemotherapy earlier before resistance develops. Clinical trials using nontraditional chemotherapy combinations at nontraditional times are breaking new ground. The use of chemotherapy in patients who are hormone sensitive is not a new concept. Trials conducted by the National Prostatic Cancer Project (NPCP) in the early 1980s addressed this issue. In one trial of diethylstilbestrol (DES) vs DES plus cyclophosphamide vs DES plus estramustine, there was a minimal survival advantage

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to the chemotherapy arms (18). Other trials using relatively ineffective chemotherapy agents have failed to demonstrate this beneﬁt (19–22). Over a decade later, a phase II trial of suramin, leuprolide, and ﬂutamide in previously untreated metastatic prostate cancer patients demonstrated a 67% overall response rate and a >4-yr median survival in a poor-prognosis group of patients. Unfortunately, a phase III intergroup trial comparing this treatment regime vs hormonal therapy alone could not be completed owing to poor accrual (14). Now that there is renewed interest in chemotherapy based on promising results in the hormone refractory prostate cancer (HRPC), the next planned intergroup trial in metastatic hormone-sensitive disease will again address the early use of chemotherapy in hormone-sensitive metastatic disease. Men will be randomized to androgen deprivation therapy with or without docetaxel chemotherapy with possible bisphosphonate therapy in both arms, pending results of the soon to be launched CALGB trial 90202 of androgen deprivation therapy with or without the bisphosphonate zoledronic acid. The earlier leap in the use of chemotherapy is in the patient with PSA-only recurrence. This patient is destined to develop gross metastatic disease. Although the lag time may be as long as 8 yr from PSA recurrence to metastases, it can be much sooner in men with a relatively short interval since initial treatment or rapid PSA doubling times (23). The role of chemotherapy in this setting is also an area of active investigation. In a pilot study, Hussain et al. (24) reported that >70% of patients with PSA-only recurrence treated with docetaxel had at least a 40% decline in PSA level prior to receiving any androgen deprivation while maintaining normal testosterone levels. Subsequent androgen deprivation resulted in PSA levels of ≤0.1 ng/mL in 89% of the men. More recently a large phase III trial has been launched (RTOG P-0014), which will randomize 1050 men with rising PSA levels after local therapy for prostate cancer to androgen deprivation therapy with or without four cycles of chemotherapy. Men must have high-risk recurrent disease deﬁned as a PSA ≥ 2 ng/mL and a PSA doubling time of ≤ 8 mo with an original Gleason score ≥ 7. The chemotherapy regimen is the choice of the treating medical oncologist. Traditionally men with PSA-only recurrent disease or hormone-sensitive metastatic disease are managed exclusively by their urologists. Accrual to clinical trials that can answer important questions regarding the impact on survival of early chemotherapy use or novel approaches such as vaccines would be enhanced by early referral to a medical oncologist. Furthermore, accrual to phase III trials often does not require being a member of the sponsoring cancer cooperative group. Mechanisms are in place through the National Cancer Institute to facilitate participation by interested nonmember physicians.

HORMONE-REFRACTORY DISEASE: THE TRADITIONAL TIME TO REFER Androgen ablation continues to be the ﬁrst-line and most effective treatment for advanced and metastatic prostate cancer. Even so, metastatic disease is still generally lethal (25). Although there has been a decrease in both morbidity and mortality in prostate cancer, approx 29,000 men are expected to die from prostate cancer in 2003, making it the second leading cancer killer of men in the United States (26). Traditionally, it is at the time of development of hormone resistance that patients receive a referral to a medical oncologist.

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Multiple relatively recent studies have improved the care of men with HRPC. Two persuasive phase III studies, a Canadian trial and a CALGB study, compared the use of the chemotherapy drug mitaxantrone plus corticosteroids (prednisone or hydorcortisone) with the use of corticosteroids alone (27,28). In the Canadian trial, painful bony metastases were required for trial entry. A greater palliative beneﬁt in terms of improved pain and reduction in analgesic use as well as 6-mo longer duration of palliative response in the combination treatment arm of the study convinced the Food and Drug Administration (FDA) to approve the use of mitaxantrone and corticosteroids for the palliation of painful bony metastasis (27). This drug combination demonstrated few toxicities, with PSA correlation found to correlate with survival (28). In 1999, Osoba et al. published separately the quality of life assessments for their initial trial (27,29). They concluded that the addition of mitoxantrone resulted in a higher and longer lasting improvement in several health-related quality of life (HRQOL) domains and symptoms compared with treatment using prednisone alone. Breaking tradition, chemotherapy clearly demonstrated palliative effectiveness and improved rather than hindered quality of life. In early trials, several bisphosphonates were also reported to have signiﬁcant analgesic effects in the palliation of painful bony metastases. The problem was that none was found to decrease the complications associated with the bony metastasis. The advent of zoledronic acid, a bisphosphonate approved by the FDA in February of 2002, improved the current treatment options for these patients (30). In prostate cancer, the approval was for men with HRPC and documented bony metastasis. This study demonstrated 25% fewer skeletal-related events and 45% fewer pathologic fractures in men treated with zoledronic acid compared with placebo. A similar earlier trial comparing the bisphosphonate pamidronate with placebo failed to show decreased skeletal complications (31). With the quality of life of high-risk prostate cancer patients fragile, this allows for improved chances in maintaining a better quality of life for as long as medically possible at this time. Further investigation is needed on the role of bisphosphonates in combination cancer treatment therapies to develop its full potential. The role of chemotherapy continues to evolve in HRPC. Phase II trials of taxanes (doxetaxel, paclitaxel) have shown promising results in terms of high objective response rates and survival rates approaching 2 yr compared with 1-yr survival rates for older chemotherapy regimens such as mitoxantrone (32,33). The promise of cytotoxic therapies that impact on both quality of life and survival has led to two highly important phase III trials, TAX-327, a global trial comparing mitoxantrone and prednisone with two schedules of docetaxel and prednisone, and SWOG 9916/CALGB 99808, comparing mitoxatrone and prednisone with docetaxel and estramustine. Both, recently closed studies have primary endpoints of survival and quality of life with anticipated analyses report in 2004. The next-generation HRPC trial is currently being planned. Access to these cutting edge studies requires collaboration between urologists and medical oncologists.

THE TERMINAL PATIENT: NEVER TOO LATE Finally, establishing a relationship with the patient before treatment allows the relationship to develop before the patient enters the ﬁnal stage of life. At this time patients are extremely vulnerable and frightened. A pre-existing relationship can make this time more peaceful and less stressful, for trust and a level of comfort have already been established with the medical oncologist. The medical oncologist, who is experienced in palliative care, has a variety of treatments to offer. Increased effectiveness and insight occurs when there has been a pre-

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existing relationship with the patient. Each patient responds to treatment as an individual. Knowing these responses and their nuances can expedite the initiation of the most effective interventions. Palliation of discomfort encountered in the dying process includes a wide variety of symptom-management opportunities. Each decision made is in conjunction with the patient and family. Uniﬁcation of goals between provider and family enhances satisfaction. Nausea, vomiting, constipation, dehydration, anemia, pain, decreased appetite, cognitive changes, physical changes, emotional needs, and spiritual needs are just a few of the symptoms/needs the medical oncologist handles daily. Available resources, support systems, and indigent program knowledge are all at their ﬁngertips.

CONCLUSIONS The use of chemotherapy in HRPC is widely accepted. There are currently several ongoing phase II trials assessing the role of chemotherapy with androgen suppression prior to radiation or prostatectomy, the role of chemotherapy in PSA-only recurrent disease following radiation therapy or surgery, and the safety and efﬁcacy of concomitant chemotherapy with hormonal therapy in locally advanced disease. The invaluable interaction of specialists in this diverse body of knowledge, approaching each patient from the moment of diagnosis, is key, each one bringing a unique insight into each case. If one takes a thread through each stage of prostate cancer diagnosis and treatment, stability is created with an integration of all potential providers where the needs encountered combine for a natural ﬂow in the disease process. The utilization of each unique body of knowledge results in greater overall satisfaction, patient understanding of treatment options, the most current and efﬁcacious options offered, and physician satisfaction in quality care provided. Clearly it is the ideal in prostate cancer care. The team approach of the medical oncologist, the urologist, and the radiation oncologist is key for optimal care of patients with prostate cancer. The various clinical states all have various combination treatments and clinical trials available to them. To maximize the overall survival and quality of life of our patients, collaborative multidisciplinary approaches with multispecialty physicians partnered in the prostate cancer battle is not merely highly recommended, it is essential.

REFERENCES 1. Savage P, Bates C, Abel P, et al. British urological surgery practice 1. Prostate cancer. Br J Urol 1997;79:749–755. 2. Moore MJ, O’Sullivan B, Tannock IF. Are treatment strategies of urologic oncologists inﬂuenced by the opinions of their colleagues? Br J Cancer 1990;62:988–991. 3. Moore MJ, O’Sullivan B, Tannock IF. How expert physicians would wish to be treated if they had genitourinary cancer. J Clin Oncol 1988;6:1736–1745. 4. Crawford ED, Bennett CL, Stone NN, et al. Comparison of perspectives on prostate cancer: analysis of survey data. Urology 1997;50:366–372. 5. O’Rourke M. Narrowing the options: the process of deciding on prostate cancer treatment. Cancer Invest 1999;17:349–359. 6. Moul JW. Therapy of early progression of prostate cancer. Clin Oncol Updates 1998;1:1. 7. Small EJ. Prostate cancer. Curr Opin Oncol 1997;9:227. 8. Partin AW, Mangold LA, Lamm DM, et al. Contemporary update of prostate cancer staging nomograms (Partin tables) for the new millennium. Urology 2001;58:843–848. 9. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy or interstitial radiation for clinically localized prostate cancer. JAMA 1998;280:969–974.

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10. Graefen M, Karakiewicz PI, Cagiannos I, et al. International validation of a preoperative nomogram for prostate cancer recurrence after radical prostatectomy. J Clin Oncol 2002;20:3206–3212. 11. Soloway MS, Pareek K, Shariﬁ R, et al. Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5 year results. J Urol 2002;167:112–116. 12. Zietman AL, Vogelzang PT, Scardino DS, et al. Locally advanced or recurrent prostate cancer. In: Comprehensive Textbook of Genitourinary Oncology. Wilkins & Wilkins, Baltimore, 1996, pp. 782–790. 13. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomized trial. Lancet 2002;360:103–106. 14. Dawson NA, Figg WD, Cooper MR, et al. Phase II trial of suramin, leuprolide, and ﬂutamide in previously untreated metastatic prostate cancer. J Clin Oncol 1997;15:1470–1477. 15. Pettaway CA, Pisters LL, Troncoso P, et al. Neoadjuvant chemotherapy and hormonal therapy followed by radical prostatectomy: feasibility and preliminary results. J Clin Oncol 2000;18:1050–1057. 16. Zelefsky MJ, Kelly WK, Scher HI, et al. Results of a phase II study using estramustine phosphate and vinblastine in combination with high-dose three dimensional conformal radiotherapy for patients with locally advanced prostate cancer. J Clin Oncol 2000;18:1936–1941. 17. Wang J, Halford S, Rigg A, et al. Adjuvant mitaxantrone chemotherapy in advanced prostate cancer. Br J Urol Int 2000;86:675–680. 18. Murphy GP, Beckley S, Brady MF, et al. Treatment of newly diagnosed metastatic prostate cancer patients with chemotherapy agents in combination with hormones versus hormones alone. Cancer 1983;51:1264–1272. 19. Osborne CK, Blumenstein B, Crawford ED, et al. Combined versus sequential chemo-endocrine therapy in advanced prostate cancer: ﬁnal results of a randomized Southwest Oncology Group study. J Clin Oncol 1990;8:1675–1682. 20. Huben RP, Murphy GP. A comparison of diethylstilbestrol or orchiectomy with buserelin and with methotrexate plus diethylstilbestrol or orchiectomy in newly diagnosed patients with clinical stage D2 cancer of the prostate. Cancer 1986;62:1881–1887. 21. Seifter EJ, Bunn PA, Cohen MH, et al. A trial of combination chemotherapy followed by hormonal for previously untreated metastatic carcinoma of the prostate. J Clin Oncol 1995;4:1365–1373. 22. Vandenbroucke F, Van Poppel H, Derluyn J, et al. Interim results on a randomized trial of mitomycin C in combination with orchiectomy for newly diagnosed metastatic prostate cancer. Am J Clin Oncol 1995;18:263–266. 23. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999;28:1591–1597. 24. Hussain A, Dawson N, Amin P, Naslund M, Engstrom C, Chen T, Docetaxel followed by hormone therapy after failure of deﬁnitive treatments for clinically localized/locally advanced prostate cancer: preliminary results. Semin Oncol 2001;28(suppl 15):22–31. 25. Robson M, Dawson N. How is androgen dependent metastatic prostate cancer best treated? Hematol Oncol Clin North Am 1996;10:727–747. 26. Jemal A, Murray T, Samuels A. Cancer statistics, 2003. CA 2003;53:5–26. 27. Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 1996;6:1756–1764. 28. Kantoff PW, Halabi S, Conaway M, et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the Cancer and Leukemia Group B 9182 study. J Clin Oncol 1999;17:2506–2513. 29. Osoba D, Tannock IF, Ernst DS, et al. Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. J Clin Oncol 1999;17:1654. 30. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94:1458–1663. 31. Lipton A, Small E, Saad F, et al. The new bisphosphonate, Zometa® (zoledronic acid) decreases skeletal complications in both lytic and blastic lesions: a comparison to pamidronate. Cancer Invest 2002;20(suppl 1):44–46. 32. Gulley J, Figg W, Dahut W, et al. Treatment options for androgen independent prostate cancer. Clin Adv Hematol Oncol 2003;1:40. 33. Hussain A, Dawson NA. Management of advanced/metastatic prostatic cancer—2000 update. Oncology 2000;14:1677–1687.

31

Management of Newly Diagnosed Metastatic Disease Thomas E. Hutson

INTRODUCTION Despite advances in our understanding of its biology and natural history, prostate cancer (CaP), once spread outside the conﬁnes of the prostate, is no longer considered curable. In the year 2003, approx 10% of patients will present with “classical” metastatic disease at the time of initial diagnosis (1). This represents a 60–70% decline in the presentation of distant disease (stage D2) over the past 15 years and correlates with the stage migration that accompanied the increased public awareness and widespread use of prostate-speciﬁc antigen (PSA)-based screening (2,3). Additionally, 30–40% of patients treated with curative intent therapy (radical prostatectomy or radiotherapy) for localized CaP will develop biochemically (PSA) deﬁned recurrent disease; over time, most of these patients will develop overt metastatic disease (4–12). Since it was ﬁrst described by Huggins and Hodges (13) in 1941, androgen deprivation by either medical or surgical castration has remained the primary treatment for patients with metastatic disease. Bilateral orchiectomy or androgen blockade by medical means results in disease regression in the vast majority of patients, but the median response duration is <2 yr (14–17). Substantial evidence suggests that patients with disease progression conﬁrmed on radiographic examination and symptomatic metastasis warrant early intervention (18). The optimal timing of androgen ablation in patients with asymptomatic, nonprogressive metastasis, as well as the roles of combined androgen blockade, intermittent androgen deprivation, and antiandrogen monotherapy, remains controversial. The evolution toward earlier use of androgen deprivation at the time of biochemical (PSA) failure has produced new challenges in the management of newly diagnosed metastatic disease. A growing number of patients now present with androgen-independent disease at the time of clinically apparent metastasis. Additional hormonal maneuvers (e.g., androgen withdrawal and second-line hormonal therapies) may provide beneﬁt for a minority of these patients, but the beneﬁt is usually of short duration (19,20). The palliative role of cytotoxic chemotherapy in this patient population continues to be deﬁned.

From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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ANDROGEN DEPRIVATION The growth, proliferation, and maintenance of normal and malignant prostate cells is dependent primarily on testicular androgen (21). The early work of Huggins et al. established the relationship between serum testosterone levels and the growth of prostatic tissue (13,22,23). Their seminal work provided deﬁnitive evidence that palliation could be achieved with hormonal manipulation (orchiectomy or estrogen therapy) and has provided the foundation for androgen deprivation therapy. The hypothalamic–pituitary–gonadal axis is well characterized (Fig. 1). The testosterone synthesized by the Leydig cells of the testes accounts for approx 95% of the androgens in man, the remainder arising from peripheral conversion of androstenedionoids (dehydroepiandrosterone [DHEA] and DHEA-sulfate [S]). Central control of testosterone production resides within the hypothalamus, where pulsatile release of luteinizing hormone-releasing hormone (LHRH) into the anterior pituitary portal circulation results in systemic release of luteinizing hormone (LH). Stimulation of the interstitial cells of Leydig by LH results in the production and secretion of testosterone, which in turn inhibits further LHRH release from the hypothalamus. In androgen-sensitive cells, testosterone is converted into the more potent androgen dihydrotestosterone by membrane-bound, 5α-reductase type II. Production of the weaker adrenal androgens (androstenedione, dehydroepiandrosterone and dehydroepiandrosterone sulfate) are under pituitary and hypothalamic control by adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH), respectively. Because androgen serves as both a survival factor and a growth factor for CaP, interference with the normal androgen-signaling pathway of the hypothalamic-pituitarygonadal axis, by either surgical or medical castration, will generate clinically meaningful remissions in most patients, as demonstrated by a reduction in symptoms, if present, and a reduction in the serum PSA level. Androgen deprivation by producing castrate levels of testosterone (<50 ng/mL), by either bilateral orchiectomy or the administration of an LHRH agonist, has become the standard palliative treatment for newly diagnosed metastatic CaP. This is based on strong evidence of their comparative efﬁcacy in patients with radiographic evidence of metastatic disease (14–16,24,25). Biochemical and objective responses are achieved in 80% of these patients; however, response durations average only 18–24 mo (25). However, a small subset of patients will demonstrate no biochemical or clinical disease progression for greater than 5 yr after initiating therapy. Several studies have analyzed predictive and prognostic factors of response and survival in patients undergoing androgen deprivation for metastatic disease (26–31). Factors associated with worse prognosis relate to disease extent and include performance status, the presence of symptoms, and lower pretreatment serum testosterone level. Normalization of the serum PSA level (< 4 ng/mL) has not consistently been demonstrated to predict response duration or survival (32). A recent study by Glass et al. (33) identiﬁed four pretreatment factors (location of osseous metastatsis, performance status, serum PSA level, and Gleason score) that predicted 5-yr survival outcomes in a large, randomized trial that compared orchiectomy and ﬂutamide with orchiectomy and placebo. Patients with appendicular osseous metastasis, good performance status (Eastern Cooperative Oncology Group [ECOG] PS = 0), serum PSA level < 65 ng/mL, and Gleason score < 8.0 had a predictive 5-yr survival of 42%. At present, no molecular markers that predict response or response duration to androgen deprivation therapy have been identiﬁed.

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Fig. 1. The hypothalamic–pituitary–gonadal axis. LHRH, luteinizing hormone-releasing hormone; ACTH, adrenocorticotropic hormone; DHT, dihydrotestosterone; FSH, follicle stimulating hormone; LH, luteinizing hormone.

TREATMENT OVERVIEW For patients with metastatic CaP, five methods of androgen deprivation exist: orchiectomy, estrogen therapy, LHRH agonist therapy, antiandrogen therapy, and inhibitors of adrenal steroidogenesis. A meta-analysis has demonstrated no difference

564

Hutson Table 1 Pharmacologic Treatment Options for Metastatic Prostate Cancer

Class LHRH agonists Goserelin Leuprolide Triptorelin Steroidal Antiandrogens Cyproterone acetate Megestrol acetate

Mechanism of action Inhibition of gonadotropin secretion

Side effects Hot ﬂushes (50%), gynecomastia, fatigue

Primary: competitive inhibition of Hot ﬂushes, fatigue, gynecomastia, androgens at the receptor level breast tenderness Secondary: progestational effect at the hypothalamus

Nonsteroidal antiandrogens Flutamide Competitive inhibition of Nilutamide androgen binding at Bicalutamide the receptor level Inhibitors of adrenal steroidogenesis Ketoconazole Inhibitor of P450 enzymes in testes and adrenals Aminoglutethimide Inhibitor of adrenal steroidogenesis by blocking P450 mediated hydroxylation

Abnormal liver studies, diarrhea (10%), reversible interstitial lung disease (bicalutamide) Adrenal insufﬁciency, hepatotoxicity, nausea, diarrhea Adrenal insufﬁciency, nausea, vomiting, many drug interactions

Abbreviation: LHRH, luteinizing hormone-releasing hormone.

in survival between patients treated with LHRH agonists or patients treated with orchiectomy or diethylstilbestrol (DES), and no difference in survival exists between patients treated with different LHRH agonists (14). Therefore, the choice of treatment must be individualized and based on several factors, including whether symptoms are present, the rate of disease progression, patient preference, and a full knowledge of the speciﬁc toxicity of the drugs used. In the United States, the most common method of androgen deprivation is use of LHRH agonists (34). Table 1 summarizes the pharmacologic treatment options for patients with newly diagnosed metastatic disease.

Bilateral Orchiectomy The testes normally produce approx 95% of the testosterone in men, and bilateral orchiectomy reduces plasma testosterone to castrate levels within 3–12 h. In metastatic disease, bilateral orchiectomy (surgical castration) is the gold standard by which other forms of androgen deprivation are compared. In the United States, orchiectomy is used in only 27% of patients with metastatic CaP, primarily because of its associated psychological impact (34). However, orchiectomy has several unique advantages including convenience and cost (compared with other modalities); it also abrogates compliance issues. In patients with symptomatic metastasis, signiﬁcant improvement in symptoms can be achieved within 24–48 h after orchiectomy, and it is a primary method for treating impending spinal cord compression or visceral crisis. The short-term morbidity associated with orchiectomy is low, and side effects are those expected with androgen deprivation, that is, loss of libido, impotence, and hot ﬂushes (35,36).

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Estrogen Therapy Estrogens exert androgen ablative effects through inhibition of LHRH production by the hypothalamus and LH production by the pituitary. Other mechanisms by which estrogens regulate prostate growth are not entirely understood (37). It has been postulated that estrogen may induce apoptosis in association with tumor growth factor (TGF)-β1 thru effects at its receptors (38). DES has been the primary synthetic estrogen studied in metastatic CaP. Initial studies demonstrated comparative efﬁcacy to bilateral orchiectomy in achieving castrate levels of testosterone at doses of 5 mg/d (18,39). However, further evaluation of DES at this dose revealed an unacceptable high rate (20–25%) of severe, often fatal cardiovascular and thromboembolic side effects (24,39). Using lower doses of DES (1 or 3 mg/d) is associated with a reduction in the frequency of thromboembolic events but produces suboptimal serum testosterone levels in up to 20% of men (40). Other estrogens (ethinyl estradiol and medroxyprogesterone acetate) have similar thrombogenic properties and are less effective then DES. Therefore, the use of estrogens has generally been reserved as a second-line alternative for patients who fail initial androgen deprivation therapy.

LHRH Agonist Therapy Since Schally et al. (41) first isolated and characterized LHRH in 1971, peptide analogs that possess partial agonistic or antagonistic properties have been used in the treatment of prostate cancer. In the United States, three agents (goserelin, leuprolide, and triptorelin) are Food and Drug Administration (FDA)-approved for the treatment of metastatic CaP. These agents are partial agonists to the LHRH receptor and differ from the naturally occurring LHRH decapeptide primarily by a substitution of the glycine residue at position 6 with a D-amino acid that prevents biodegradation (42). Binding to the LHRH receptor results in a biphasic response, initially causing elevations of LH and a surge in testosterone, followed by downregulation of the release of LHRH from the hypothalamus and LH from the anterior pituitary gland leading to testosterone suppression. Castrate levels of testosterone are usually achieved within 14–21 d from the start of therapy. The initial surge or “flare” in testosterone may transiently worsen symptoms, and therefore LHRH agonists are absolutely contraindicated in patients with severe ureteral obstruction or severe, painful vertebral metastasis (43,44). The use of an antiandrogen may abrogate the clinical effects of the testosterone flare, and it has become common practice to give these agents concurrent with an LHRH agonist for 1 mo when initiating therapy (45). Because of the belief that some CaP clones may retain sensitivity to androgen deprivation, LHRH agonists, once started, are continued indefinitely in patients despite the eventual emergence of androgen independence. Advantages of LHRH agonists over estrogens include lower frequencies of cardiovascular effects, gynecomastia, breast tenderness, gastrointestinal upset, and peripheral edema. LHRH agonists do cause hot ﬂushes in 50–70% of patients, which may cause some patients to discontinue therapy. Other notable side effects include reduced libido and impotence; also, LHRH agonists are expensive compared with DES or orchiectomy. The individual selection of an LHRH agonist depends on cost and on the desired administration schedule. LHRH agonists are believed to be equally efﬁcacious; however, no prospective randomized phase III trials have been conducted directly comparing individual agents. Depot formulations have been developed that permit either monthly, every 3- and 4-mo, or yearly administration.

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Goserelin acetate is available as a monthly and a 3-mo implant administered subcutaneously. Goserelin is available in a formulation consisting of 3.6 mg (monthly) or 10.8 mg (every 3 mo) of drug in a biodegradable D, L-glycolic acid-lactic acid matrix. When administered monthly, serum testosterone levels are maintained at castrate levels for up to 5 wk. FDA approval for the treatment of metastatic CaP was granted after a series of trials comparing goserelin acetate with orchiectomy showed no difference in effectiveness (15,17,46). In a randomized trial of 283 men with metastatic (stage D2) CaP, there was no signiﬁcant difference between goserelin and orchiectomy in objective response (82% vs 77%), median time to treatment failure (52 vs 53 wk), and survival (119 vs 136 wk) (46). Leuprolide acetate is available as an injectable suspension given subcutaneously daily (1 mg) or intramuscularly monthly (7.5 mg), every 3 mo (22.5 mg) and every 4 mo (30 mg) as a depot injection. A recent new forumulation allows for subcutaneous administration every 12 mo. The efﬁcacy of leuprolide in patients with metastatic CaP, leading to its FDA approval, was established in a phase III trial in which patients were randomized to receive either a 1-mg daily subcutaneous dose of leuprolide or 3 mg per day of DES (24). Although there was no statistical difference in effectiveness, there was a marked reduction in cardiovascular toxicity favoring leuprolide. Similar to goserelin, a single intramuscular depot injection of 7.5 mg of leuprolide maintains castrate testosterone levels for up to 5 wk. Triptorelin acetate, the newest LHRH agonist, has a twofold greater potency than leuprolide and was approved for use in CaP in 2000. Triptorelin is available as a 3.75-mg injectable suspension given intramuscularly every month. In a randomized trial, triptorelin suppressed testosterone to castration levels in 91% of patients with advanced CaP during the ﬁrst month of treatment, with levels maintained through d 253 in 96% of patients (47). Because of a tendency toward elevated blood pressure during treatment with triptorelin, blood pressure monitoring is recommended during the ﬁrst 4–8 wk of therapy. A large randomized trial comparing leuprolide and triptorelin in advanced CaP is ongoing.

Antiandrogen Therapy The antiandrogens competitively inhibit the binding of testosterone to the androgen receptor. There are two broad categories of antiandrogens: (1) steroidal compounds, which have progestational activity in addition to binding competitively to the androgen receptor; and (2), nonsteroidal compounds, which competitively bind to the androgen receptor but possess no direct gonadotropic or progestational activity. The steroidal antiandrogens block the interaction between androgen and its receptor as well as suppress testosterone through negative feedback at the pituitary and hypothalamus. The two primary steroidal antiandrogens are cyproterone acetate (CPA) and megestrol acetate (MGA). When used as monotherapy, these agents are capable of suppressing testosterone, but after several months, serum testosterone levels rise toward normal. As a result, these agents are not recommended for use as initial androgen deprivation therapy for patients with metastatic CaP. CPA is a synthetic hydroxyprogesterone, which, when compared in a dose of 250 mg/d with 3 mg/d of DES had similar efﬁcacy with fewer cardiovascular effects (48). MGA has most commonly been used in a dose of 40–120 mg/d in combination with 0.1 mg/d of DES as an alternative in CaP patients failing initial LHRH agonist therapy (49). The nonsteroidal antiandrogens (ﬂutamide, nilutamide, and bicalutamide) are capable of competitively binding with testosterone and the adrenal androgens at both intracytoplasmic and intranuclear androgen receptors without significant stimulation

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(50,51). Direct comparisons among bicalutamide, ﬂutatmide, and nilutamide have not been conducted. Toxicities differ among the agents but all include gynecomastia, fatigue, elevation in serum transaminases, and diarrhea. Flutamide is more frequently associated with diarrhea, gynecomastia, and (rarely) liver toxicity. Bicalutamide and nilutamide offer an advantage over ﬂutamide because they can be given as a once-daily formulation, whereas ﬂutamide administration is required three times daily. The nonsteroidal antiandrogens have been used in three clinical settings: ﬁrst, as part of combined androgen blockade; second, as an alternative in patients failing initial androgen deprivation therapy; and, third, as initial monotherapy. They can also be used to block the ﬂare response from the initial rise in testosterone from LHRH agonists. Several small clinical trials have demonstrated both their efﬁcacy (as evidenced by their ability to reduce serum PSA levels) as single agents and in combination with ﬁnasteride (a potent 5-α reductase inhibitor), and their ability to preserve potency by maintaining serum levels of testosterone (52–54). However, two randomized trials failed to demonstrate equivalency of monotherapy with nonsteroidal antiandrogens to orchiectomy or DES (55,56). In two other studies, bicalutamide at 150 mg/d was equivalent to orchiectomy or goserelin only in patients without metastatic disease (57). In a large meta-analysis involving 2717 patients in eight clinical trials comparing nonsteroidal antiandrogens with either orchiectomy, DES, or LHRH agonists, three trials found a lower survival rate that was statistically signiﬁcant, and none favored nonsteroidal antiandrogen monotherapy (58). The hazard ratio compared with orchiectomy was 1.2027 (CI 0.973–1.487) for bicalutamide and 1.9583 (CI 0.369–10.394) for ﬂutamide. In this meta-analysis, no trials were identiﬁed that evaluated nilutamide as monotherapy or directly compared different nonsteroidal antiandrogens. Based on the currently available data, nonsteroidal antiandrogens should not be used as monotherapy in patients with metastatic disease.

Inhibitors of Adrenal Steroidogenesis Several potent inhibitors (ketoconazole and aminoglutethimide) of adrenal steroidogenesis have been used to treat patients relapsing from initial androgen deprivation therapy and infrequently, as ﬁrst-line therapy for metastatic CaP. Ketoconazole is an antifungal that, when used at supratherapeutic doses (400 mg three times daily), can inhibit cytochrome P450-mediated steroidogenesis in the testes and adrenals. Initial trials have failed to demonstrate equivalency to orchiectomy or estrogen therapy in achieving castrate levels of testosterone (59). However, ketoconazole has become an alternative to orchiectomy in the treatment of patients with visceral crisis or spinal cord compression, because serum testosterone levels fall within hours of administration (60). Aminoglutethimide, which was originally marketed as an anticonvulsant, blocks several steps in cytochrome P450-mediated hydroxylation of adrenal steroid precursors, resulting in a “medical” adrenalectomy. Because of its potent inhibitory effects on adrenal steroid synthesis, aminoglutethimide must be administered with a corticosteroid. The usual dosage is 125 mg orally four times a day, but it may be increased to 250 mg four times a day. Response rates of 15% have been reported in CaP patients who had prior hormonal therapy lasting 24–290 wk (61,62). Adverse effects include sedation, skin rash, and weakness.

SIDE EFFECTS AND QUALITY OF LIFE Signiﬁcant side effects exist as a result of androgen deprivation, regardless of which therapy is utilized (14). Androgen deprivation results in male menopausal symptoms—

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sweating, hot ﬂushes, loss of libido, weight gain, asthenia, mild gynecomastia, changes in the texture of the hair and skin, and total impotence. With long-term use, metabolic complications may occur such as osteoporosis, loss of muscle mass, anemia, fatigue, changes in lipid proﬁle, and glucose intolerance. Over the past 10 years, there has been an increasing awareness of the impact the choice of therapy and its associated side effects have on the quality of life (QOL) of men with metastatic CaP. A recent European Organization for the Research in Treatment of Cancer (EORTC) Genitourinary Group study evaluated QOL in patients enrolled in a randomized phase III trial comparing orchiectomy vs the LHRH depot preparation goserelin plus ﬂutamide in patients with metastatic CaP (63). Fatigue, reduced social life, and impaired sexual life were identiﬁed as having an important role in the overall psychologic well-being of these previously untreated patients. Similar results were seen in a population-based QOL study in men with localized prostate cancer initially treated with androgen deprivation therapy (64). In the patients receiving therapy, sexual function and physical well-being were signiﬁcantly reduced in comparison with a cohort of men not treated. The reported decline in QOL of men with metastatic CaP treated with androgen deprivation therapy also correlates with their spouses’ perceived QOL (65). In a study by Clark et al. (66), 201 men with metastatic CaP were surveyed to assess the regret of treatment decisions (surgical vs medical castration) and its association with QOL. Of the 23% of men who expressed regret, 43% had surgical castration (p = 0.03), 54% had experienced nausea in the past week (p = 0.010), and 56% reported erectile dysfunction (p = 0.048). The inclusion of QOL endpoints in future prospective trials of androgen deprivation will further deﬁne the impact of this palliative treatment on men with metastatic CaP.

Hot Flushes Androgen deprivation, whether surgical or medical, produces a vasomotor syndrome characterized by hot ﬂushes and sweating. Although the exact pathogenesis is debated, current evidence suggests an association with hypothalamic catecholamines and endogenous opiates (β-endorphin) (67). After bilateral orchiectomy, up to half of patients will develop hot ﬂushes (68,69). With LHRH agonist therapy, the incidence approaches 70% and may not resolve when treatment is stopped (70,71). Hot ﬂushes, although not a serious adverse effect, can signiﬁcantly impact the QOL of many men and cause some to discontinue therapy. In large randomized trials, agents such as clonidine, megestrol acetate, ﬂuoxetine, and venlafaxine have been demonstrated to reduce the severity of hot ﬂushes and may provide beneﬁt to some patients (72–74).

Osteoporosis Prevention of osteoporosis during androgen deprivation therapy is imperative in order to decrease fracture risk. All men beginning therapy should receive calcium and vitamin D and should maintain a moderate exercise program. Bisphosphonates have been shown to reduce bone resorption, decrease fracture risk, and improve bone pain, and they may even have anticancer properties (75,76). In addition, these agents are capable of reducing the hypercalcemia associated with osseous metastasis. However, clinical studies of bisphosphonates to prevent osteoporosis in metastatic CaP have produced conﬂicting results, and the routine administration of these agents without objective evidence of osteoporosis is not yet supported by available data (77,78). Baseline and at least one follow-up bone density measurement should be considered when initi-

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ating androgen deprivation therapy, with bisphosphonate treatment a possibility in those in whom osteoporosis develops (78). In patients with painful bony metastasis or evidence of osteolytic bone destruction, bisphosphonates may improve symptoms and decrease the risk of fracture (79,80). The two bisphosphonates used most commonly in CaP are pamidronate and zoledronate (81). Pamidronate is administered intravenously in doses ranging from 30–60 mg weekly to 90–120 mg every 3 or 4 wk. Because of its ability to cause renal damage, pamidronate should be infused over 1 or 2 h. Zoledronate is available in a single dose of 4 mg administered intravenously over 15–30 min. As with pamidronate, caution must be used in patients with renal failure, and it is contraindicated when the serum creatinine is >3.0 mg/dL.

Anemia Anemia from androgen deprivation has been well described in patients with metastatic CaP (82,83). In a study by Strum et al. (83), over 75% of patients receiving a LHRH agonist and ﬂutamide for newly diagnosed metastatic CaP developed a moderate normochromic normocytic anemia (hematocrit 30–36%) within 3 mo of starting therapy. The mean hemoglobin decrease was 4.2 g/dL, and 13% of patients developed symptoms (angina and dyspnea) requiring treatment. As in other advanced cancers, anemia in metastatic CaP may also result from bone marrow involvement or as a result of nonspeciﬁc processes, such as the inhibitory effects of tumor necrosis factor that accounts for the “anemia of chronic disease.” Several studies have demonstrated significant improvements in symptoms, need for blood transfusions, and QOL with erythropoietin (epoetin alfa, Procrit®) therapy in patients with cancer-related anemia (84–87). However, the strongest evidence of beneﬁt exists in chemotherapy-induced anemia, and its use in this setting is supported by current clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology (88). In metastatic CaP, patients with either anemia from androgen deprivation or cancerrelated anemia may beneﬁt from erythropoietin therapy. Erythropoietin is administered subcutaneously at a dose of 150 U/kg three times weekly or alternatively at a dose of 40,000 U/wk. Therapy should be continued for a minimum of 4 wk and titrated to response. Continuing erythropoietin beyond 6–8 wk in the absence of a response (i.e., <1–2 g/dL rise in hemoglobin) is not recommended. A new agent, darbepoetin alpha, can be administered in a dose of 6.75–10.0 µg/kg every 3–4 wk (89). The decision to start therapy should be individualized (in general, hemoglobin < 10.0 g/dL and symptoms) and continued until the hemoglobin is >12 g/dL. Serum iron studies should be obtained prior to initiating therapy with iron replacement, if indicated.

COMBINED ANDROGEN BLOCKADE The contribution of adrenal androgens to the maintenance of CaP was ﬁrst recognized in 1945, when Huggins and Scott (90) treated men with hormone-refractory CaP by bilateral adrenalectomy. Since then, combined androgen blockade (CAB), or the addition of an antiandrogen to medical or surgical castration to block the action of residual adrenal androgens, has been extensively studied. Numerous trials combining various types of castration (orchiectomy and LHRH agonists) with various antiandrogens have been conducted (Table 2). However, the beneﬁts of CAB over monotherapy have not been conclusively deﬁned, and controversy exists regarding its role in the initial management of metastatic CaP.

570

Hutson Table 2 Selected Trials of Combined Androgen Blockade (CAB) in Patients With Metastatic Prostate Cancer

Primary author

No.

Trials supporting CAB Crawford et al. (26)

603

Bertagna et al. (91)

1056

Denis et al. (92)

310

Trials against CAB Iversen et al. (95)

262

Fourcade et al. (97)

Eisenberger et al. (32)

245

1387

Treatment

Response rate (%)

Leuprolide + placebo vs leuprolide + ﬂutamide Orchiectomy + placebo vs orchiectomy + nilutamide Orchiectomy + placebo vs goserelin + ﬂutamide Orchiectomy + placebo vs goserelin + ﬂutamide Goserelin + placebo vs goserelin + ﬂutamide Orchiectomy + placebo vs orchiectomy + ﬂutamide

Survival (mo)

36.1 vs 42.8

22.3 vs 35.6 (p = 0.0035)

33 vs 50

10% increase (p = NS)

59 vs 58

27.1 vs 34.4 (p = 0.02)

27.6 vs 22.7 (p = NS) 80.8 vs 77.9

Not reported

61 vs 81

29.9 vs 33.5 (p = NS)

Abbreviation: NS, not signiﬁcant.

Several randomized trials have shown a beneﬁt to CAB in patients with metastatic CaP (26,91–93). In a study conducted by the Southwest Oncology Group (SWOG; INT 0036), in which 603 men with metastatic CaP were randomized to either leuprolide (1 mg/d) or to CAB with leuprolide and ﬂutamide (250 mg three times daily) resulted in a signiﬁcant improvement in both disease progression and median survival in favor of CAB (median survival 28.3 mo vs 35.6 mo; p = 0.035) (26). Patients with minimal disease and good performance status had greater beneﬁt (48 mo for CAB and 19 mo for single-agent leuprolide), and adverse events were equivalent between therapies. Although the results seem to suggest beneﬁt for patients with minimal disease, there is concern about compliance and possible effects of testosterone ﬂare contributing to the worse outcome seen in the leuprolide arm. Bertagna et al. (91) reported the results of a meta-analysis of seven randomized, placebo-controlled studies that compared CAB with orchiectomy plus nilutamide to orchiectomy plus placebo in 1056 men with metastatic CaP. Risk of disease progression (16% increase, p = 0.05), response rate (50% CAB vs 33% orchiectomy alone), and survival (10% increase, p = NS) favored CAB therapy. In addition, statistically signiﬁcant improvement in bone pain and normalization of PSA favored CAB. Another meta-analysis by Caubet et al. (94), which excluded studies published only as abstracts, as well as studies that did not present data on survival or used only short-term antiandrogens, a beneﬁt was seen in favor of CAB (RR 0.78; 95% CI 0.67–0.90).

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Although superior to monotherapy in several large trials, CAB remains controversial because several studies refute these ﬁndings (32,54,57,95–97). In the largest CAB study to date, an intergroup study (INT 105) reported by Eisenberger et al. (32), in which 1387 men with metastatic CaP were randomized to either orchiectomy alone or CAB with ﬂutamide (250 mg three times daily) combined with orchiectomy, there was a difference in PSA normalization favoring CAB but no difference in overall survival between therapies. In an attempt to reconcile the conﬂicting results from various CAB studies, a metaanalysis of 22 randomized trials involving 5710 patients was performed by the Prostate Cancer Trialist’s Collaborative Group (98). There was no overall beneﬁt for CAB, although this meta-analysis has been criticized because of the inclusion of trials that had heterogenous treatments. In a second meta-analysis performed by the Agency for Health Care Policy and Research, no beneﬁts of CAB were seen at 2 yr, although a modest beneﬁt was observed at 5 yr (hazard ratio, 0.861; 95% CI 0.78–0.95) (14). At present, there is no clear consensus regarding the advantage to CAB as initial therapy for all patients with metastatic CaP. However, studies have shown subsets of patients that may beneﬁt from CAB. Patients with a good performance status and minimal extent of disease and those whose PSA level normalizes within the ﬁrst few months of therapy are likely to beneﬁt from CAB. This beneﬁt is modest at best (approx 3.4% improvement in survival at 5 yr) and must be weighed against the potential for more side effects and the additional cost of therapy.

INTERMITTENT ANDROGEN DEPRIVATION Most men with CaP will develop androgen-independent disease regardless of which type of androgen deprivation therapy is used. Basic and clinical studies have suggested that intermittent androgen deprivation, which involves discontinuing androgen deprivation at the time of maximal testosterone suppression and reinstitution of therapy at the time of PSA progression, may mitigate the development of resistance to androgen deprivation (99–105). However, the clinical studies demonstrating the feasibility of intermittent androgen deprivation have been small, single-institution studies of different patient populations involving various androgen deprivation therapies. In a study by Goldenberg et al. (103), 47 men (14 stage D2, 10 stage D1, 19 stage C, and 4 stage A/B) were treated with either CPA (100 mg/d) and DES (0.1 mg/d) or an LHRH agonist plus an antiandrogen (CPA or ﬂutamide). The median time to progression was 108 wk, and the average length of an androgen replacement-withdrawal cycle was 75 wk. In another study by Grossfeld et al. (105), 47 patients with clinically localized CaP were treated with either CAB or an LHRH agonist. After 24 mo, only one patient failed to respond to reinstitution of androgen deprivation therapy. The average cycle length was 14 mo, with patients spending 47% of their time off therapy. In both studies, libido and potency returned during nontreatment periods. Although it appears that intermittent androgen deprivation is feasible, and may even improve the QOL of men with metastatic CaP, it is unknown whether this form of therapy will improve progressionfree or overall survival. A large, randomized intergroup study comparing continuous androgen deprivation with intermittent therapy is ongoing.

EARLY VS DELAYED ANDROGEN DEPRIVATION Timing of androgen deprivation for metastatic CaP has been a point of controversy in the literature. Although substantial evidence supports immediate androgen deprivation

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in patients with symptomatic metastasis, no randomized controlled trial has demonstrated a survival beneﬁt in asymptomatic patients. In these patients, the decision to institute therapy is confounded by its side effects and cost. The re-evaluation of the survival data from the Veterans Administration Cooperative Urological Research Group (VACURG) I study provided new insights into this common dilemma (18,106). The VACURG I study randomized patients with locally advanced and metastatic CaP to placebo, orchiectomy plus placebo, DES (5 mg/d) or orchiectomy plus DES. As initially reported, in men with metastatic CaP, there was no difference in disease-speciﬁc or overall survival at 9-yr follow-up (106). However, upon re-evaluation, it appeared that younger patients with high-grade tumors (Gleason score 7–10) and stage D disease derived a survival beneﬁt from the initiation of androgen ablation at the time of diagnosis (18). Three large randomized trials now offer evidence that supports the early use of androgen deprivation therapy in advanced and metastatic CaP (107–109). In the ﬁrst study, by the EORTC, 415 men with locally advanced (T3 or T4) or high-grade CaP were randomized to radiotherapy alone or with goserelin (with CPA for 1 mo) started at the time of radiotherapy and continued for 3 yr (107). The actuarial 5-yr survival favored the radiotherapy-goserelin group (79% vs 62%, p = 0.001), suggesting a beneﬁt to the earlier institution of androgen deprivation. The second study, by the ECOG, in which 98 men undergoing radical prostatectomy with evidence of positive lymph nodes were randomized between early androgen deprivation therapy (LHRH agonist or orchiectomy plus an antiandrogen) started immediately after prostatectomy or to deferred therapy (108). At the time of last follow-up, 36 men in the immediate treatment group vs 9 men in the delayed treatment group were alive without evidence of detectable serum PSA or clinical evidence of disease (p < 0.001), suggesting beneﬁt to early androgen deprivation after radical prostatectomy in advanced CaP. The third study, by the Medical Research Council (MRC), randomized 938 men with locally advanced or metastatic CaP to receive either early androgen deprivation therapy (orchiectomy or LHRH agonist) or delayed androgen deprivation therapy (109). Both disease progression and CaP-related deaths occurred earlier and more frequently in the delayed treatment group (p = 0.001), providing compelling evidence of beneﬁt to early androgen deprivation therapy. There have been many criticisms of these three randomized trials; however, it appears that earlier initiation of androgen deprivation may improve the quality of life and prevent complications from advanced metastasis, such as bladder outlet obstruction, uremia, or spinal cord compression. Although the currently available evidence would suggest that early androgen deprivation therapy may offer a survival advantage to asymptomatic patients with metastatic CaP, these studies do not conclusively deﬁne the optimal timing of therapy. Symptomatic patients and those with clinical or radiographic evidence of progression warrant immediate androgen deprivation therapy.

CHEMOENDOCRINE THERAPY Chemoendocrine therapy, or the combination of cytotoxic chemotherapy with androgen deprivation therapy, has been evaluated in the initial management of metastatic CaP. Several small, single-institution trials of CAB (orchiectomy, LHRH agonist or DES plus an antiandrogen) and chemotherapy (epirubicin, cisplatin, or methotrexate)

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in patients with previously untreated metastatic CaP have demonstrated prolongation in progression-free and overall survival (110–113). However, larger prospective randomized trials have not conﬁrmed these results (114–116). In a trial by the SWOG, 143 patients with advanced CaP were randomized between combined vs sequential chemoendocrine therapy (DES or orchiectomy alone or combined with cyclophosphamide and doxorubicin) (115). Patients receiving combined chemoendocrine therapy had a slightly higher response rate (63% vs 48%), but times to treatment failure and survival were identical. In another randomized trial by Sagaster et al. (114), 53 patients with newly diagnosed metastatic CaP (stage D2) were randomized to CAB (orchiectomy plus ﬂutamide) alone or combined with methotrexate. There was no signiﬁcant difference between the response rate, progression-free survival, or overall survival with the addition of methotrexate to CAB. To date, all the reported chemoendocrine trials have utilized less than optimal cytotoxic agents. Now, with the development of more active chemotherapy (i.e., docetaxel and gemcitabine), a new generation of studies is being developed to clarify the role of chemoendocrine therapy in patients with metastatic CaP. A large randomized trial by the Radiation Therapy Oncology Group (RTOG P-0014) has recently opened to accrual and will be comparing androgen deprivation with early vs delayed chemotherapy in patients presenting with biochemical failure after curative intent therapy (surgery or radiation). Until the results of ongoing and future studies are known, chemoendocrine therapy should be considered experimental.

CONCLUSIONS Androgen deprivation by either surgical or medical castration is the primary treatment for men with metastatic CaP. The development of synthetic LHRH agonists, combined with the development of multiple antiandrogen agents, has provided many choices in the management of these patients. However, androgen deprivation remains palliative, and the choice of treatment has significant effects on QOL. Until the optimal therapy (monotherapy vs CAB; intermittent androgen deprivation) and timing of therapy are defined, treatment should be individualized and based on several factors, including whether symptoms are present, the rate of disease progression, and patient preference.

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Management of the Patient With Androgen-Independent Metastatic Prostate Cancer Robert Dreicer

INTRODUCTION Among the consequences of the widespread utilization of prostate-speciﬁc antigen (PSA) testing in the management of patients with prostate cancer is a clinically signiﬁcant stage migration manifested as men with evidence of biochemical failure, i.e., persistent/rising PSA level following curative intent therapy with surgery or radiotherapy. As signiﬁcant numbers of patients with biochemical failure have received hormonal therapy, this in turn has led to another new subset of patients with advanced prostate cancer, those with androgen-independent prostate cancer, biochemically deﬁned. In spite of the potential of PSA-based screening to lead to improved cure rates by detecting and treating prostate cancer at an earlier stage, it is estimated that approx 29,000 men will die of prostate cancer in 2003 (1). Over the past decade, a series of clinical trials has provided evidence that systemic chemotherapy can improve the quality of life of patients with advanced prostate cancer, but conﬁrmation that any of these interventions improve survival is lacking. A large number of novel small molecules and other targeted therapies are entering clinical trials in advanced prostate cancer. As we await reports from several recently completed phase III chemotherapy trials, representatives of a number of new classes of chemotherapy agents are also entering clinical trials both as single agents and in combination with standard agents.

ANDROGEN-INDEPENT PROSTATE CANCER DEFINED The historical image of hormone-refractory metastatic prostate cancer is that of a patient with extensive bone metastases (resulting in progressive pain), progressive fatigue and wasting and a median survival of 6–12 mo. With the widespread utilization of PSA testing, new diagnostic subsets of prostate cancer have emerged, including patients with biochemical failure only following curative intent therapy with radiotherapy From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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or prostatectomy. Despite the lack of unequivocal evidence of beneﬁt, there has been widespread use of “early” hormonal therapy in patients with rising PSA values following radiotherapy or radical prostatectomy. This in turn has created a subset of patients with androgen-independent prostate cancer biochemically deﬁned (rising PSA with no clinical/radiographic evidence of metastases). Prostate cancer is widely viewed as a heterogeneous disease with variable responses to initial and secondary hormonal manipulations. Scher and colleagues (2) have proposed a model in which patients are divided into three categories: hormone-naïve, androgen-independent but hormone-sensitive (progression on luteinizing hormonereleasing hormone [LHRH] therapy or orchiectomy but sensitive to secondary manipulations), and hormone-refractory disease (resistant to all hormonal manipulations).

SECOND-LINE HORMONAL THERAPY One of the consequences of the PSA-induced stage migration that has occurred over the last decade is the earlier recognition of developing androgen independence in patients with advanced prostate cancer and a signiﬁcant increase in the utilization of secondary hormonal maneuvers. As noted above, historically, patients with metastatic prostate cancer had a median duration of response to initial hormonal therapy of approx 18 mo, following which there was a relatively rapid clinical progression limiting the utility of salvage interventions (3). With a large subset of patients receiving hormonal therapy for biochemical failure, there are now a signiﬁcant number of individuals whose disease is androgen-independent, without clinical evidence of metastatic disease. Many of these patients are closely monitored, are understandably anxious about their disease status, and typically are highly motivated to receive additional therapy. In 1993 Kelley and Scher (4) ﬁrst reported what is now widely referred to as the antiandrogen withdrawal syndrome. The pathophysiology of the antiandrogen withdrawal syndrome, i.e., a 50% decline in PSA following withdrawal of an antiandrogen in patients having combined androgen ablation, is poorly understood and, although androgen receptor gene mutations have been the most widely held explanation, recent work by investigators in the Cancer and Leukemia Group B (CALGB) fails to support this hypothesis (5,6). This phenomenon has now been reported in patients withdrawing from a range of agents including other antiandrogens, aminoglutethimide, megace, and ketoconazole (5,7,8). Although early reports suggested that approx 30% of patients could be expected to demonstrate a withdrawal response, more recent evidence suggests that the actual response rate is in the 15% range, with a median duration of response of 3 mo (9). The recognition of the antiandrogen withdrawal syndrome and an appreciation that approx 10% of circulating testosterone in human males originates from the adrenals led investigators to study various strategies for blocking adrenal sources of testosterone and evaluating alternative antiandrogens in an attempt to take advantage of the differential response to some agents as a consequence of androgen receptor mutations (10,11). Four classes of agents (corticosteroids, non-corticosteroid adrenal steroidogenesis inhibitors, antiandrogens, and estrogens) have been evaluated as second-line hormonal therapy agents (Table 1) (12). The potential utility of second-line antiandrogens was ﬁrst proposed by Fowler et al. (13) when they reported signiﬁcant PSA responses (>50% decline) to ﬂutamide in 80%

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Table 1 Selected Trials of Second-Line Hormonal Therapy Author Dawson et al. (43) Tannock et al. (16) Joyce et al. (44) Sartor et al. (45) Small et al. (46) Shahidi et al. (47)

Treatment Megestrol acetate Prednisone Bicalutamide (150 mg) Aminoglutethamide + hydrocortisone + AAWD Ketoconazole + hydrocortisone DES (3 mg)

No. of 50% PSA response Response patients proportion (%) duration (mo) 149 81 51 29

12 22 14 48

NR 4.0 4.0 4.0

128 115

27 32

NR NR

Abbreviations: AAWD, antiandrogen withdrawal drugs; DES, diethylstilbestrol; NR, not reported.

and 54% of patients with localized and metastatic disease, respectively, who had disease progression following primary hormonal therapy. Fossa and colleagues (14) conducted a phase III study of second-line hormonal therapy in 201 men with advanced, androgen-independent prostate cancer. Patients received either ﬂutamide 250 mg three times a day or 20 mg of prednisone in divided doses. There was no difference in median time to disease progression or overall survival. Biochemical responses were seen in 23% of the ﬂutamide-treated patients, and 21% of those receiving prednisone. There was a statistically signiﬁcant improvement in quality of life measures favoring prednisone (14). Tannock et al. (15) reported a 38% palliative response to 10 mg of prednisone in a phase II trial in advanced prostate cancer. Two subsequent phase III trials comparing mitoxantrone and corticosteroids with corticosteroids alone demonstrated responses to 10 mg of prednisone and 40 mg of hydrocortisone of 12 and 8%, respectively (16,17). Among the nonsteroidal agents whose mechanism of action is inhibition of adrenal steroidogenesis, ketoconazole and aminoglutethamide are the most widely investigated. Aminoglutethamide plus hydrocortisone has a reported partial response rate of approx 9% and is associated with mild-moderate toxicities including nausea and vomiting and fatigue (12). Ketoconazole, when administered in doses of 400 mg three times daily, has reported response rates ranging from 15% to as high as 63%. Although PSA responses are most frequently observed, a recent CALGB phase II trial of ketoconazole and antiandrogen withdrawal demonstrated a 27% PSA response with a 13% measurable disease response (18). Although some studies suggest response rates with acceptable toxicity, to date there is no compelling evidence that second-line hormonal interventions result in a survival improvement; most patients who respond have short-lived responses, and there are costs to patients in terms of both side effects and economic costs that most be considered when utilizing this approach.

CHEMOTHERAPY Although widely investigated in the 1970s and 1980s, systemic chemotherapy was thought by many to be ineffective in advanced prostate cancer given the signiﬁcant toxicity and limited efﬁcacy associated with its administration (19). Lack of effective

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agents and a uniquely difﬁcult neoplasm in which to assess response to therapy using conventional techniques were contributing factors. Tannock and colleagues (15), long critics of conventional phase II evaluations of chemotherapy in prostate cancer, began a series of clinical trials using novel palliative endpoints such as improvement in pain and quality of life as a means of response assessment. A study of prednisone alone was followed by a phase II trial of mitoxantrone, a semisynthetic antracenedione with structural similarities to doxorubicin in combination with prednisone (15). In the latter study, 9 of 25 evaluable patients achieved a palliative response, with modest toxicity (20). This observation lead to the seminal phase III trial conducted by Tannock and colleagues (16) comparing mitoxantrone plus prednisone with prednisone alone. One-hundred sixty-one patients with symptomatic androgen-independent metastatic prostate cancer were randomized to receive either prednisone at 10 mg daily or mitoxantrone at 12 mg/m2 every 3 wk plus 10 mg of prednisone daily. A palliative beneﬁt, deﬁned as improvement in pain, was observed in 29% of patients receiving mitoxantrone compared with 12% receiving prednisone alone (p = 0.01). The duration of the palliative beneﬁt was signiﬁcantly greater for those patients receiving chemotherapy with a median of 43 vs 18 wk (p < 0.0001). Although there was no signiﬁcant difference in overall survival, it is important to recognize that 50 patients initially randomized to prednisone were allowed to cross over to receive mitoxantrone at time of disease progression. Interestingly, although there was a higher probability of PSA response in the group receiving chemotherapy, this difference did not reach statistical signiﬁcance. A somewhat similar phase III study conducted by the CALGB in 242 patients compared mitoxantrone plus hydrocortisone vs hydrocortisone alone (17). This study did not have a crossover design and was powered to evaluate survival. Although there was a delay in time to treatment failure and disease progression favoring the chemotherapy arm, there was no difference in overall survival (12.3 mo for the combination vs 12.6 mo for hydrocortisone alone). Of particular interest is the fact that the objective response rate to the combination arm was only 7% (4% for hydrocortisone alone). With the limited objective responses produced by mitoxantrone, an array of antineoplastics have been evaluated with emphasis on agents that target the nuclear matrix and microtubular function (21,22). Estramustine is a complex of a estradiol phosphate derivative linked to a non-nitrogen mustard molecule. Although it was initially developed as an alkylayting agent and gained Food and Drug Administration (FDA) approval for use in prostate cancer in 1981, its activity in prostate cancer is now believed to be unrelated to either its hormonal or its alklylating effects. Estramustine binds to microtubule-associated proteins in the nuclear matrix and inhibits microtubular function (23). As a single agent, estramustine has objective response rates reported in the 14–48% range (24). For many years after its approval, estramustine had little usage as it was widely perceived to provide very modest efﬁcacy with a difﬁcult side effect proﬁle. Its re-emergence as a potentially important agent in advanced prostate cancer is based on evidence that adding estramustine to other antineoplastics with antimicrotubular activity results in an improved response rate, as discussed below. Vinka alkaloids such as vinblastine and vinorelbine bind to tubulin and prevent microtubule assembly. Vinblastine as a single agent has a reported objective response rate of 21%, similar to the 16% response rate reported for vinorelbine (25,26). In vitro data demonstrating additive effects when vinca alkaloids are combined with estramus-

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Table 2 Selected Trials of Taxane-Based Chemotherapy in Advanced Cancer Author Roth et al. (31) Picus et al. (35) Hudes et al. (48) Petrylak et al. (36) Saverse et al. (37) a

Treatment Paclitaxel Docetaxel Paclitaxel + estramustine Docetaxel + estramustine Docetaxel + estramustine

No. of patients

50% PSA response (%)

Overall responsea

Median survival (mo)

23 35 63

4 46 58

4 28 27

9 27 NR

33

63

28

NR

47

68

50

20

Measurable disease.

tine led to a series of phase II trials of the estramustine/vinblastine combination. These studies demonstrated evidence of antitumor activity, with major PSA response rates (>50% decline) reported in the 40–54% range (27–29). Hudes and colleagues (30) performed a phase III study comparing vinblastine with estramustine + vinblastine (EM-V) in 201 patients with advanced prostate cancer. The median survival was 11.9 months in the EM-V arm vs 9.2 mo for those receiving vinblastine. Although overall survival was not signiﬁcantly different between the two treatment arms, there was a statistically signiﬁcant improvement in time to disease progression and PSA response favoring the EM-V arm (30). The taxanes have emerged as among the most active class of antineoplastics in advanced prostate cancer (Table 2). Although the initial phase II trial of paclitaxel given as a 24-h infusion was unimpressive (31), work in human prostate cancer cell lines provided evidence that prolonged exposure to paclitaxel enhances the antimitotic effects of estramustine (32). Additional studies in human prostate cancer cell lines suggest that chemotherapy resistance in prostate cancer can in part be correlated with bcl2 over expression. Haldar et al. (33) demonstrated that paclitaxel could induce apoptosis in bcl-2-expressing PC-3 prostate cancer cells via phosphorylation of bcl-2, which may be a an effect from taxane-induced cell cycle arrest. Hudes and colleagues (34) subsequently performed a series of trials combining paclitaxel and estramustine demonstrating more interesting levels of antineoplastic activity and leading to a large number of phase II and subsequent phase III clinical trials evaluating paclitaxel, docetaxel, and estramustine. Docetaxel, a semisynthetic taxoid, has a wide range of activity in several epithelial cancers. Picus et al. (35) treated 35 patients with advanced prostate cancer with docetaxel administered at a dose of 75 mg/m2 every 21 d. Forty-six percent of patients had a >50% PSA decline, and four patients (28%) had an objective response including one complete responder. The median overall survival for this group was reported as 27 mo. Toxicity included two treatment-related deaths (35). Petrylak et al. (36) performed a phase I trial of docetaxel and estramustine that demonstrated a 28% objective response rate. Interestingly 7 of the 13 responding patients had previously been treated with estramustine alone (36). Saverese and colleagues (37) from the CALGB performed a

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large phase II trial of docetaxel 70 mg/m2 every 3 wk plus oral estramustine, 280 mg three times a day for 5 d plus hydrocortisone 40 mg daily in men with advanced prostate cancer. Of the 46 evaluable patients, there was a 50% objective response rate including 3 complete responders. A ≥50% decline in PSA values was seen in 68% of patients. Combining measurable and PSA response, there was an overall response rate of 54%. Neutropenia was common, and 9% of patients had a thromboembolic complication. The median survival of the group was reported as 20 mo (37). Two recently completed phase III trials may better deﬁne the role of chemotherapy in advanced prostate cancer. The Southwest Oncology Group compared mitoxantrone (12 mg/m2 q21d) and prednisone (5 mg bid) with docetaxel (60 mg/m2 q21d) plus estramustine (280 mg tid, d 1–5 q21d) in over 600 patients with advanced, androgen-independent prostate cancer. Patients receiving docetaxel plus estramustine were premedicated with decadron and received daily aspirin as prophylaxis for thromboembolic complications. An industry-sponsored phase III study randomized over 1000 patients with advanced, androgen-independent prostate cancer into three treatment arms: mitoxantrone (12 mg/m2 q21d) and prednisone (5 mg bid); docetaxel 75 mg/m2 q21d plus prednisone 10 mg/d; and docetaxel 30 mg/m2 weekly 5 out of 6 wk plus prednisone 10 mg/d. In contrast to the historical view of chemotherapy in advanced prostate cancer, there is now compelling evidence to support its role in the palliative management of patients with advanced disease. Many unanswered questions remain, including the impact of chemotherapy on progression-free survival and overall survival. The optimal drugs and schedules remain undeﬁned. Phase II studies suggest a higher objective response rate when estramustine is added to both docetaxel and paclitaxel, but with added toxicity and costs. Investigation into the role of earlier administration of chemotherapy in androgen-independent disease is actively being pursued. The Eastern Cooperative Oncology Group has activated E1899, a randomized trial of ketoconazole plus hydrocortisone vs docetaxel plus estramustine in patients with rising PSA values following androgen suppression.

SUPPORTIVE CARE ISSUES Despite advances in the management of advanced prostate cancer, ultimately patients progress, typically with the triad of progressive pain, wasting (cachexia/ anorexia), and fatigue. External beam radiotherapy has been the mainstay of the management of painful bone metastases for decades. Radiotherapy has a proven role in palliation of pain from bone metastases, with numerous randomized trials obtaining response rates in the 70–90% range (38). Although the efﬁcacy of radiotherapy is not in doubt, the optimal dose and fractionation schema remains controversial. Advocates of a single large radiotherapy fraction (8–10 Gy) point to the potential for rapid response and convenience; critics note an increased toxicity proﬁle and that a decrease in total dose may compromise the duration of response. Prolonged schedules (40 Gy in 20 fractions or 50 Gy in 25 fractions) result in less acute toxicity and may provide longer control but are problematic for many patients. Typical treatment schedules in North America consist of 20 Gy in 5 fractions or 30 Gy in 10 fractions (38). Radiopharamaceuticals represent another systemic therapy option for patients with multiple painful bony metastatic sites. Strontium-89, the ﬁrst radiopharmaceutical approved for use in the United States, is a pure β-emitting radioactive analog of cal-

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cium that selectively irradiates metastatic sites in bone while generally sparing normal bone tissue. Other radiopharmaceuticals either approved or in clinical trials include samarium-153 ethylenediaminetetramethylene phosphonate, rhenium-186 hydroxyethylidene diphosphonate, and tin-117m (4+) diethylene triaminepentaacetic acid. Studies suggest that 60–80% of patients with prostate cancer derive a palliative beneﬁt from systemic administration of bone-seeking β-emitting radiopharmaceuticals (39). As the role of chemotherapy has evolved, the utility of radiopharmaceuticals has become less clear, given the potential for long-term effects on bone marrow from repeated administration of many of these agents. The role of bisphosphonates in advanced disease continues to evolve. Clinical trials involving older generation bisphosphonates such as pamidronate and clodronate have failed to demonstrate meaningful clinical beneﬁt (40,41). Recently a phase III doubleblind trial comparing two doses of a new generation bisphosphonate, zoledronic acid, was compared with placebo in 600 plus patients with androgen-independent metastatic prostate cancer. At the 4-mg dose, zoledronic acid decreased the number of skeletal related events (deﬁned as pathologic fracture, spinal cord compression, surgery, or radiotherapy to bone or changes in antineoplastic therapy to treat bone pain) compared with placebo. Therapy at the 4-mg dose was well tolerated; the 8-mg dose was found to have an unacceptable rate of renal insufﬁciency (42).

CONCLUSIONS Despite aggressive efforts at early detection and intervention, signiﬁcant numbers of men with prostate cancer ultimately develop disease progression and die of disease. In the last decade a series of additions to our therapeutic armamentarium have led to improvements in the quality of life of some patients with advanced disease. As our understanding of the molecular biology of the disease improves, we will need to develop the next generation of clinical trials to test these emerging therapies in the most expeditious manner so they can be rapidly introduced into clinical practice.

REFERENCES 1. Jemal A, Murray T, Samels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin 2003;53:5–26. 2. Scher H, Steineck G, Kelly W. Hormone-refractory prostate cancer: reﬁning the concept. Urology 1995;46:142–148. 3. Gittes R. Carcinoma of the prostate. N Engl J Med 1991;324:236–245. 4. Kelly WK, Scher HI. Prostate speciﬁc antigen decline after antiandrogen withdrawal: the ﬂutamide withdrawal syndrome. J Urol 1993;149:607–609. 5. Kelly WK, Slovin S, Scher HI. Steroid hormone withdrawal syndromes. Pathophysiology and clinical signiﬁcance. Urol Clin North Am 1997;24:421–431. 6. Taplin ME, Halabi S, Rajeshkumar B, et al. Androgen receptor mutations in androgen independent prostate cancer do not correlate with anti-androgen withdrawal response: CALGB 9663. Proc Am Soc Clin Oncol 2001;20:1738 abst. 7. Wehbe TW, Stein BS, Akerley WL. Prostate-speciﬁc antigen response to withdrawal of megestrol acetate in a patient with hormone-refractory prostate cancer. Mayo Clin Proc 1997;72:932–934. 8. Small EJ, Bok R, Simultaneous antiandrogen withdrawal and treatment with ketoconazole and hydrocortisone in patients with advanced prostate carcinoma. Cancer 1997;80:1755–1759. 9. Sartor AO, Tangen C, Hussain M, Eisenberger M, Crawford ED. Anti-androgen withdrawal in prostate cancer: results from SWOG 9426. Proc Am Soc Clin Oncol 2002;21:197a (abst 785). 10. Taplin ME, Bubley GJ, Shuster TD, et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med 1995;332:1393–1398.

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11. Dowsett M, Shearer RJ, Ponder BA, Malone P, Jeffcoate SL. The effects of aminoglutethimide and hydrocortisone, alone and combined, on androgen levels in postorchiectomy prostatic cancer patients. Br J Cancer 1988;57:190–192. 12. Oh WK. Secondary hormonal therapies in the treatment of prostate cancer. Urology 2002;60(suppl 3A):87–92. 13. Fowler JE Jr, Pandey P, Seaver LE, Feliz TP. Prostate speciﬁc antigen after gonadal androgen withdrawal and deferred ﬂutamide treatment. J Urol 1995;154:448–453. 14. Fossa SD, Slee PH, Brausi M, et al. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group. J Clin Oncol 2001;19:62–71. 15. Tannock I, Gospodarowicz M, Meakin W, Panzarella T, Stewart L, Rider W. Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol 1989;7:590–597. 16. Tannock IF, Osaba D, Stackler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 1996;14:1756–1764. 17. Kantoff PW, Halabi S, Conaway M, et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol 1999;17:2506–2513. 18. Small EJ, Halabi S, Picus J, et al. A prospective randomized trial of antiandrogen withdrawal alone or antiandrogen withdrawal in combination with high-dose ketoconazole in androgen independent prostate cancer patients: results of CALGB 9583. Proc Am Soc Clin Oncol 2001;20:695 (abst). 19. Tannock IF. Is there evidence that chemotherapy is of beneﬁt to patients with carcinoma of the prostate? J Clin Oncol 1985;3:1013–1021. 20. Moore MJ, Osoba D, Murphy K, et al. Use of palliative endpoints to evaluate the effects of mitoxantrone and low-dose prednisone in patients with hormonally resistant prostate cancer. J Clin Oncol 1994;12:689–694. 21. Ranganathan S, Benetatos CA, Colarusso PJ, Dexter DW, Hudes GR. Altered beta-tubulin isotype expression in paclitaxel-resistant human prostate carcinoma cells. Br J Cancer 1998;77:562–566. 22. Laing N, Dahllof B, Hartley-Asp B, Ranganathan S, Tew KD. Interaction of estramustine with tubulin isotypes. Biochemistry 1997;36:871–878. 23. Pienta KJ, Lehr JE. Inhibition of prostate cancer growth by estramustine and etoposide: evidence for interaction at the nuclear matrix. J Urol 1993;149:1622–1625. 24. Goodin S, Rao VK, Dipaola RS. State-of-the-art treatment of metastatic hormone-refractory prostate cancer. Oncologist 2002;7:360–370. 25. Morant R, Hsu Schmitz SF, Bernhard J, et al. Vinorelbine in androgen-independent metastatic prostatic carcinoma—a phase II study. Eur J Cancer 2002;38:1626–1632. 26. Dexeus F, Logothetis CJ, Samuels ML, Hossan E, von Eschenbach AC. Continuous infusion of vinblastine for advanced hormone-refractory prostate cancer. Cancer Treat Rep 1985;69:885–886. 27. Seidman AD, Scher HI, Petrylak D, Dershaw DD, Curley T. Estramustine and vinblastine: use of prostate speciﬁc antigen as a clinical trial end point for hormone refractory prostatic cancer. J Urol 1992;147:931–934. 28. Hudes GR, Greenberg R, Krigel RL, et al. Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer. J Clin Oncol 1992;10:1754–1761. 29. Attivissimo LA, Fetten JV, Kreis W. Symptomatic improvement associated with combined estramustine and vinblastine chemotherapy for metastatic prostate cancer. Am J Clin Oncol 1996;19:581–583. 30. Hudes G, Einhorn L, Ross E, et al. Vinblastine versus vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: a Hoosier Oncology Group and Fox Chase Network phase III trial. J Clin Oncol 1999;17:3160–3166. 31. Roth BJ, Yeap BY, Wilding G, Kasimis B, McLeod D, Loehrer PJ. Taxol in advanced, hormone-refractory carcinoma of the prostate. A phase II trial of the Eastern Cooperative Oncology Group. Cancer 1993;72:2457–2460. 32. Speicher LA, Barone L, Tew KD. Combined antimicrotubule activity of estramustine and taxol in human prostatic carcinoma cell lines. Cancer Res 1992;52:4433–4440. 33. Haldar S, Chintapalli J, Croce CM. Taxol induces bcl-2 phosphorylation and death of prostate cancer cells. Cancer Res 1996;56:1253–1255. 34. Hudes GR, Nathan F, Khater C, et al. Phase II trial of a 96-hour paclitaxel plus oral estramustine phosphate in metastatic hormone-refractory prostate cancer. J Clin Oncol 1997;15:3156–3163.

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35. Picus J, Schultz M. Docetaxel as monotherapy in the treatment of hormone-refractory prostate cancer: preliminary results. Semin Oncol 1999;26(suppl 17):14–18. 36. Petrylak DP, Macarthur RB, O’Connor J, et al. Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol 1999;17:958–967. 37. Savarese DM, Halabi S, Hars V, et al. Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a ﬁnal report of CALGB 9780. Cancer and Leukemia Group B. J Clin Oncol 2001;19:2509–2516. 38. Catton CN, Gospodarowicz MK. Palliative radiotherapy in prostate cancer. Semin Urol Oncol 1997;15:65–72. 39. McEwan AJB. Unsealed source therapy of painful bone metastases: an update. Semin Nucl Med 1997;27:165–182. 40. Lipton A, Small E, Saad F, et al. The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate. Cancer Invest 2002;20(suppl 2):45–54. 41. Dearnaley DP, Sydes MR, on behalf of the MRC Pr05 Collaborators. Preliminary evidence that oral clodronate delays symptomatic progression of bone metastases from prostate cancer: ﬁrst results of the MRC Pr05 Trial. Proc Am Soc Clin Oncol 2001;20(abst):174a. 42. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94:1458–1468. 43. Dawson NA, Conaway M, Halabi S, et al. A randomized study comparing standard versus moderately high dose megestrol acetate for patients with advanced prostate carcinoma: cancer and leukemia group B study 9181. Cancer 2000;88:825–834. 44. Joyce R, Fenton MA, Rode P, et al. High dose bicalutamide for androgen independent prostate cancer: effect of prior hormonal therapy. J Urol 1998;159:149–153. 45. Sartor O, Cooper M, Weinberger M, et al. Surprising activity of ﬂutamide withdrawal, when combined with aminoglutethimide, in treatment of “hormone-refractory” prostate cancer. J Natl Cancer Inst 1994;86:222–227. 46. Small EJ, Halabi S, Picus J, et al. A prospective randomized trial of antiandrogen withdrawal alone or antiandrogen withdrawal in combination with high-dose ketoconazole in androgen independent prostate cancer patients: results of CALGB 9583. Proc Am Soc Clin Oncol 2001;20(abst):695. 47. Shahidi M, Norman AR, Gadd J, et al. Prospective review of diethylstilbestrol in advanced prostate cancer no longer responding to androgen suppression. Proc Am Soc Clin Oncol 2001;20(abst):2455. 48. Hudes GR, Manola J, Conroy J, Habermann T, Wilding G. Phase II study of weekly paclitaxel by 1hour infusion plus reduced-dose oral estramustine in metastatic hormone-refractory prostate carcinoma. Proc Am Soc Clin Oncol 2001;20(abst):697.

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Bone-Targeted Therapy for Prostate Cancer Navjeet Gandhok and Oliver Sartor

INTRODUCTION Both prostate cancer and treatments for prostate cancer have potentially harmful effects on bone. Prostate cancer reliably metastasizes to bone in its advanced stages, and these metastatic deposits have a variety of deleterious effects on patients including pain and pathologic fractures. In addition, commonly utilized androgen deprivation strategies used in prostate cancer treatment reduce bone mineral density, which in turn can lead to osteopenia or osteoporosis with its attendant risks. Thus, a relatively unique series of relationships exists in prostate cancer patients among the bone, the cancer, and commonly administered treatments. Although bone metastasis occurs in a variety of human solid tumors, several aspects related to these metastases are relatively unique to patients with prostate cancer. First, the frequency of clinically signiﬁcant metastases to bone in patients with advanced prostate cancer is exceptionally high. Second, the ratio of soft tissue to bone metastases is exceptionally low. Third, the survival of patients with bone metastases and prostate cancer is relatively prolonged compared with that of patients with bone metastases from other common solid tumors such as lung cancer. As a consequence, the prevalence of this condition is high compared with that of other malignant conditions. Fourth, metastatic prostate cancer is remarkably osteoblastic compared with the lesions caused by most other metastatic tumors. This chapter focuses attention on two broad methods of therapeutically targeting bone metastases in prostate cancer patients. These include the bone-seeking radioisotopes and the bisphosphonates. This is not to say that other therapies are not applicable to the treatment of bone metastases in prostate cancer patients; quite clearly external beam radiation and a variety of systemic therapies (including hormonal therapy and chemotherapy) may play an important therapeutic role in these patients. However, as these therapies are not bone targeted, they are not covered in this chapter. Because androgen deprivation therapies induce osteoporosis, aspects related to this therapyinduced condition are covered as well. From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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THE PATHOPHYSIOLOGY OF BONE METASTASES Studies of venous blood samples in prostate cancer patients reveal that cytokeratin and prostate-specific antigen (PSA) mRNA-expressing cells can be detected in a substantial percentage of cases (1–3). These results imply that circulating prostate cancer cells are common in men with prostate cancer. Despite this finding, which implies that virtually all organs will be seeded with prostate cancer cells, overt metastases are restricted to bone in approx 80% of cases in patients with advanced prostate cancer (4–7). This provides validation for the “seed and soil” hypothesis of metastastic disease originally proposed by Paget in 1889 (8). Also providing evidence in support of this hypothesis is the finding that careful examination of autopsy materials in patients with advanced prostate cancer indicates that microscopic metastases are widespread (particularly in the lung) but that macroscopic lesions are relatively uncommon outside of the bone (6). It has long been known that hematopoietic precursors “home” to bone marrow by virtue of cellular interactions between various soluble and insoluble factors. Cytokines and their receptors, various matrix proteins and their receptors, and cell/cell interactions have all been implicated in this process (9,10). It is now assumed that interactions between various receptors expressed on prostate cancer cell receptors and the bone stroma/bone matrix/bone vasculature are necessary for the development of bone metastases. The precise ligand/receptor systems involved with the homing and growth of prostate cancer bone metastases are under current study in various laboratories. It is known that bone marrow stromal cells, unlike the stroma derived from a number of other tissues, are distinctly supportive of prostate cancer growth (10,11). Thus stromal/epithelial interactions are thought to be central to the fertile “soil” hypothesis. The CXCR4 receptor and its ligands stromal-derived factor-1A (SDF-1A or CXCL12) have been implicated by some investigators in “homing” responses of a variety of cells including prostate cancer (9). Bone matrix proteins such as osteopontin and osteonectin may also play a critical role as these ligands interact with integrins on the cell surface of prostate cancer cells and promote a variety of malignant processes including migration, invasion, and protease activation (12,13). Direct cell-cell interactions may or may not be important in the metastatic process, but it is known that gap junctional communication can be established between stroma and epithelial cells and that communication can be established via this mechanism (14). In addition it is known that stroma and epithelial cells may also have various interactions via cell surface molecules (15). Which of these interactions, or combination of interactions, are most important in establishing clinically relevant metastases is an area of active and ongoing investigation. As noted above, the osteoblastic nature of prostate cancer bone metastases is also a unique feature of this disease. Although numerous metastatic cancers may cause osteoblastic reactions in bone, none do so as frequently as prostate cancer. Multiple hypotheses have been constructed to explain this observation. Prostate cancer cells are known to secrete various factors that stimulate bone growth. Table 1 brieﬂy summarizes the factors involved in the regulation of osteoblast and osteoclast function and potentially related to prostate cancer bone metastases. One such group, bone-morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) superfamily. These proteins, including BMP-1–BMP-7, regulate integrin expression and, as a consequence, cell adhesion. Normal human prostate and neoplastic human prostate cell lines

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Table 1 Potential Factors Involved in the Regulation of Osteoblast and Osteoclast Function in Prostate Bone Metastases Potential osteoblast proliferation/differentiation promoters Endothelin-1 Transforming growth factor-β Insulin-like growth factor-I (IGF-I) Acidic and basic ﬁbroblast growth factors (FGFs) Platelet-derived growth factor (PDGF) Bone morphogenetic proteins (BMPs) Prostate-speciﬁc antigen (PSA) Osteoclast promoters and inhibitors Receptor activator of nuclear factor-κ B (RANK) RANK ligand (RANKL) Osteoprotegerin (OPG) Parathyroid hormone-related peptide (PTHrP)

express BMPs, with BMP-4 being among those most frequently reported (15–18). Of interest, BMP-6 expression in radical prostatectomy specimens has been shown to correlate with increased recurrence rates and decreased survival (18). TGF-β itself may promote osteoblastic change. TGF-β is a key negative growth regulator in the normal prostate. Although TGF-β inhibits the proliferation of normal prostate cells and functions as a tumor suppressor in early tumorigenesis, it acts as a tumor promoter in later stages of tumor progression. Overexpression of TGF-β aids tumorigenesis by stimulating angiogenesis and suppressing the immune system and also by acting directly on the prostate tumor cells with induction of extracellular matrix proteins, cell adhesion proteins, and proteases (19,20). Serum TGF-β has also been shown to be a biochemical marker for disease recurrence (21). TGF-β directly enhances both osteoblast activation and replication and may play a direct role in the development of osteoblastic metastases. Osteoblast and stromal cells are also involved in osteoclast differentiation and activation as part of a complex interplay between the cellular components in bone. RANK ligand (RANKL), a transmembrane molecule located on bone marrow stromal cells and osteoblasts, binds to RANK, which is located on the surface of osteoclast precursors. RANKL plays an important role in tumor-induced promotion of osteoclast activity. Also known as nuclear factor-κ B ligand, a soluble form of RANKL is produced by prostate cancer bone metastases and enables these metastases to induce osteolysis through osteoclast activation (22). Osteoprotegerin (OPG) is a soluble osteoclastogenesis inhibitor produced by osteoblasts and stromal cells that regulate bone turnover. OPG is overexpressed in prostate cancer cells present in bone metastases and acts as a decoy receptor in the RANK-RANKL signaling system. OPG binds to RANKL, sequestering it from binding to RANK, which results in a signiﬁcant inhibition of osteoclastogenesis (23). Serum OPG levels may be related to disease progression, and further studies are ongoing in this ﬁeld. RANKL and OPG expression may have implications for the establishment and development of blastic bone metastases in advanced prostate cancer, and this system is now being exploited in terms of novel therapeutic approaches (see below).

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In addition to the factors noted above, prostate cancer cells produce growth factors that promote osteoblast growth and/or differentiation, including insulin-like growth factors (IGFs) and endothelin-1 (ET-1) (Table 1). ET-1 activates osteoblasts and causes osteoblast proliferation and bone formation (24,25). Plasma ET-1 levels are signiﬁcantly elevated in men with metastatic prostate cancer. Antagonists to endothelin receptors are now in clinical trials for prostate cancer with preliminary results that are provocative (see below). Insulin-like IGFs also stimulate osteoblasts (26). Proteases such as PSA are produced by prostate cancer cells and may activate IGF and TNF by cleaving them from their binding proteins (26). PSA may also directly activate osteoblasts. Parathyroid hormone-related peptide (PTHrP) is produced by prostate cancer cells and can promote both osteoclastogenesis and increased osteoclast activity (22). Other growth factors involved in osteoblast proliferation include both acidic and basic fibroblast growth factors (aFGFs and bFGFs) and possibly platelet-derived growth factor (PDGF) (26). Taken together, the interactions among tumor, bone stroma, osteoclasts, and osteoblasts are mediated via a variety of potential factors that are under active investigation at this time. Soluble factors, insoluble matrix factors, and direct cell-to-cell interactions may all govern tumor-bone interactions in a complex array of interdependent interactions. Therapeutic approaches based on these observations are currently under investigation; both OPG and endothelin antagonists have reached clinical trials at this time.

CLINICAL, RADIOGRAPHIC, AND BIOCHEMICAL EVALUATION OF THE PATIENT CONSIDERED FOR BONE-TARGETED THERAPIES Currently approved bone-targeted therapies (bisphosphonates and radiopharmaceuticals) for prostate cancer metastases are presently indicated only for patients with hormone-refractory disease. When evaluating prostate cancer patients, clinicians should distinguish those patients with hormone-refractory disease from others, as this simple categorization is of signiﬁcant value in many respects. Although many potential deﬁnitions of hormone-refractory (androgen-independent disease) disease have been proposed, the simplest and most direct deﬁnition is that of prostate cancer growth as evidenced by disease progression in the face of castrate testosterone levels. Although the term “castrate” is imprecise, many protocols and investigators have accepted levels of total testosterone of <50 ng/dL as being castrate. The most common evidence of hormone-refractory disease today is a rising PSA in the face of a castrate level of testosterone. Rare patients may have radiographic or clinical progression in the absence of PSA progression. Bone metastases may or may not be painful when initially detected. In addition, pain is not a reliable indicator of skeletal metastases, especially in an older patient population that is frequently afﬂicted with degenerative joint disease and other musculoskeletal disorders. Studies of patients previously diagnosed with stage D2 prostate cancer and treated with endocrine therapy have been carefully evaluated. These data indicate that PSA will rise approx 6 mo before the onset of new bone scans changes and that new bone scan changes will occur approx 4 mo before the patients reports the onset of pain (27). These data indicate that in patients with previously diagnosed D2 disease pain will follow the onset of hormone-refractory disease by 10 mo on average. The relationship among PSA rise, bone scan change, and pain has not been studied in hor-

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mone-refractory patients initially diagnosed with earlier (non-D2) disease. Given that many patients today are treated with hormonal therapies prior to the onset of bone metastases, this remains an important unanswered question in the natural history of this complex disease. The relationship between PSA and a positive bone scan has been well studied in patients initially diagnosed with prostate cancer. In patients with well to moderately differentiated tumors, there is a clear relationship between PSA level and the probability of a positive bone scan. Patients with a PSA of <10 ng/mL in this setting very rarely have a positive scan, and there is reason not to order a bone scan in this subset of patients (28). Patients with poorly differentiated prostate cancer have a less predictable relationship between PSA and bone scan positivity. Patients previously treated with a deﬁnitive therapy who then experience a PSA rise also have a strong relationship between PSA level and bone scan positivity (29). The relationship between PSA level and bone scans in patients previously treated with medical or surgical castration prior to the onset of documented bone metastases remains unexplored. The most expedient way to determine the presence or absence of bone metastases in a prostate cancer patient is a conventional bone scan; however, it is important to recognize that bone scans are imperfect tests and that demonstrating increased uptake on bone scan clearly does not equate to the presence of metastatic disease. Worsening of bone scan lesions may be associated with healing bone, and the issue of “ﬂare” has been raised in patients favorably responding to a therapeutic change. Typical MDP-Tc99 bone scans show increased uptake in Paget’s disease, trauma, and arthritis as well as in the presence of osteoblastic lesions. One study evaluated bone scans with one or two new abnormalities in cancer patients with no known metastases and showed that metastatic disease was conﬁrmed only for 25/231 scans (11%) with one new abnormality and for 17/70 (24%) scans with two new abnormalities (30). Another study in patients with early-stage breast cancer (invasive T1 or T2 lesions) showed a 32.6% incidence of false-positive bone scans, with patients over 50 yr of age having a signiﬁcantly greater incidence of false-positive scans (31). A retrospective review of 2851 bone scans done at a cancer center over a period of 4 yr suggested that solitary rib lesions were uncommon as the ﬁrst abnormal scintigraphic ﬁnding and were most frequently (90%) associated with benign etiology (32). Another study with 199 patients showed that 11/93 (11.8%) patients had a solitary malignant rib hot spot and suggested that follow-up bone scans and radiographs are needed for further investigation of these solitary rib lesions (33). In a prospective review of bone scintigraphic ﬁndings in breast cancer patients without known metastatic disease, an association was seen between the number of new lesions and the likelihood of metastatic disease. Prevalence of metastatic disease increased from 11% for scans with one new lesion to 100% for those with ﬁve or more new abnormalities (34). Clearly, new lesions are a more reliable ﬁnding than changes in prior lesions; however, even new lesions must be interpreted with caution as they may not represent advancing disease. Although these ﬁndings have been reported in metastatic breast cancer, it is considered most likely that they are applicable to the prostate cancer patient as well. Bone scan ﬁndings therefore need to be interpreted in the context of clinical picture, laboratory data, and correlative radiologic studies, as well as clinical follow-up data. All imaging tests, including additional radiographic testing, are limited in the sense that disease volume must exceed a certain threshold prior to overt positivity.

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LABORATORY FINDINGS ASSOCIATED WITH BONE METASTASES Laboratory ﬁndings in patients with prostate cancer and bone metastases may or may not include an abnormal PSA. It is important to recognize that patients previously diagnosed with bone metastases treated with medical or surgical castration will often normalize their PSA after such therapies. Given that PSA values change rapidly and that bone scans changes occur slowly, it is not uncommon for such patients to have a normal PSA and a bone scan compatible with metastatic disease. Elevated serum alkaline phosphatase, increased urinary hydroxyproline and deoxypyridoline, and anemia are common in patients with bone metastases. Each of these laboratory markers is typically proportional to the extent of bony metastatic disease; however, speciﬁc treatments may alter these relationships. Anemia may be exacerbated by androgen deprivation (35–38), radiation (37), bisphosphonates (39–41), or chemotherapies (42). Bisphosphonates may reduce markers associated with bone turnover such as urinary hydroxyproline and deoxypyridoline, as discussed later. Total alkaline phosphates may be elevated in the presence of either liver or bone disease, and an enzyme isotype analysis may be required to distinguish between these possibilities. Both osteoblastic and osteolytic lesions are characterized by increased bone resorption. Osteolytic disease is rare in prostate cancer except in patients with very poorly differentiated tumors. This is important for treatment purposes as currently available bone-targeted radiopharmaceuticals speciﬁcally target osteoblastic but not osteolytic lesions.

BONE-TARGETED RADIOISOTOPE THERAPY For patients with multiple painful bony osteoblastic metastases who have failed initial chemotherapy or hormonal therapy and who do not have cord compression, pathologic fracture, or impending pathologic fracture, therapeutic radioisotopes have emerged as a viable therapeutic option for many patients. Radioisotopes are also useful in patients previously treated to their maximal normal tissue tolerance with external beam radiation but with symptoms of persistent bone pain (43). When considering radioisotope therapy, an important consideration is effectiveness and patient tolerance to conventional analgesic treatment. If opioid analgesics are controlling pain with minimal side effects, the need for alternative palliative therapy is diminished. External beam radiation is an excellent treatment choice for patients with hormone-refractory prostate cancer and focal skeletal involvement. Relative indications and contraindications for radiopharmaceutical therapy are summarized in Table 2. A baseline complete blood count needs to be done to rule out signiﬁcant thrombocytopenia and neutropenia prior to therapy, as these agents cause marrow suppression. Severe renal dysfunction is a contraindication to radioisotope treatment, as currently used agents are predominantly excreted via the kidney. Three radioisotopes are currently approved for the treatment of bone pain: phosphorus-32 (32P), strontium-89 (89Sr) chloride (Metastron®), and samarium-153 (153Sm) complexed with ethylenediaminetetramethylene-phosphonic acid (EDTMP), also called Quadramet®. These isotopes are incorporated into bony metastases and other sites of active bone turnover where therapeutic activity results from emission of β-particles. The mechanism of metastatic localization varies. 89Sr is similar to calcium in its localization to bone and can be viewed as a calcium analog. Retention of 89Sr has been shown to be enhanced in areas of metastatic disease compared with normal bone. 32P is targeted nonspeciﬁcally to phosphorus pathways. 153Sm does not target to bone per se;

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Table 2 Current Indications/Contraindications for Radiopharmaceuticals in Patients With Hormone-Refractory Metastatic Prostate Cancer Indications Painful bone metastasis Bone scan positive Diffuse skeletal involvement Hormone-insensitive tumor Poor analgesic control of pain Analgesic intolerant patient Relative contraindications Present or impending pathologic fracture Present or impending spinal cord compression Unifocal bone lesions. Absolute Contraindications Bone scan negative Severe marrow suppression Signiﬁcant renal impairment

however, when administered as a chelated complex with EDTMP, is utilizes the phosphonic acid groups of EDTMP to localize to areas of high bone turnover in a manner analogous to a conventional technetium methylene diphosphonate bone scan. The osteoid surrounding the osteoblastic lesion is comprised of proteins that provide a rich and selective source of binding sites for this compound. It is important to recognize that none of the currently available bone-targeted isotopes target the tumor itself, but rather the region of abnormal bone adjacent to the tumor. Comparative half-lives and β-particle energy are summarized in Table 3. The β-particles from 32P (1.71 MeV maximum, 0.69 MeV average) and 89Sr (1.46 MeV maximum, 0.58 MeV average) are of higher energy than those from 153Sm (0.81 MeV maximum, 0.29 MeV average). The tissue penetration of the β-particles associated with each isotope increases as a function of the energy of the emitted particle. The 89Sr particles will penetrate approx 3.4 mm in bone, whereas the 153Sm will penetrate only about half that distance. Even though conceptually more attractive for therapeutic purposes, higher energy particles are associated with greater marrow toxicity as a consequence of larger volumes of marrow being exposed to radiation. Because of myelosuppression, 32P is rarely used in the United States for palliation of bone pain. However, 32P has been used for speciﬁc suppression of marrow activity in myeloproliferative diseases like polycythemia vera. Compared with 32P, the newer radioisotopes are more selectively incorporated into the skeletal system. The half-life of 89Sr is 50.5 d, that of 32P is 14 d, and that of 153Sm is 1.9 d or 46 h. This shorter half-life of the samarium isotope means a shorter dose delivery time, with 75% of the β-emission for 153Sm delivered over 3.8 d (two half-lives). For 89Sr, 75% of the β-particles are delivered over approx 101 d (two half-lives). With 89Sr, pain relief is typically delayed in onset, occurring 7–20 d post injection, whereas pain relief is sooner with 153Sm. 153Sm has signiﬁcant γ-emissions that can be used for bone scan-like imaging and prospective dose estimation. Scans obtained with 153Sm are identical to traditional bone scans; however, the isotope is not approved for sole imaging purposes.

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Isotope Samarium-153 Strontium-89 Phosphorus-32

Half-life (d)

Beta-energy (average/maximum) (MeV)

Bone penetration (mm)

Gamma

1.9 50.5 14.3

0.22/0.81 0.58/1.46 0.7/1.71

0.55 2.4Z 2.7

Yes No No

Several other potential radioisotopes merit mention: 186Rhenium-hydroxyethilidine diphosphonate (186Rh-HEDP), 188Rh-EDTMP, 117Tin-diethylenetriaminepentaacetic acid (DTPA), and 223Radium. These are investigational radioisotopes that have been used in various settings for the treatment of bone pain; however, none are Food and Drug Administration (FDA)-approved for use in the United States.

EFFECTIVENESS OF RADIOISOTOPES AS INDIVIDUAL AGENTS FOR TREATMENT OF PAINFUL BONE METASTASES AS EVALUATED BY RANDOMIZED TRIALS Given the potential vagaries of assessing pain in the absence of controlled settings, the review of clinical trials assessing efﬁcacy will be restricted to those trials that are randomized. We note that the exact mechanisms of pain relief after radioisotope administration are poorly understood (44). A small double-blind study compared strontium with placebo in 32 patients with hormone-refractory prostate cancer patients with painful bone scan-positive disease. Both efﬁcacy and toxicity were evaluated at a single time point (5 wk) after injection of 4 mCi of 89Sr or placebo. Of the 32 patients, 26 were evaluated at the 5-wk endpoint and were found to have a higher percentage of pain improvement with 89Sr injection compared with placebo. Substantial conclusions could not be made from the study as the number of evaluable patients were few, and quantitative assessment of analgesic consumption and pain were not reported (45). In another randomized study, 49 patients with skeletal metastases from androgenindependent prostate cancer were assigned to 89Sr (75 MBq or 2 mCi) or placebo, each administered three times at monthly intervals. Although the timing of pain evaluation was not speciﬁed, no signiﬁcant differences in pain relief were noted between the two treatment groups. Analgesic consumption was not monitored, nor was toxicity reported. The authors concluded that 89Sr was ineffective in relieving bone pain at this dose and schedule. The 2-yr survival rate was 46% in patients receiving 89Sr compared with 4% in patients treated with placebo. Although potentially of interest, this survival advantage has not been conﬁrmed in other studies using 89Sr alone (46). In a United Kingdom study comparing 200 MBq 89Sr and conventional radiotherapy, 284 men with symptomatic hormone-resistant prostate cancer were randomly assigned to receive 89Sr or conventional radiotherapy (focal or hemibody irradiation). Study endpoints included pain at the index site, appearance of new painful sites, requirement for additional palliative radiotherapy, and survival. All treatments provided effective pain relief that was sustained at 3 mo. Signiﬁcantly fewer patients

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reported new pain sites after 89Sr. Compared with focal (but not hemibody irradiation), fewer patients treated with the radioisotope required subsequent radiation (47). For 153Sm-EDTMP, two prospective, placebo, randomized multi-institutional double-blind phase III trials have been performed, both using palliative primary endpoints. In the ﬁrst trial, 118 patients, with a variety of histologically conﬁrmed cancers and painful bone scan-positive lesions, were randomly assigned to a single intravenous injection of one or two doses of 153Sm-EDTMP (0.5 or 1.0 mCi/kg) or to the placebo (152Sm-EDTMP, a nonradioactive form of samarium). Nonresponders at wk 4 could be unblinded and receive the radioactive isotope. Most patients had prostate cancer (68%); the second most common diagnosis was breast cancer (18%). Compared with placebo (the nonradioactive samarium-EDTMP complex), patients treated with the higher dose of 153Sm-EDTMP (1 mCi/kg or 37 MBq/kg) had signiﬁcantly decreased pain scores in wk 1–4 after treatment. Seventy-two percent of the patients treated with 1.0 mCi/kg experienced some degree of pain relief, which was still present in approx one-half of the responding patients 16 wk later. Compared with the placebo treatment group, patients receiving the therapeutic radioisotope had a decline in analgesic consumption. No differences in survival were noted between the treatment groups. Toxicity proﬁles were comparable in all respects in the three groups except for a transient decrease in circulating platelets and leukocyte counts in the isotope-treated groups. Recovery of myelosuppression was essentially complete by 8 wk, underscoring the reversible nature of myelosuppression in this cohort of patients (48). Of note, only a minority of these patients were pretreated with chemotherapy, and conclusions regarding the extent and reversibility of myelosuppression may not be applicable in the postchemotherapy setting. The second double-blind multi-institutional placebo-controlled trial evaluated 153Sm-EDTMP vs 152Sm-EDTMP (placebo) in bone pain palliation and was limited to 151 patients with metastatic hormone-refractory prostate cancer. Patients were randomized to 153Sm-EDTMP or 152Sm-EDTMP in a 2:1 ratio. Nonresponders were unblinded after 4 wk and offered open-label therapy. Pain was signiﬁcantly reduced at 1–2 wk following radioisotope injection and remained lower than placebo during the 4 wk of statistically valid follow-up. Compared with those receiving active therapy, the placebo group had signiﬁcantly higher analgesic consumption at 3 and 4 wk. Adverse events were similar between the two groups except for mild decreases in platelets and leukocyte counts. Nadirs were reached approx 4 wk after drug administration, and counts recovered approx 8 wk later (49). Studies have not been reported comparing 153Sm-EDTMP with external beam radiation therapy or other radioisotopes. 186Rh-HEDP was compared with placebo in a double-blinded crossover study, and the results showed a signiﬁcantly greater decrease in pain scores with 186Rh-HEDP (50). The β-emission half-life is short (17 h). This isotope appears promising for further evaluation in both combination and dose-intense therapy; however, continued commercial development of this isotope is not being pursued at this time. In summary, treatment-related toxicities are predominantly myelosuppression for all the radioisotopes. Blood counts should be monitored for at least 8 wk after dosing with the short-half lived radioisotopes and longer for 89Sr, given the 50.5-d half-life. Pain ﬂare, an increase in bone pain occurring hours to days after administration, occurs in <10% of patients but can be severe. This may be associated with a marked increase in analgesic requirements. Acute leukemia has been reported as a potential complication

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of 89Sr and 32P but not 153Sm-EDTMP (51). However, keeping in mind the short life expectancy of this group of patients with widely metastatic disease, the risk of leukemia transformation is generally thought to be low. Radioisotope treatment in men with hormone-refractory prostate cancer has been associated with only minor decreases in PSA in placebo-controlled studies; radiographic criteria for response have not been met.

RANDOMIZED TRIALS USING COMBINATIONS OF RADIOPHARMACEUTICALS AND RADIATION OR CHEMOTHERAPY Radiopharmaceutical combinations with chemotherapy and external beam radiation have been evaluated. Prospective, randomized, placebo-controlled trials have used a combination of external-beam radiation and 89Sr (52) and a combination of doxorubicin and 89Sr (53). A prospective multicenter Canadian trial evaluated 89Sr as an adjuvant therapy with local-ﬁeld external beam radiation for management of patients with advanced hormone-refractory metastatic prostate cancer. One hundred twenty-six men were randomized to receive a 10.8-mCi dose of 89Sr or placebo 0–7 d after conventional external beam radiation was completed. The primary endpoints of the study were effectiveness of therapy on the new painful metastatic bone lesions and on existing painful lesions, quality of life, survival, and toxicity. Both treatment groups had similar pain control at the irradiated in the index lesion and similar survival. However, a greater proportion of patients discontinued analgesics at 3 mo in the experimental arm (17% vs 2%). Treatment with 89Sr also resulted in signiﬁcantly better freedom from new painful metastatic lesions (59% vs 34%) and a prolonged time to next external beam radiotherapy treatment by a median of 15 wk. In the quality of life analysis, statistically signiﬁcant improvement in two parameters (pain and physical activity) was also demonstrated. Toxicity in the study was primarily hematologic (52). Grade IV thrombocytopenia toxicity was noted in 10.4% of patients treated with 89Sr. The duration of thrombocytopenia was not speciﬁed in this manuscript. This ﬁnding underscores the need for monitoring patients after 89Sr treatment. A single-institution randomized phase II study (53) evaluated the effectiveness of 89Sr in combination with doxorubicin for 72 patients with bone scan-positive hormonerefractory prostate cancer who had demonstrated responsive or nonprogressive disease following two to three cycles of induction chemotherapy consisting of estramustine and vinblastine alternating with doxorubicin and ketoconazole. These patients with responding or stable disease following induction chemotherapy were randomized to receive single-agent doxorubicin for six doses (20 mg/m2/wk) with either 89Sr (4 mCi) or placebo. The primary endpoints were time to progression and survival. Patients randomized to. 89Sr and chemotherapy had a signiﬁcantly prolonged median time to progression (13 vs 7 mo) and median survival (28 vs 19 months). Grade 4 neutropenia occurred more commonly in the 89Sr group, whereas the incidence of grade 4 thrombocytopenia was similar (54). Further multi-institutional studies are planned to conﬁrm these ﬁndings as the survival beneﬁt was unprecedented in a study of this type in patients with hormone-refractory metastatic prostate cancer. A randomized phase III trial compared 89Sr alone (4 mCi) with a combination of 89Sr and cisplatin in 70 patients with hormone-refractory prostate cancer with painful bone metastases. Cisplatin was given as three separate infusions (for a 50 mg/m2 total dose)

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Fig. 1. General chemical structure of a bisphosphonate.

Table 4 Structure of Selected Bisphosphonates Drug Etiodranate Clodronate Pamidronate Zoledronate

Relative potency

R1 side chain

R2 side chain

1 10 100 10,000

–OH –C12 –OH –OH

–CH3 –C12 –(CH2)2NH2 –CH2-imidazole

over an 11-d period prior to and after 89Sr. Study endpoints were palliation of bone pain at 2 mo, new-onset bone pain, progression of bone metastases, and survival. Pain improvement at 2 mo was reported as 91% vs 63% favoring combination therapy. There was no difference in new onset of painful bone lesions or survival. Progression of bone metastases was 64% in the combination arm vs 27% with radioisotope alone (54). Taking these data together there is increasing interest in utilizing combinations of chemotherapy and radioisotopes in the treatment of metastatic prostate cancer. As newer and more active chemotherapies evolve, particularly if they are shown to be efﬁcient radiosensitizing agents, a new generation of trials combining radiopharmaceuticals and chemotherapy will certainly follow.

BISPHOSPHONATES IN THE MANAGEMENT OF BONE METASTASES Bisphosphonates have been shown to prevent and delay skeletal complications in patients with bony involvement from multiple tumors including, more recently, prostate cancer. Bisphosphonates are characterized by a phosphorus-carbon-phosphorus backbone and R1 and R2 carbon side chains (Fig. 1). R1 is usually a hydroxyl group that confers high-afﬁnity binding to calcium phosphate, whereas R2 varies (Table 4) and determines the antiresorptive potency of the drug (55). The scientiﬁc rationale for using bisphosphonates in prostate cancer is compelling, despite the fact that bisphosphonates act primarily on osteoclasts. Although the osteoblastic nature of prostate cancer bone lesions is clear, both blastic and lytic processes are active. Histomorphometric studies reveal that sclerotic prostate metastases involve both lytic and blastic processes, suggesting that the normal coupling between the two processes may be dysregulated, but not lost (56–58). TGF-β, which is

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produced by prostate cancer cell lines (59), activates both osteoblast bone deposition and osteoclastic bone resorption. In addition, some data suggest that suppressing osteoclast activity results in a decrease in osteoblastic lesions (60). Bisphosphonates inhibit bone resorption by several mechanisms. The molecular mechanisms by which tumor cells metastasize to bone probably involve invasion, cell adhesion, and the release of soluble mediators from tumor cells that stimulate osteoclastmediated bone resorption. Bisphosphonates are powerful inhibitors of osteoclast activity and are therefore used in the treatment of osteolytic metastases. Bisphosphonate pretreatment of tumor cells inhibits tumor cell adhesion to unmineralized and mineralized osteoblastic extracellular matrices in a dose-dependent manner. Bisphosphonates have been reported to inhibit breast and prostate carcinoma adhesion to bone (61). Bisphosphonates have also been shown to inhibit breast and prostate cancer cell invasion, an early event in the formation of bone metastases. Pamidronate is a second-generation bisphosphonate that has been shown to be an effective treatment for bone lesions associated with multiple myeloma and metastatic breast cancer (62,63). A randomized phase III trial of pamidronate at 90 mg vs placebo did not show a reduction in skeletal related events in patients with bone pain from metastatic prostate cancer. The trial included 378 men with androgen-independent prostate cancer and symptomatic bone metastases who were randomized to standard care and pamidronate vs standard care and placebo. The primary endpoints were pain scores and narcotic requirements (64). In a phase III trial of another bisphosphonate, oral clodronate at 2080 mg daily, men with prostrate cancer who were beginning or responding to hormonal therapy slightly increased their time to new symptomatic bone lesions. The time to development of symptomatic bone metastases in 311 men with prostate cancer was 23.6 mo in those who received adjuvant clodronate compared with 19.3 mo in those who received placebo. Clodronate was also, however, associated with a signiﬁcant gastrointestinal side effects (65). Zoledronic acid is a third-generation nitrogen-containing bisphosphonate that was shown in earlier studies to be as effective as pamidronate in reducing skeletal complications in patients with myeloma or breast cancer (66). A randomized, placebo-controlled trial studied the effect of zoledronic acid on skeletal complications in 643 patients with hormone-refractory prostate cancer and a history of bone metastases. Patients were randomized to a double-blind treatment regimen of intravenous zoledronic acid at 4 mg (n = 214), zoledronic acid 8 mg (n = 221), which was subsequently decreased to 4 mg (because of renal dysfunction), or placebo (n = 208) every 3 wk for 15 mo. Skeletal related events, time to ﬁrst skeletal related event, skeletal morbidity rate, pain and analgesic scores, disease progression, and safety were assessed. Skeletal related events included radiation to bone lesions, pathologic fractures, change of antineoplastic therapy for bone pain, spinal cord compression, and surgery to bone. Approximately 38% of patients who received 4 mg zoledronic acid, 28% who received 8/4 mg, and 31% who received placebo completed the study. A greater proportion of patients who received placebo had skeletal related events than those who received the 4-mg dose or those who received 8/4 mg (44.2% vs 33.2% vs 38.5%, respectively). Median time to ﬁrst skeletal related event was 321 d for patients who received placebo, was not reached for patients who received zoledronic acid at the 4-mg dose (statistically signiﬁcant compared with placebo), and was 363 d for patients who received 8/4 mg (statistically signiﬁcant compared with placebo). Urinary markers

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for bone resorption were statistically signiﬁcantly decreased in patients who received either dose of zoledronic acid compared with placebo. Pain and analgesic scores increased more in patients who received placebo than in patients who received zoledronic acid, but there was no difference in disease progression, performance status, or quality of life scores among the groups. The 8-mg dose was associated with renal function deterioration, thus leading the authors to recommend zoledronic acid at a 4-mg dose to reduce skeletal related events in prostate cancer patients with bone metastases. Overall survival was unchanged between the zoledronic acid and placebo groups (67). A decrease in bone resorption markers has been associated with clinical response to treatment in prostate cancer patients with bone metastases (68,69). A marked decrease in urinary biomarkers of bone resorption (such as urinary pyridoline, deoxypyridinoline-, and N-telopeptide to creatinine ratios) was associated with treatment with zoledronic acid but not with placebo, indicating inhibition of active osteolysis. Serum bone alkaline phosphatase levels, an indicator of osteoblastic activity, showed little change in patients who received bisphosphonate therapy but increased in patients receiving placebo. The main adverse effects noted in the study were a transient acute phase reaction, anemia, electrolyte changes, and a small excess risk of serum creatinine increase, which was associated with the dose and rate of infusion. In conclusion, the study showed that zoledronic acid decreases in a statistically signiﬁcant manner skeletal related events in patients with metastatic prostate cancer, with a safety proﬁle similar to that of other intravenous bisphosphonates.

NOVEL DRUGS IN CURRENT CLINICAL TRIAL An endothelin-A receptor antagonist (atrasentan) has now entered prostate cancer clinical trials for patients with metastatic hormone-refractory prostate cancer (70). As noted above, endothelin is known to activate osteoblasts and stimulate bone formation (24,25). A double-blind placebo-controlled phase II randomized trial compared placebo and two doses of atrasentan (2.5 and 10 mg/d). Although the intent to treat analysis was not statistically signiﬁcant, the primary endpoint of time to progression was signiﬁcantly prolonged in the evaluable patients treated with the 10-mg/d dose. Median time to PSA progression was prolonged in both the intent to treat and evaluable patient subsets in the 10-mg/d treatment group. Headache, peripheral edema, and rhinitis were observed as drug-related adverse events. Additional trials are planned with atrasentan. Osteoprotegerin is a RANKL decoy receptor (23) that diminishes osteoclast activation. AMGN-0007 is a recombinant osteoprotegerin construct that has entered phase I clinical trials (71) in patients with metastatic breast cancer and myeloma. Although it is clearly too early to make any deﬁnitive statements regarding antitumor activity, bone resorption was signiﬁcantly decreased after a single injection in a rapid and sustained manner. Toxicities were minimal but included asymptomatic hypocalcemia.

ANDROGEN DEPRIVATION THERAPY AND BONE CHANGES Androgen deprivation therapy in its various forms has been shown to be associated with a decrease in bone mineral density in numerous studies (72–75). Androgen deprivation therapy by either orchiectomy or treatment with gonadotropin-releasing hormone agonists clearly decrease bone mineral density. The fracture risk that accompanies the decrease in bone density is not nearly as well documented as the bone mineral density

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changes (76). Given that men have a considerably higher baseline bone density compared with women, on a percentage basis decreases in bone mineral density measurements do not confer equal risk of fracture in men and women. Smoking cessation, moderate alcohol consumption, supplemental calcium and vitamin D, and regular weight-bearing exercise should be encouraged in men undergoing androgen deprivation therapies. Who should be treated more aggressively with pharmacologic agents is currently a topic of considerable debate (77). Several alternative approaches to hormonal therapy have been demonstrated to result in less bone mineral loss than medical or surgical castration. Bicalutamide monotherapy results in bone mineral density gains (78). Intermittent hormonal therapy is associated with a lesser extent of bone loss compared with continuous androgen deprivation. Low-dose oral estrogen (such as diethylstilbestrol) may ameliorate the bone loss associated with androgen deprivation (78). Selective estrogen receptor modulators are also being explored in this arena as they have a low thrombotic risk combined with the proven capacity to treat osteoporosis in women. A study of bone loss during androgen deprivation therapy for nonmetastatic prostate cancer showed an 8.5% decrease in trabecular bone mineral density of the lumbar spine after approx 1 yr of leuprolide therapy in men with advanced or recurrent prostate cancer. Pamidronate at 60 mg intravenously every 12 wk showed a signiﬁcant decrease in the amount of bone loss (79). Zoledronic acid (4 mg intravenously every 3 mo) not only prevents bone loss but also increases bone mineral density. A study of 106 men with locally advanced or recurrent, nonmetastatic prostate cancer showed a 5.3% increase in mean bone mineral density in the lumbar spine and a 1.1% increase in the hip (80). Alendronate is approved to treat osteoporosis in men and women (81). Additional studies are needed to evaluate the effect of this drug in men with castrate testosterone levels.

CONCLUSIONS Skeletal complications are a major cause of morbidity in men with prostate cancer. Treatment with radioisotopes offers an effective method for pain palliation in patients with painful bony lesions. Recent studies using radiopharmaceuticals in combination with chemotherapy have shown promising results in selected patients with regard to survival. Further studies are needed to evaluate combination therapy with radioisotopes and other treatment modalities including agents targeting key signaling pathways. Earlier use and repetitive dosing of radioisotopes need to be further evaluated. Newer bisphosphonates have been shown to be effective in reducing skeletal related events in men with hormone-refractory prostate cancer and bone metastases. Optimal timing of administration will be evaluated with regard to the role of these agents in prevention of bone metastases and the treatment of androgen deprivation-induced osteopenia. Newer agents have entered early-phase clinical trials. These agents include endothelin antagonists and osteoprotegerin constructs. Additional studies with these agents are warranted.

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55. Rogers MJ, Watts DJ, Russell RG. Overview of bisphosphonates. Cancer 1997;80(8 suppl):1652–1660. 56. Scher HI, Chung LW. Bone metastases: improving the therapeutic index. Semin Oncol 1994;21:630–656. 57. Clarke NW, McClure J, George NJ. Morphometric evidence for bone resorption and replacement in prostate cancer. Br J Urol 1991;68:74–80. 58. Charhon SA, Chapuy MC, Delvin EE, et al. Histomorphometric analysis of sclerotic bone metastases from prostatic carcinoma special reference to osteomalacia. Cancer 1983;51:918–924. 59. Ikeda T, Lioubin MN, Marquardt H. Human transforming growth factor type beta 2: production by a prostatic adenocarcinoma cell line, purification, and initial characterization. Biochemistry 1987;26:2406–2410. 60. Erlebacher A, Derynck R. Increased expression of TGF-beta 2 in osteoblasts results in an osteoporosislike phenotype. J Cell Biol 1996;132:195–210. 61. Boissier S, Magnetto S, Frappart L, et al. Bisphosphonates inhibit prostate and breast carcinoma cell adhesion to unmineralized and mineralized bone extracellular matrices. Cancer Res 1997;57:3890–3894. 62. Berenson JR, Lichtenstein A, Porter L, et al. Efﬁcacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med 1996;334:488–493. 63. Hortobagyi GN, Theriault RL, Porter L, et al. Efﬁcacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 1996;335:1785–1791. 64. Lipton A, Small E, Saad F, et al. The new bisphosphonate, Zometa™ (zoledronic acid) decreases skeletal complications in both lytic and blastic lesions: a comparison to pamidronate [abstract 34]. Cancer Invest 2001;20:45–47. 65. Dearnaley DP, Sydes MR, on behalf of the MRC Pr05 Collaborators. Preliminary evidence that oral clodronate delays symptomatic progression of bone metastases from prostate cancer: ﬁrst results of the MRC Pr05 Trial [abstract]. Proc ASCO 2001;20:174a. 66. Rosen LS, Gordon D, Antonio BS, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 2001;7:377–387. 67. Saad F, Gleason DM, Murray R, et al. Zoledronic Acid Prostate Cancer Study Group. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94:1458–1468. 68. Garnero P, Buchs N, Zekri J, Rizzoli R, Coleman RE, Delmas PD. Markers of bone turnover for the management of patients with bone metastases from prostate cancer. Br J Cancer 2000;82:858–864. 69. Ikeda I, Miura T, Kondo I. Pyridinium cross-links as urinary markers of bone metastases in patients with prostate cancer. Br J Urol 1996;77:102–106. 70. Carducci MA, Padley RJ, Breul J, et al. Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized phase II placebo controlled trial. J Clin Oncol 2003;21:679–689. 71. Body JJ, Greipp P, Coleman RE, et al. A phase I study of AMGN-0007, a recombinant osteoprotegerin construct in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer 2003;97(3 suppl):887–892. 72. Daniell HW. Osteoporosis after orchiectomy for prostate cancer. J Urol 1997;157:439–444. 73. Townsend MF, Sanders WH, Northway RO, Graham SD Jr. Bone fractures associated with luteinizing hormone-releasing hormone agonists used in the treatment of prostate carcinoma: Cancer 1997;79:545–550. 74. Hatano T, Oishi Y, Furuta A, Iwamuro S, Tashiro K. Incidence of bone fracture in patients receiving luteinizing hormone-releasing hormone agonists for prostate cancer. BJU Int 2000;86:449–452. 75. Oefelein MG, Ricchuiti V, Conrad W, et al. Skeletal fracture associated with androgen suppression induced osteoporosis: the clinical incidence and risk factors for patients with prostate cancer. J Urol 2001;166:1724–1728. 76. Ross RW, Small EJ. Osteoporosis in men treated with androgen deprivation therapy for prostate cancer. J Urol 2002;167:1952–1956. 77. Smith MR. Diagnosis and management of treatment-related osteoporosis in men with prostate carcinoma. Cancer 2003;97(3 suppl):789–795. 78. Smith MR, Fallon MA, Goode MJ. Cross-sectional study of bone turnover during bicalutamide monotherapy for prostate cancer. Urology 2003;61:127–131.

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79. Scherr D, Pitts WR, Jr, Vaughn ED Jr. Diethylstilbestrol revisited: androgen deprivation, osteoporosis, and prostate cancer. J Urol 2002;168:1506–1507. 80. Smith MR, McGovern FJ, Zietman AL, Fallon MA, Hayden DL, Schoenfeld DA. Pamidronate to prevent bone loss during androgen deprivation therapy for prostate cancer. N Engl J Med 2001;345:948–955. 81. Smith MR, Eastham J, Gleason DM, Shasha D, Tchekmedyian S, Zinner N. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 2003;169:2008–2012. 82. Orwoll E, Ettinger M, Weiss S, et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med 2000;343:604–610.

IV

APPLIED MOLECULAR BIOLOGY

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Biology of PSMA As a Diagnostic and Therapeutic Target Sam S. Chang, Neil H. Bander, and Warren D.W. Heston

INTRODUCTION Prostate cancer remains the most common cancer type in men in the United States. Efforts are increasing to evaluate and discover diagnostic and therapeutic markers for prostate cancer patients. One of these, prostate-speciﬁc membrane antigen (PSMA), is a transmembrane protein highly expressed in all types of prostatic tissue, especially cancer. The radioimmunoconjugate form of the anti-PSMA monoclonal antibody (MAb) 7E11, known as the ProstaScint® scan, is currently being used to diagnose prostate cancer metastasis and recurrence. The antibody used in the ProstaScint scan recognizes an intracellular epitope of PSMA, making it most accessible in cells that are dead. The ProstaScint antibody is also a mouse antibody that can result in the generation of human anti-mouse antibodies (HAMAs). Therefore second-generation antibodies have been developed that are either genetically engineered humanized antibodies or are fully human antibodies that recognize the extracellular portion of the PSMA protein. Early promising results from various phase I and II trials have demonstrated the utility of PSMA as a target for both imaging and therapy. Recently, PSMA expression in endothelial cells of tumor-associated neovasculature has been described. PSMA’s possible role in malignant angiogenesis expands the realm of its possible beneﬁcial uses. This chapter focuses on the biology of PSMA as a diagnostic and therapeutic target.

BIOLOGY OF PSMA PSMA Discovery PSMA is a type II membrane protein originally characterized as the unknown membrane protein antigen recognized by the MAb 7E11C5.3 (1). It is expressed in all forms From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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of prostate tissue including benign epithelium, benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), and carcinoma (1–5). In the original description, nonprostatic tissues were found to be negative for expression of PSMA by immunohistochemistry (1).

PSMA Cloning The PSMA gene was fully sequenced in the laboratory of Dr. Heston and was found to encode a transmembrane type II protein. Type II membrane proteins by deﬁnition have the amino terminus inside the cell and the carboxy terminus outside the cell. PSMA has a short intracellular domain of 19 amino acids, a transmembrane domain region of 24 amino acids, and a 707-amino acid external domain (3,6,7). The gene itself is located on the short arm of chromosome 11 in a region that is seldom deleted in prostate cancer (7). Because it is a membrane protein and so strongly expressed in prostate cancer, it seemed reasonable that it would serve as an excellent target for the development of imaging or therapeutic agents. The question arose: what does PSMA do? PSMA has homology (approx 45% in one region) with the membrane receptor transferrin TfR (8,9). However, PSMA does not bind either the apo- or iron-loaded form of transferrin (unpublished data).

PSMA Enzymatic Activity As a Glutamate-Preferring Carboxypeptdase FOLATE HYDROLASE (γ-LINKED GLUTAMATE HYDROLASE) Because we found some PSMA expression in the proximal small intestine, we considered that this protein may be similar if not the same as the uncharacterized protein intestinal membrane folate hydrolase (10,11). This is a protein carboxypeptidase that hydrolyzes glutamate from polygammaglutamated folate one at a time, generating folate. The degammaglutamated folate is recognized by the folate transporters, taken into the body, and used as a vitamin. We found that PSMA has enzymatic activity as a folate carboxypeptidase. We demonstrated that PSMA-expressing LNCaP cells have the ability to act as a carboxypeptidase and sequentially remove the γ-linked terminal glutamates from polygammaglutamated folate. Polygammaglutamated folate is the intracellular storage form of folate present in foods (10,11). Polygammaglutamated folate is not recognized by folate transport proteins and is not absorbed. This enzymatic capability was found to be speciﬁc to PSMA, as other prostate cancer cell lines such as PC-3 and DU-145 that do not express PSMA did not demonstrate this hydrolytic capability, but do have folate hydrolase activity when the cells are transfected with and express PSMA. This unique folate hydrolase activity may be useful as a prodrug activation strategy, as folate antagonists such as methotrexate triglutamate (MTX Glu3) can be polygammaglutamated (12). In this treatment strategy, theoretically only PSMA-expressing cells would cleave the glutamates of MTX Glu3 and would allow the cytotoxic MTX to accumulate within the cell (11,12). NAALADASE α-LINKED GLUTAMATE HYDROLASE PSMA also simulates the activity of a certain rat brain neurocarboxypeptidase known in the neurobiology literature as N-acetylaspartylglutamate peptidase (NAALADASE). The protein is a peptide hydrolase that cleaves the α-linked dipeptide bond of the neurotransmitter, NAAG, N-acetylaspartylglutamate (13). Work by Carter et al. (14,15) identiﬁed a partial cDNA from a protein from the rat brain that had an 86% homology with a region of the PSMA gene that was the rat homolog of human PSMA. PSMA-expressing

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LNCaP cells again were the cell model for these studies and were discovered to express the same enzyme activity as this rat brain protein, a neurocarboxypeptidase that cleaved α-linked glutamates from N-acetylaspartylglutamate (14,15). It is currently unclear how this enzymatic function relates to human prostate tissue activity, but within the human prostate, there are numerous neuroendocrine and secretory cells that may in fact utilize this enzymatic activity.

Internalization and Intracellular Binding INTERNALIZATION MOTIF Human PSMA has an internalization signal (MXXXL) that is responsible for the internalization of the protein on the cell surface into the endosomal and lyzosomal compartment (16). A motif known for internalization is the dileucine motif, LL, which is associated with internalization of mannose 6 phosphate/insulin-like growth factor 2 receptor, and it was thought that the dileucine repeat of the cytoplasmic (or intracellular) amino acid segment of PSMA was responsible for its internalization. However, LL motifs are responsible for internalization of basolaterally localizated proteins and PSMA is located on the apical aspect. It was discovered that a novel motif, MXXXL, is actually the internalization motif (16). In rats, this motif is not present, and the rat homolog is not internalized. As a therapeutic target, a protein that will internalize provides a mechanism for the targeted agent to gain access to the cell interior, especially if that targeting agent also increases the rate of PSMA internalization, as does the J591 antibody. An as yet unanswered question is whether there is a natural ligand for PSMA such as the ligand transferrin is for the transferrin receptor. Transferrin is internalized and provides iron for growth and other cell needs. No such nutritive or growth-associated ligands have yet been identiﬁed for PSMA. Folate is a potential ligand, but its relationship to folate utilization by the cell and whether it can participate in folate transport remain to be determined. It does not appear that binding of ligands or antagonists of PSMA’s hydrolytic function alters the rate of PSMA internalization (Heston, unpublished data). It may be that the product of the reaction, glutamate, may be involved in prostate function. In gene array analysis of mRNA expression by the cell line LNCaP from which PSMA was initially identiﬁed, metabotropic glutamate receptor expression was identiﬁed and its potential role in signaling is being pursued (Heston, unpublished data). FILAMIN A BINDING The cytoplasmic tail of PSMA has been found to interact with the intracellular protein ﬁlamin A (17). Filamin A is a dimeric actin crosslinking phosphoprotein located in the cortical cytoplasm adjacent to the plasma membrane. Filamin A will link with actin, serving to facilitate the orthogonal branching of actin ﬁlaments. It also serves as a docking site for various cell surface receptors and intracellular proteins involved in signal transduction. In prostate cells that are ﬁlamin A-positive, PSMA cycles following internalization to the recycling endosomal compartment, whereas in ﬁlamin A-negative cells it does not localize in any distinct endosomal compartment (17).

PSMA-Like and PSM′ Forms Two variations of the PSMA protein have been described and designated as PSMA and the spliced variant PSM′, but their individual roles have not been deﬁnitively elucidated (27). Because of alternative splicing of the mRNA, PSM′ lacks 266 nucleotides

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near the 5′ amino terminus and as a result does not have a transmembrane portion. Thus, PSM′ exists solely within the cell cytoplasm. PSMA is the predominant form in prostate cancer, whereas PSM′ predominates in the benign prostate (27). We also identiﬁed and cloned a gene that was 97% identical to PSMA; however, it totally lacks exon 1 and is probably a cytosolic protein that would not be a therapeutic target, as it lacks folate hydrolase activity; also, being intracellular, it is not accessible to antibodies, and it is not expressed in prostate cancer or in tumor blood vessels but is expressed in liver and kidney (18). PSMA probably resulted from a gene duplication event that happened about 14 million yr ago. In mice, the homolog for PSMA resides on a chromosomal location syntenic with that for PSM-like, and thus the location of PSM-like may represent the older gene location. When the duplication occurred a substantial piece of chromosome was duplicated, as other genes such as NADP oxidase and a portion of the tyrosinase gene were also duplicated to region 11p11.12 from 11q14 (7).

Promoter and Enhancer It was not clear what was responsible for the strong expression of PSMA in prostate and prostate cancer cells. We examined the promoter region and found that although it activated transcription, it was not as active or speciﬁc as we knew transcription to be in the prostate and prostate cancer (7). To identify a potential enhancer element, we digested our genomic PSMA clones and linked them to a green ﬂuorescent protein reporter and the PSMA promoter region to identify any possible enhancer elements in the genomic PSMA DNA (19,20). We succeeded in identifying a 350-bp region in enhancer 3 that serves to increase transcription rates over 200-fold. We also found that the enhancer did not require the PSMA promoter region for activity, but that it would work with any number of promoters, thus allowing the potential development of mix and match promoters/PSMA enhancer for gene therapy strategies. We have found in preclinical studies that the PSMA promoter can be used to drive expression specifically in prostate tumor cells, resulting in selective killing of prostate cells (19,21). Although the enhancer region contains a number of potential sites for known transcriptional factors, one transcription factor that binds to the enhancer has been recently identified as NFATcI and is thought to act with a yet to be identified factor in controlling PSMA transcriptional activity (22). The presence of NFATcI suggests that increased intracellular calcium may be taking part in the strong expression of PSMA in prostate cancer (22). This is of interest because of the increased expression of Trp8, a selective calcium channel in prostate cancer (23).

Human PSMA Transgenic and Mouse PSMA Knockout Mice The biologic function of PSMA is unknown. Potential information about the functional biology of PSMA can be obtained in animals by knocking out the analog of PSMA in mice, as well as creating transgenic animals that express the human version of PSMA in their prostates. KNOCKOUT MICE We cloned the mouse homolog of human PSMA. We identiﬁed that it resides on chromosome 7D of the mouse chromosome. This is the location that is syntenic with the PSM-like gene in the human (24). The knockout animals all appear healthy and fertile and with no gross neurologic defects, in contrast to the expected embryonic lethal outcome predicted by neurobiologists. Inhibitors of the enzymatic activity of

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NAALADASE (PSMA) had been shown to attenuate nerve damage in models of stroke. The PSMA knockout animals were likewise more resistant to damage by ligation-induced ischemia, or vitamin B neurotoxicity, or nerve crush (25,26). It is thought that one possible explanation for this sparing of stress-induced toxicity stems from the large release of N-aceylaspartylglutamate by stress, which, if PSMA is present, will be metabolized to N-acetylaspartate and glutamate. The large amount of released glutamate would then activate N-methyl-D-aspartate (NMDA) receptors, ﬂooding the cell with calcium and resulting in cell death. In the neurobiology literature, NAALADASE/ PSMA may play a role in modulating a number of neurologic diseases such as diabetic neuropathy, schizophrenia, pain, amyotrophic lateral sclerosis, Alzheimer’s, head trauma, spinal chord injury, stroke, cognition enhancement, and peripheral demyelinating diseases, to name a few, and the PSMA knockout animals will help serve a role in identifying NAALADASE/PSMA action in these diseases. The other tissue in which PSMA is expressed in mice is the kidney. In the knockout animals the one change that might be associated with the deletion of PSMA is lower blood pressure in the knockout animals (26). Additional work will have to be conducted to deﬁne the underlying cause for the change in blood pressure. TRANSGENIC HPSMA MICE In the mouse prostate we have not observed the strong expression of mouse PSMA to the extent that human PSMA is expressed in the human prostate (24). We have used the PSA promoter/enhancer to create transgenic mice that express PSMA in their prostate. We observed strong expression of the protein in the acinar epithelial cells in the dorsal, lateral, and ventral prostate, but not in the anterior prostate, nor seminal vesicles, nor most other tissues (Bacich and Heston, unpublished data). In preliminary studies, the early generation mice derived from different founder animals developed hyperplasia and dysplasia as the animal aged, whereas the littermates that did not express PSMA did not. These initial ﬁndings are being further examined to determine whether PSMA may be inﬂuencing abnormal growth of the prostate (Bacich and Heston, unpublished data). We brieﬂy review PSMA’s clinical characteristics, functions, and clinical applications. New clinical strategies continue to evolve that utilize PSMA in the realm of prostate cancer and possibly in nonprostatic malignancies.

Anti-PSMA Antibodies The MAb 7E11 was the ﬁrst and only anti-PSMA MAb for several years. Originally selected for binding to ﬁxed LNCaP cells (the immunization was not done with ﬁxed cells, but 7E11 was selected in an assay measuring binding to ﬁxed cells), 7E11 recognizes and binds a 6-amino acid segment of the PSMA intracellular region (1,28,29). Thus far, much of PSMA research has been based on 7E11, but new MAbs have subsequently been developed (1,28–31). Subsequent to the development of 7E11, Liu et al. (30) described the ﬁrst four IgG anti-PSMA MAbs (J591, J533, J415, and E99) that bind locations on the extracellular PSMA domain. The binding characteristics of these antiPSMA MAbs have been carefully described, and they each have a remarkably high afﬁnity to PSMA (32). By binding the extracellular portion of PSMA, these MAbs are distinctly different from 7E11. Researchers at Hybritech Incorporated, a subsidiary of Beckman Coulter Company, have developed an extracellular domain-binding antibody, PEQ226.5, as well as PM2J004.5, a MAb that binds an intracellular PSMA epitope (33).

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Murphy et al. (34) have also reported multiple antibodies including 3F5.4G6, 3E11, 3C2, 4E10-1.14, 3C9, and 1G3 that bind the extracellular portion of PSMA. One aspect of mouse monoclonal antibodies that is a drawback is that humans often develop HAMAs, which would limit the ability to give repeated administrations of the antibody. This is being circumvented by new molecular approaches in which the mouse antibody is genetically engineered to remove the likely antigenic regions of the mouse antibody and replace them with human homologous regions, to create a humanized antibody, as has been done for J591 antibody, or to generate the antibody in mice in which the mouse antibody genes have been replaced with human antibody genes so that the antibodies made will be fully human, as is being done with mice from Abgenix or Medarex (35,36). A joint venture between Cytogen and Progenics is developing such fully human antibodies (35). directed at the extracellular domain. The interest in developing new antibodies to the PSMA external domain is owing in large part to the fact that the internal domain-binding anti-PSMA MAbs, e.g., 7E11 and PM2J004.5, do not bind viable cells (29–31). This inability to bind live cells makes the currently available 7E11 (Capromab) MAb a less attractive option for possible in vivo purposes, especially since the newer anti-PSMA MAbs bind to live, viable cells and cause PSMA to undergo internalization (30,34–38).

CLINICAL FINDINGS Tissue Studies Studies have consistently demonstrated 7E11 staining in prostatic tissue (4,5). The immunoreactivity is present in a higher percentage and with a stronger intensity in PIN and cancer cells compared with benign epithelial cells (Fig. 1) (1,2,5). The binding occurs in the secretory-acinar epithelium; basal epithelium and stromal cells are PSMA-negative. In the most recent comprehensive series, Bostwick et al. (39) described positive immunoreactivity in all 184 prostate specimens examined. In addition, they demonstrated an incremental increase in the percentage of staining from benign epithelial tissue (69.5% of cells positive) to high-grade PIN (77.9% of cells positive) to malignant cells (80.2% of cells positive) (39). We have reported similar staining patterns with the 7E11 MAb and with the previously uncompared anti-PSMA MAbs, J591, J415, PM2J004.5, and PEQ226.5 (31). Using a PSMA-derived RNA probe in in situ hybridization studies, Kawakami and Nakayama (40) correlated PSMA expression with severity of the prostate cancer. PSMA mRNA expression increased in hormone-refractory disease and in higher Gleason’s score tumors. In vitro data have demonstrated PSMA upregulation in cells grown in an androgendeprived state. LNCaP cells incubated with the androgen dihydrotestosterone (DHT) have decreased PSMA expression, whereas those cells grown in an androgen-stripped medium displayed significantly increased PSMA expression. Androgens, in fact, downregulated the PSMA mRNA message in vitro (3). By retrospectively examining 20 prostate cancer patients treated with castration or long-term androgen deprivation, Wright et al. (41) found that 11 of 20 patient specimens had increased PSMA protein immunoreactivity after long-term androgen deprivation. As opposed to PSA’s correlation with androgen levels, PSMA expression appears to be inversely related to androgen levels, and thus manipulation of patients’ androgen levels during treatment has been hypothesized to affect PSMA expression. Such manipulation could improve the efﬁcacy of any antibody-directed diagnostic/therapeutic targeting. We,

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Fig. 1. Images of clinically localized prostate cancer with predominant disease seen in right side of the prostate on whole mount pathology. (A) Computed tomography (CT). (B) ProstaScint/Singlephoton emission CT. (C) Fusion-dedicated CT-SPECT.

however, did not ﬁnd this true for short-term (3-mo) neoadjuvant deprivation therapy in clinically localized prostate cancer (42). Possible explanations for this lack of change in PSMA expression include the short, 3-mo course of androgen deprivation prescribed and the well-differentiated nature of these tumors. PSMA expression differences may have been too subtle to delineate only on an immunohistochemical level. Finally, our patient population may have had tumors that were not as aggressive as necessary to demonstrate a change in PSMA expression. Further study is needed to examine longer courses of hormonal manipulation in more advanced cancers to determine effects on PSMA expression. Human Normal Nonprostate Tissue Although consistently and highly expressed in prostatic tissue, several other tissue types also express PSMA. Israeli et al. (3) via ribonuclease protection assay demonstrated (in frozen human tissue) PSMA expression in the brain, salivary gland, and small bowel, but showed no expression in muscle, kidney, liver, or mammary gland. Silver et al. (4) (in parafﬁn-ﬁxed tissue) demonstrated positive binding to duodenum, proximal renal tubule cells, and neuroendocrine cells of the colon but observed no binding to brain, skeletal muscle, parotid, breast, and normal vasculature. Differing tis-

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sue preparations have been indicated as a possible cause for these variations in 7E11 binding, and these studies utilized only the 7E11 MAb. Recent work including other anti-PSMA MAbs has clariﬁed PSMA expression. Anti-PSMA MAbs bind duodenal epithelial (brush border) cells and proximal tubule cells in the kidney (30,31). The proximal small bowel, speciﬁcally the duodenum, is known to have a high folate hydrolase activity, and the proximal tubule cells of the kidney also have a known role in folate reabsorption at the apical membrane. This role in folate metabolism may explain the binding of the anti-PSMA MAbs to these tissues.

Human Malignant Tissue: Neovasculature No study has demonstrated PSMA expression by the vascular endothelial cells in benign tissues, even in those tissues like prostate or proximal duodenum that demonstrate PSMA expression. Reactivity of the anti-PSMA MAbs to the endothelium of malignant tissue neovasculature, however, has recently been reported. Studying 7E11, Silver et al. (4) demonstrated what they described as “neoexpression of PSMA in endothelial cells” of vessels (not the tumor cells) associated with certain tumors including renal cell cancer (unspeciﬁed type), transitional cell carcinoma of the bladder, and colon carcinoma. Liu et al. (30) reported positive PSMA staining in the tumor-associated vasculature in 23 nonprostatic carcinoma specimens that included renal, urothelial, lung, and metastatic adenocarcinoma to the liver. We have also examined a wide number of carcinomas including conventional (clear cell) renal cell, transitional cell of the bladder, testicular-embryonal, neuroendocrine, colon, and breast, and the different types of malignancies consistently and strongly expressed PSMA in their neovasculature (31). By immunohistochemistry, we compared ﬁve different anti-PSMA MAbs, and we conﬁrmed their binding to tumor-associated neovascular endothelial cells by using CD34 binding in sequential tissue sections. Vessels in noncancerous tissue did not display immunoreactivity, and the vasculature of the corresponding normal tissue samples also did not demonstrate PSMA expression. As noted previously, the different malignant cells and the vessels in noncancerous tissue, however, were PSMA-negative. Interestingly, this binding of the neovasculature associated with solid malignancies does not seem to occur in prostate cancer. Silver et al. (4) noted that prostatic cancer specimens they examined with 7E11 stained strongly in prostate cells but not in vascular endothelial cells. Similarly, Bostwick et al. (39) did not ﬁnd 7E11 binding in the vascular endothelium. As in previous studies, we also could not demonstrate consistent binding of these MAbs to the tumor-associated neovasculature in prostate cancer. The reason for the lack of reactivity in prostatic cancer remains unclear, but prostatic malignancies do not classically have an impressive angiogenic characteristic compared with many solid malignancies and thus do not incite an impressive stromal desmoplastic response. This lack of response may inhibit PSMA expression, or there may be other inhibitory factors associated with prostatic cancer or prostatic tissue. Perhaps a negative feedback loop plays a role since the tumor cells of this cancer type so strongly express PSMA.

Diagnostic Assays: Serum Studies With the advent of PSA, serum screening for prostate cancer has become an integral part of the diagnosis, staging, and therapy for prostate cancer. Similarly, researchers have attempted to utilize circulating PSMA, but results have been conﬂicting. By

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enzyme-linked immunosorbent assay (ELISA) and Western blot, the original discoverers of 7E11 detected circulating PSMA in the serum of prostate cancer patients (1). Murphy et al. (37) have reported that serum PSMA levels are elevated in prostate cancer patients, and this elevation remains even in the presence of low PSA levels. This PSMA serum level correlation with prostate cancer stage, however, has not been a universal ﬁnding (43). Like us, others have been unable to detect serum PSMA levels consistently, but this work involved the 7E11 MAb, not the more recently developed MAbs. Newer antibodies may improve detection consistency. As with other cancer types, attempts to increase the sensitivity of cancer detection and staging have utilized reverse transcription-polymerase chain reaction (RT-PCR) assays. Moreno et al. (44) were the ﬁrst to use this technique with PCR primers based on the cDNA sequence of PSA to detect circulating tumor cells in patients with metastatic prostate cancer. They detected occult circulating cells in one-third of their patients. Israeli et al. (45) utilized a more sensitive “nested” RT-PCR technique utilizing PSMA and found circulating prostate cells in 48/77 patients with prostate cancer, compared with only 7/77 utilizing a PSA primer. Unfortunately, results have been inconsistent. Murphy et al. (46), who pooled the results of a number of RT-PCR studies, noted that although RT-PCR of serum PSMA was more sensitive (63%) compared with RT-PCR of serum PSA (50%) in patients with metastatic prostate cancer, neither assay was adequate enough to base clinical therapy on it. Neither assay contributed more than the currently established prognostic indicators—Gleason sum, serum PSA, or clinical stage (46). In an attempt to improve staging accuracy, Grasso et al. (47) combined PSMA and PSA RT-PCR assays. They concluded that this combination assay better predicts extracapsular tumor extension than preoperative serum PSA, clinical stage, or biopsy Gleason sum (47). Although promising, current RT-PCR strategies overpredict biologic meaningful spread of disease in early-stage cancer. Until we understand the predictive meaning and biologic potential of these circulating prostate/prostate cancer cells, this technique is clearly not recommended for clinical use (48).

Diagnostic-Radiologic Imaging PROSTASCINT SCANNING The FDA-approved radiographic test marketed under the name ProstaScint (Cytogen, Princeton, NJ) utilizes the MAb 7E11 by linking it to 111In to produce a radiodiagnostic marker, 111In-capromab pendetide (46,49–51). Most studies show a sensitivity rate of 60–80% and a speciﬁcity of 70–90% for this noninvasive detection method. In an early study by Kahn et al. (52), 27 patients with rising PSA values status post radical prostatectomy underwent ProstaScint scan. Of these 27 patients, 22 patients had a lesion on their ProstaScint scan, and 50% (11/22), had conﬁrmation by other radiologic diagnostic means. In a follow-up study, 183 patients were examined in a similar situation. Once again, 50% of the positive scans were conﬁrmed, but this time by biopsy of the suspected lesion (51). Initial concern regarding the development of a humanantimurine IgG antibody (HAMA) reaction has been allayed, and few side effects have been reported (51,52). Recently, Polascik et al. (53) examined a cohort of 198 men with organ-conﬁned or locally advanced prostate carcinoma (clinical stages T2 or T3) who were at high risk for lymphatic metastasis, and in fact, 39% were positive by pathologic staging. In an attempt to predict true pathologic stage, a combination of algorithms, nomograms, and

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the ProstaScint scan were analyzed. Prior to staging lymphadenectomy, these patients underwent a ProstaScint scan. The results of the scans proved to have a statistically improved positive predictive value better than that of currently used predictive nomograms and algorithms, and the combination of algorithms and ProstaScint scan provided an impressive 72% positive predictive value for metastatic disease (53). In terms of prediction for therapy, however, enthusiasm is dampened by the recent results of Thomas and colleagues (54) who found that the results of the Prostascint scan for ﬁndings outside of the prostate fossa were not predictive of biochemical control after irradiation therapy. PROSTASCINT MULTIMODALITY SCANNING In an another attempt to improve staging accuracy, Sodee et al. (55) used a combination of single-photon emission tomography (SPECT) imaging with ProstaScint. This technique successfully distinguished normal from cancerous prostate tissue within the prostate gland. These researchers derived a prostate cancer/normal tissue ratio that was highly predictive of recurrent or residual prostatic cancer as conﬁrmed by prostate biopsy (55). Long-term results may show that this scan’s false-positive rate may decrease as lesions outlined by this scan manifest clinically at a later date. For some, the scan provides another informative variable in determining treatment course, but few clinicians today use it as a single entity to dictate clinical management. Adaptations and modiﬁcations such as those described by Sodee and colleagues (56) may improve its efﬁcacy to make it more attractive to all clinicians. These combined techniques may serve to enhance the correct identiﬁcation of disease vs study artifact and are quickly becoming the standard of care. However, more research is needed to verify that the combined images are related to tumor-associated pathology. Therefore, research continues to attempt to improve the imaging of primary localized prostate cancer. Accurate and precise pretreatment staging of prostate cancer remains a difﬁcult goal. We are currently examining the ProstaScint scan combined with SPECT and computed tomography (CT) fusion imaging in localized cancers (Fig. 1; Chang, unpublished data). The fusion image demonstrates increased areas of uptake whose deﬁnition is helped by adding the tissue landmarks obtained by CT. What is needed is to compare those images to whole mount pathologic sections. We have begun to study this at our institution. Preliminary work by Drs. Kapelian, Klein, Levin, and Hafeli have compared the whole mount histologic presence of prostate cancer in the prostatectomy specimens with the concentration of radiolabeled ProstaScint antibody as measured by autoradiography. In the small number of specimens examined to date, we have not observed a high colocalization: some tumor areas have a high prostaScint concentration, other areas have equally high prostaScint concentrations but no tumor, and other areas have low ProstaScint in areas containing tumor (Fig. 2; Kupelian, Klein, Levin, and Haeﬁli, unpublished data). Why there is antibody present is not clear, as ProstaScint is proposed to bind to dead cells, and the prostate (even in areas of cancer) is usually not necrotic. The question remains open of whether the fusion images will provide an accurate picture of tumor within the prostate. Also, will the use of second-generation antibody improve the imaging in the prostate, given the improvement seen with second-generation antibodies in imaging tumor metastasis in the bone. If the increased ability to take up antibody is like that seen with bone metastasis, it could represent a strong improve-

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Fig. 2. The prostatectomy specimen was sectioned and submitted for autoradiograpy of the radiolabeled ProstaScint antibody that is represented by the reddish appearance, with the greater intensity reﬂective of a greater concentration of antibody. The narrow-line yellow circle represents the location of prostate cancer. Although there are some areas of match between intensity of radiolabel and tumor, there are also a number of areas of discordance.

ment on our ability to scan the prostate for sites of active tumor. In Dr. Bander’s series, of patients who had not had a prior prostatectomy and received radiolabeled J591 treatment for metastatic disease, only one prostate was imaged. That one had been treated with hormone therapy and chemotherapy and did produce an image. All the prostates that had been irradiated either did not image or exhibited minimal images, which suggests that imaging the prostate with second-generation antibodies may be possible in prostates that have not been irradiated. It would certainly be desirable to compare ProstaScint imaging with imaging of the second-generation antibodies such as J591.

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What is needed is a method that provides accurate enough images to tell whether a tumor is at or through the margins and to ﬁnd regions of tumor in the prostate to enable a boost in the dose of irradiation for those being treated with irradiation. Even though the use of fusion images may prove to be helpful in ProstaScint scanning, a major advance has occurred in that second-generation antibodies against the external domain of PSMA have been developed for imaging and therapy. These antibodies have either been humanized or are fully human and bind to living cells. SECOND-GENERATION ANTIBODY IMAGING OF METASTATIC PROSTATE CANCER AND NEOANGIOGENESIS IN NONPROSTATIC TUMORS ProstaScint imaging has been problematic in areas of metastasis such as bone. This may be because of the presence of tumor that is more viable and not necrotic. Secondgeneration antibodies have been more able to image tumor in the bone. In addition, an incidental renal cell carcinoma was discovered by a 111In-capromab pendetide scan. The scan revealed suspicious uptake in a kidney that subsequent conventional imaging revealed to be a solid renal mass with necrosis (56). Benign kidneys on the ProstaScint scan do not “light up,” and this example may conﬁrm in an in vivo setting the recognition by the anti-PSMA MAb 7E11 of tumor-associated neovasculature in areas of necrosis. Studies demonstrating PSMA expression in neovasculature have involved pathologic tissue, and more research is necessary to determine the in vivo activity of anti-PSMA MAbs in regard to nonprostatic primary and metastatic malignancies. Prostate cancer is no longer the sole disease entity that may utilize PSMA as a target. PSMA expression by the tumor-associated neovasculature of nonprostatic malignancies expands the possible therapeutic options. To grow and metastasize, all cancers require angiogenesis, and it is this neovasculature that expresses PSMA, not vasculature in existing blood vessels of normal tissue. In addition, the presence of an endothelial cell target in vessels obviates the requirement for any antibody-based treatment to traverse the vasculature and stroma to enter the cancerous cell. Although ProstaScint is available, new second-generation antibodies are being developed that recognize the external domain of PSMA and are able to bind to living cells. One such antibody, a mouse MAb designated J591, is being developed by Neil Bander and colleagues at the Department of Urology of the Cornell Weil School of Medicine. The problem with mouse MAbs is that they may not be able to be used in multiple dosing because of the development of HAMA reactions. Following the identiﬁcation of the best mouse antibody against the external domain, Dr. Bander had the mouse antibody deimmunized by removal of the amino acid segments and replacement with human amino acid sequences using genetic engineering. The modiﬁed humanized antibody retained all the characteristics of the original mouse antibody. Dr. Bander then worked in concert with BZL Pharmaceuticals and Millinium Pharmaceuticals to generate a clinical-grade antibody for clinical trials (35,57). In a clinical trial by Bander et al. (58), 53 patients received either Indium-111, Yittrium-90, or Lutecium-177 radiolabeled J591 antibodies in which the radionuclides were bound to the antibody by chelation with DOTA. In 42 of the 43 evaluable patients, J591 imaging accurately targeted bone and/or soft tissue lesions. Of the seven patients with no lesions visible on conventional imaging, three were positive by J591, and all were subsequently conﬁrmed to be positive by other imaging modalities. In 35 patients in whom there was no visible extrahepatic soft tissue metastasis, 34 were also negative by J591 scan. In this study 29 patients had prostates in situ, the remainder having

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undergone prostatectomy. Only 1 of 14 had good visualization of the prostate. The patient with good visualization had received only hormonal and chemotherapy but no radiation therapy, whereas all the patients with poor or no visualization had received radiation therapy. In this study patients received multiple doses of radionuclide, and in every case the J591 scans were consistent with the results of the conventional scans (for examples see Figs. 3–7) (36,58). The imaging results with J591 were strikingly improved over ProstaScint, especially in the area of the bone metastasis; these results serve to verify the hypothesis that antibodies binding to the extracellular part of PSMA and to living cells would be better imaging agents than an antibody that binds to an internal part of PSMA and does not bind to viable cells. They also verify the pathologic studies of tissue that have demonstrated strong expression of PSMA in prostate cancer in primary and metastatic sites. It may yet be that the use of both antibodies against both the internal and external regions would be useful to give an indication of the amount of necrosis and viable tumor within metastatic deposits. Finding the extent to which J591 and second-generation antibodies are able to image tumor within the prostate will require comparison studies with ProstaScint in nonirradiated prostates.

Therapeutic Approaches RADIOACTIVE AND CYTOTOXIC AGENTS Hormonal therapy has been the cornerstone of prostate cancer treatment. Unfortunately, hormonal therapy is purely palliative, and improved systemic therapies are necessary. MAbs have proved valuable in the treatment of several diseases including cancer. MAbs act by focusing an immune response on or targeting delivery of highly cytotoxic agents to the cancer cells without targeting normal cells. PSMA represents an ideal antigenic targeting agent. PSMA is the most well-established highly restricted antigenic target in prostate cancer. It is expressed at high density on the cell surface of all prostate cancers, and after binding antibodies such as J591 the PSMA/antibody complex is rapidly internalized into the cell, delivering any payload carried by the antibody. The J591 antibody is being evaluated for target radiation therapy and cytotoxic chemotherapy. Recent studies with the anti-PSMA MAb J591 have utilized linkages to radionuclides to treat metastatic prostate cancer. No toxicity has been noted, and the antibody localizes to tumor in vivo, especially to bony sites of metastatic disease; a dose response with higher doses producing tumor regressions or PSA reductions has been noted (58). IMMUNOTHERAPY Another therapeutic method utilizes immunotherapeutic principles—an attractive choice that avoids foreign DNA or other vectors and uses the patient’s own cells. Gong et al. (59) have developed a unique approach involving creation of an artiﬁcial T-cell receptor to target cells expressing PSMA. This artiﬁcial T-cell receptor incorporates a PSMAspeciﬁc single-chain antibody fused to a ζ-chain signal transduction domain. Promising in vitro results demonstrate successful lysis of PSMA-positive prostate cancer cells with no effect on PSMA-negative cells. In addition, an impressive proliferation of these modiﬁed T-cells in response to the presence of PSMA-expressing cells occurred that was augmented by costimulation. In vivo trials are currently in progress (59). Tjoa et al. (60,61) reported follow-up on phase I and II trials utilizing PSMA peptides to help generate an immune response by infusing dendritic cells pulsed by these

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Fig. 3. (A) Bone scan and (B) J591 scan from same patient. Bone scan shows multiple focal lesions throughout axial skeleton. The large right rib lesion seen on bone scan is partially obscured by the liver uptake on the J591 scan. There is excellent correlation between the bone and J591 scan, with a few additional lesions apparent on the latter but not the former. (Reprinted with permission.)

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Fig. 4. (A) Bone scan and (B) J591 scan from same patient. Bone scan shows excretion through kidneys and bladder as well as multiple areas of increased uptake in ribs, spine, and pelvis. The injection site is apparent in the left antecubital fossa. The J591 scan, in addition to liver excretion of radiometal, shows superimposable areas of J591 accumulation/targeting. J591 scan shows more intense uptake than bone scan as well as an additional lesion just superior to dome of liver, not seen in the bone scan. (Reprinted with permission.)

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Fig. 5. (A) Bone scan and (B) J591 scan from the same patient. In addition to axial skeletal involvement, lesions can be seen in the cranium, humeri, and femori, often better visualized on the J591 scan. The bone scan injection site is apparent in the right antecubital fossa. This patient had previously received radiation therapy to the LS spine many months earlier with subsequent disappearance of pain in that area. The previously radiated area is photopenic on bone scan and J591 scan, probably indicating eradication of disease in that site.

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Fig. 6. Bone scan (A) and J591 images from a patient who received two doses of radiolabeled J591. (B) J591 image taken 5 d after ﬁrst dose. (C) J591 image taken 6 d after second dose of antibody. Dose number 2 was given 3 mo after dose 1. Scans are virtually superimposable, demonstrating persistent expression of PSMA and continued ability to localize to tumor sites. (Reprinted with permission.)

PSMA peptides. A small number of patients who had metastatic disease and hormonerefractory cancer (9/33) had a partial response deﬁned as >50% reduction in serum PSA (60,61). Recently, these researchers have modiﬁed their dose scheduling, giving higher concentrations of pulsed dendritic cells with fewer infusions, and have had similar response rates (62). By using different combinations of anti-PSMA antibodies or antibodies to other previously described targets like GM2, KSA, TF, or others yet to be identiﬁed, one could develop a precisely targeted treatment strategy for prostate cancer (63–65). As with

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Fig. 7. (A) CT scan showing soft tissue mass measuring 4 × 6 cm in left pelvis. (B) Anterior view of J591 scan showing accumulation in the left pelvic mass. (Reprinted with permission.)

other MAbs, however, these current antibodies are not absolutely restricted to prostate tissue or angiogenic neovasculature. Clearly, PSMA is not absolutely prostate-speciﬁc, but lack of absolute cancer speciﬁcity has not hindered current therapeutic MAbs currently approved for clinical use (65,66). GENE THERAPY Present data imply that the PSMA promoter and PSMA gene, or surrounding gene sequence, must contain transcriptional enhancer regions that selectively activate PSMA transcription in tumor-associated neovasculature and not in benign vessels. By

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isolating these speciﬁc enhancer regions of the PSMA gene, one could develop an antiangiogenic gene therapy construct. This same exciting strategy would easily apply to targeting prostate cancer cells that express PSMA (19,21).

CONCLUSIONS PSMA is an excellent target for both diagnostic and therapeutic modalities in prostate cancer. Multiple anti-PSMA MAbs exist and are being utilized to take advantage of their binding characteristics. The possible clinical role of these anti-PSMA antibodies, however, now extends beyond prostate cancer. PSMA represents a unique angiogenic target expressed in malignant neovasculature but not in normal benign vessels. Thus, theoretically, a PSMA target-based therapy would be less risky to normal vasculature and also applicable to a variety of neoplasms. Anti-PSMA MAbs will probably become increasingly important in the diagnosis and possible treatment of prostate cancer and may become a novel antiangiogenic targeting tool for nonprostatic malignant tumors.

ACKNOWLEDGMENTS The authors thank Gail Daniels and Kelley Harsch for their help in the preparation of this manuscript. This work was supported in part by grants from the NIH DK/CA 47650 and from the Koch and CaPCure Foundations. N.H.B. developed the antibodies to PSMA/ext that were patented by the Cornell Research Foundation and licensed to BZL Biologics, Inc. N.H.B. is a paid consultant of BZL Biologics, Inc.

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60. Tjoa BA, Simmons SJ, Bowes VA, et al. Evaluation of phase I/II clinical trials in prostate cancer with dendritic cells and PSMA peptides. Prostate 1998;36:39–44. 61. Murphy GP, Tjoa BA, Simmons SJ, et al. Infusion of dendritic cells pulsed with HLA-A2-speciﬁc prostate-speciﬁc membrane antigen peptides a phase II prostate cancer vaccine trial involving patients with hormone-refractory metastatic disease. Prostate 1999;38:73–78. 62. Murphy GP, Tjoa BA, Simmons SJ, Rogers MK, Kenny GM, Jarisch J. Higher dose and less frequent dendritic cell infusions with PSMA peptides in hormone-refractory metastatic prostate cancer patients. Prostate 2000;43:59–62. 63. Zhang S, Zhang HS, Reuter VE, Slovin SF, Scher HI, Livingston PO. Expression of potential target antigens for immunotherapy on primary and metastatic prostate cancers. Clin Cancer Res 1998;4:295–302. 64. Zhang S, Zhang HS, Cordon-Cardo C, Ragupathi G, Livingston PO. Selection of tumor antigens as targets for immune attack using immunohistochemistry protein antigens. Clin Cancer Res 1998;4:2669–2676. 65. Gottlinger HG, Funke I, Johnson JP, Gokel JM, Riethmuller G. The epithelial cell surface antigen 171A, a target for antibody-mediated tumor therapy: its biochemical nature, tissue distribution, and recognition by different monoclonal antibodies. Intl J Cancer 1986;38(1):47–53. 66. Pegram MD, Lipton A, Hayes DF, Weber BL, Baselga TM, Tripathy D, et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Onc 1998;16:2659–2671.

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Opportunities for Targeted Molecular Therapy for Prostate Cancer Evan Y. Yu, William C. Hahn, Daniel J. George, and Philip W. Kantoff

INTRODUCTION Because of increased screening in the United States, prostate cancer is now frequently diagnosed at a clinically localized stage that is amenable to local therapy. Nevertheless, prostate cancer remains the second most common cause of cancer death in men. A substantial subset of patients with clinically localized prostate cancer will relapse after local therapy, and up to 20% of all patients still present initially with metastatic disease. These patients will generally respond to androgen deprivation therapy, but the vast majority will eventually develop disease progression, refractory to sustained hormonal manipulation. Typically, such patients progress ﬁrst with a rise in their serum prostate-speciﬁc antigen (PSA) level, followed months later by systemic symptoms such as weight loss, fatigue, and complications from metastases, such as bone pain, cord compression, and/or urinary obstruction. Unfortunately, standard therapeutic options at this stage of disease are limited. Although activity has recently been demonstrated with chemotherapy for hormonerefractory prostate cancer (HRPC) patients, the response is generally short-lived (1). For these reasons, the challenge is to discover new treatment strategies that target androgen-independent prostate cancer. Identifying molecular targets involved in the tumorigenesis and progression of prostate neoplasms provides opportunities for the development of new agents with greater therapeutic potential and better speciﬁcity. Patients with advanced or recurrent disease that has progressed to a hormone-refractory state are good candidates for studies that test the efﬁcacy of these new agents. An alternative strategy is to study new molecularly targeted agents prior to local therapy, or neoadjuvantly, in patients with clinically localized prostate cancer. This approach provides the advantage of rapidly evaluating both pathologic and clinical endpoints. Agents that show promise in this setting can then undergo more traditional testing in a randomized phase II or III adjuvant study. Biologic correlates can also be evaluated since tissue is obtained for study when deﬁnitive local therapy is given. From: Current Clinical Urology: Management of Prostate Cancer, Second Edition Edited by: E. A. Klein © Humana Press Inc., Totowa, NJ

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Moreover, if the agent has true efﬁcacy, it can render the patient more likely to be surgically cured. Finally, this setting facilitates clinical development since fewer patients are required to establish activity of the agent. Although few new agents have progressed to phase III clinical trials, great strides have been made in understanding the biology of this disease, and many functional targets have been identiﬁed for exploration. This chapter describes promising molecular targets for which speciﬁc manipulating agents are being studied, identiﬁes the putative signal transduction pathways involved in prostate tumorigenesis, and outlines the preclinical and early clinical data in regard to these agents.

HORMONAL MANIPULATION Androgen deprivation therapy was one of the ﬁrst forms of molecular targeted therapy. Androgen, usually in the form of dihydrotestosterone (DHT), binds its receptor in the cytoplasm. This complex then translocates into the nucleus, where it activates transcription after engaging androgen response elements (AREs) in the promoter regions of androgen-responsive genes. These gene products can either directly or indirectly serve as mitogenic stimuli. Modern methods to achieve androgen deprivation target this pathway at several levels. One technique is to utilize a gonadotropin-releasing hormone agonist, which decreases steroidogenesis and testosterone production. Antiandrogens are also used that block the binding of testosterone and other androgenic ligands to their speciﬁc target androgen receptor. This approach carries the additional advantage of inhibiting the functional effects of androgens produced outside the testes. Androgen deprivation therapy usually provides only temporary control of advanced prostate cancer. It is unclear whether this is because hormone-insensitive cells are present in small numbers from the onset or whether they develop after prolonged treatment (2). Although HRPC is associated with ampliﬁcation and overexpression of androgen receptor (AR) (3), it is likely that alternative signaling pathways are operative for continued growth. These pathways (to be discussed below) are crucial for the progression from an androgen-dependent to an androgen-independent state and are promising targets for future drug development. In addition to independent effects on growth and development, many distinct signal transduction pathways transactivate with the AR pathway. For instance, epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and keratinocyte growth factor (KGF) all have a role in expression or transactivation of the AR in HRPC cells (4). Also, interaction of the AR with protein kinase A signaling (5,6) and Her-2/neu (7) signaling have been noted independent of androgen stimulation. Finally, multiple effectors of mitogen-activated protein kinase (MAPK) signaling, such as EGF (8), Her2/neu (9), IGF-1, and Janus kinase-signal transducers and activators of transcription (JAK-STAT) (10) have been implicated in AR activation. Thus, it is clear that other receptors and pathways are closely tied to the AR signaling pathway.

DIFFERENTIATION THERAPY It is well established that many cancers exhibit arrested or abnormal differentiation. In some cancers, including HRPC, promoting differentiation can lead to cell cycle arrest (terminal differentiation), restoration of normal homeostasis, and in some cases apoptosis. In normal prostate development, AR signaling plays a key role in specifying

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Fig. 1. The role of differentiation agents in prostate cancer. Ligands bind to their appropriate receptors, leading to heterodimerization with ligand-bound retinoid X receptor (RXR). These heterodimers then enter the nucleus and bind to speciﬁc promoter elements such as the vitamin D response elements (VDREs), the peroxisome proliferators response elements (PPREs), and even the androgen response elements (AREs). Receptor X represents any of these above receptors bound to its respective ligand and promoter element. The result is transcription of multiple genes, leading to differentiation of the malignant cell.

the normal prostate architecture. Thus, there may be a close relationship between androgen signaling pathways and differentiation pathways. There are many androgen-related family members that could be potential targets for differentiation therapy. Some of these receptors can heterodimerize with the retinoid X receptor (RXR) (Fig. 1). Although retinoids seem to have yielded no clinical responses in human prostate cancer (11), other members of the retinoic acid superfamily, such as the vitamin D receptor, probably play an important role in tumorigenesis and cancer progression (12,13). Another member of the nuclear receptor superfamily that heterodimerizes with the RXR is the peroxisome proliferator-activated receptor γ (PPARγ). This receptor has also been found to be expressed in LNCaP, PC-3, and DU145 human prostate carcinoma cell lines (14).

Vitamin D Epidemiologic studies ﬁrst identiﬁed vitamin D deﬁciency as an independent risk factor for prostate cancer. In 1990, Schwartz and Hulka (15) showed that a relationship

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with known risk factors for prostate cancer, including age, race, and living in northern latitudes, was associated with low serum levels of vitamin D (15). Corder et al. (16) later showed in a prospective study that low serum 1,25-dihydroxy vitamin D (calcitriol) levels correlated with an increased risk for the development of palpable and anaplastic tumors. Ligand binding experiments have demonstrated that functional vitamin D receptors (VDRs) (17–19) are expressed by prostate carcinoma, LNCaP, PC-3, and DU-145 cell lines, and primary prostate epithelial cells derived from patients with normal prostate and benign prostatic hyperplasia (BPH) cells. This nuclear receptor, which belongs to the nuclear receptor superfamily of ligand-dependent transcription factors (20,21), mediates the physiologic actions of 1α,25-dihydroxy vitamin D3. When bound to ligand, the VDR dimerizes with the RXR, resulting in a heterodimer that regulates target gene transcription (22). This dimer interacts with speciﬁc genetic sequences, termed vitamin D response elements (VDREs), present in the promoter region of target genes. This complex binds not only calcium metabolism regulatory genes but also genes such as c-fos, c-myc, p21, p27, and Hox A10, which are involved in cellular differentiation and proliferation (23). Through these interactions, vitamin D controls differentiation as well as cell cycle arrest and/or apoptosis. Several lines of evidence reveal that varying concentrations of calcitriol induce differentiation and reduce cellular proliferation (18,19). In addition to its antiproliferative effect in LNCaP cells, 1,25-dihydroxy vitamin D enhances PSA secretion and AR expression in a dose-dependent manner (17,18). When the RXR ligands are combined with calcitriol, synergistic inhibition of LNCaP cell growth is observed (12). Metastasis and invasion may also be directly affected by calcitriol, as the high invasive capability of DU-145 cells is stiﬂed with treatment (13). These ﬁndings have led to multiple animal studies which demonstrate the therapeutic efﬁcacy of treatment with 1,25-dihydroxy vitamin D alone (24) or in conjunction with cytotoxic agents (25). Unfortunately, early attempts at testing the effects of calcitriol alone in men with HRPC revealed no clinical responses (26). In patients with advanced malignancies, hypercalciuria was seen at all dose levels (2–10 µg po qod), and dose-limiting hypercalcemia was reached (27). Treatment of patients with advanced cancer once weekly for 4 wk with calcitriol at 0.06 µg/kg with dose escalation up to 2.8 µg/kg did not yield doselimiting toxicity or hypercalcemia (28). Perhaps the most compelling study to date was performed in the early recurrent prostate cancer setting, as deﬁned by rising PSA, in patients who had received deﬁnitive surgery or radiotherapy. This small study showed that oral calcitriol signiﬁcantly decreased the rate of rising PSA in six of seven patients; however, hypercalciuria was noted in each patient, and two patients developed asymptomatic small nephrolithiases (29). An early report revealed a 81% PSA response rate, determined by a 50% serum PSA reduction, in patients receiving weekly high-dose calcitriol and docetaxel (30). Ongoing trials include the study of calcitriol in combination with dexamethasone (31) or with cytotoxic agents (paclitaxel or carboplatin) (32). To separate the therapeutic effects of vitamin D from hypercalcemia, several groups have studied vitamin D analogs that differ from calcitriol in their side chains. These analogs include 16-dienes, 1-dienes, 19-nor, and ﬂuorine derivatives, and all have demonstrated activity against prostate cells (33–35). EB1089 is more potent than calcitriol in binding to the VDR, and it has greater antiproliferative activity against PC-3 and LNCaP cells (35). A phase I trial with EB1089 showed stabilization of disease in patients with advanced breast and colorectal cancer (36). These vitamin D analogs will

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require further study in the prostate cancer patient population, but preliminary results are encouraging.

Peroxisom vce Proliferator-Activated Receptor ␥ PPARγ is another member of the nuclear receptor superfamily that functions as a regulator of numerous genes and induces differentiation in multiple tissue types. For example, PPARγ is highly expressed in adipocytes and induces differentiation of several preadipocyte cell lines (37). Additionally, its overexpression in ﬁbroblasts and myoblast cells also induces adipocyte differentiation (38). This receptor is also expressed in other tissues, including intestine, liver, kidney, breast, and prostate, but the physiologic role at these sites is not well characterized. PPARγ appears to be activated by multiple ligands, including prostaglandins (39), arachidonic acid metabolites (40), and a new class of antidiabetic drugs, the thiazolidinediones. After ligand binding, PPARγ, like the retinoic acid receptor and the VDR, forms a heterodimer with the RXR. The resulting complex binds to peroxisome proliferators response elements (PPREs) in the promoters of target genes. Transcription of these genes then activates adipocyte differentiation and potential tumor suppressor-like functions in some cell types. PPARγ is highly expressed in prostate cancer cell lines, although normal prostate tissue has extremely low expression (14,41,42). In a recent immunohistochemical study, PPARγ was found at high levels in human prostate cancer and prostatic intraepithelial neoplasia (PIN), but only weak or no immunoreactivity was detected in BPH and normal prostate (43). However, both PPARα and PPARβ were expressed in all tissue subtypes, implying unique activity of PPARγ in malignant prostate tissue. PPARγ ligands, such as 15-deoxy-δ-12,14-prostaglandin J2 (15d-PGJ2), 15Shydroxyeicosatetraenoic acid (15S-HETE), and the thiazolidinediones (troglitazone, rosiglitazone, and pioglitazone), have been shown to inhibit proliferation of human prostate cancer cells in multiple studies (14,41,42,44). In vitro studies found this growth inhibition to be secondary to nonapoptotic cell death, with cells accumulating in S-phase, although the mechanism of cell cycle manipulation is unclear (41,42). Treatment of the three main prostate cancer cell lines with 15d-PGJ2 induced obvious morphologic changes, including prominent enlargement of the cytoplasm and the development of numerous cytoplasmic vacuoles (14). Troglitazone inhibited PSA production by 50% in LNCaP cells (14). Treatment of subcutaneously placed PC-3 tumors on immunodeﬁcient mice revealed signiﬁcant inhibition of growth after treatment with troglitazone (14). There have only been two published clinical trials using troglitazone in patients with prostate cancer. Hisatake et al.(45) reported PSA stabilization and a notable decrease in PSA velocity after troglitazone (600–800 mg/d) was initiated in a man with an androgen-dependent recurrence as denoted by a rising PSA after radical prostatectomy (45). At the Dana-Farber Cancer Institute (DFCI), 41 patients with either androgen-dependent (n = 12) or androgen-independent (n = 29) recurrence after deﬁnitive local therapy or androgen deprivation received troglitazone (800 mg/d) for at least 12 wk (41). An unexpectedly high incidence of prolonged stabilization of PSA, absence of new metastases, and disease-related symptoms were noted. After already receiving 16 mo of treatment, one patient with androgen-sensitive disease had a dramatic decrease in PSA to nearly undetectable levels. However, no men with androgen-independent prostate

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cancer experienced ≥50% PSA decreases; seven other patients had decreases of <50%. Treatment was well tolerated, but one patient did suffer transient grade 3 transaminitis. In April 2000, troglitazone was withdrawn from the market in the United States because of idiosyncratic liver toxicity. Thus, at the DFCI, a randomized, placebo-controlled, phase II trial is ongoing with rosiglitazone in patients with a rising PSA after local therapy. The primary study endpoint is post-treatment changes in PSA doubling time.

GROWTH FACTOR RECEPTORS Multiple interconnected pathways that are triggered by a variety of exogenous and endogenous stimuli regulate cell survival and proliferation. Small peptide growth factors, operating through autocrine and paracrine loops, are frequently the initiating agents for these growth signals. These growth factors can activate receptor tyrosine kinases (RTKs) on the cell surface. Ligand binding to the extracellular domains of transmembrane RTKs results in dimerization of the receptors and autophosphorylation of speciﬁc tyrosine residues. This leads to recruitment of other intracellular signaling molecules that amplify the signal to the nucleus by a cascade of phosphorylation events involving many protein kinases and adaptor molecules. Such events lead to the activation of transcription factors that increase or decrease expression of speciﬁc genes involved in cell proliferation, differentiation, and apoptosis. Numerous growth factors have been implicated in prostate cancer development, growth, and metastasis. Although some of these processes are also regulated in part by androgens, dysregulation of these pathways also occurs independent of androgen control. Thus, the androgen-independent state may be driven by these many growth factors and their downstream mediators. The RTK family, well characterized by the epidermal growth factor family of receptors, probably plays a large role in the development of HRPC.

Epidermal Growth Factor EGF is a mitogen required for normal prostate epithelial cells (46); it is found in large quantities in normal human prostatic ﬂuid (47,48) and prostate cancer cells (49). Both normal and malignant prostate epithelium express the EGF receptor, and EGF or transforming growth factor-α (TGF-α) serve to activate this receptor in vitro (50,51) or in vivo (52). EGF and its receptor appear to signal through the MAPK pathway, enhancing protein kinase A activity (8); AR signaling can also be induced by EGF (4). Not surprisingly, blocking EGF receptor signaling in LNCaP and DU-145 cells inhibits cell proliferation (8). Increased expression of the EGF receptor correlates with prostate cancer development and progression. Immunohistochemical evidence supports the notion that there is increased EGF receptor expression in the neoplastic state (53) compared with BPH and normal prostate (54). Consistent with these observations, the androgen-independent DU-145 cell line expresses 10-fold greater EGF receptor than the androgen-sensitive LNCaP cell line does (55). Immunohistochemical data in prostate cancer support the concept that EGF receptor expression correlates with disease relapse and progression to the androgen-independent state (56). Recently new evidence has emerged to support the ﬁnding of mutant EGF receptors (EGFRvIII) (57) that are not always readily detectable with EGF receptor antibodies. In certain instances in which EGF receptor expression is low, EGFRvIII protein levels are highly expressed.

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EGF and its receptor also play a role in prostate tumor cell invasion and metastasis. Introduction of EGF increases the invasive capacity of PC-3 cells in Boyden chamber microinvasion assays (58). When the EGF receptor is overexpressed in DU-145 cells, metastatic potential appears to be increased (59). In the transgenic adenocarcinoma mouse prostate (TRAMP) model, the invasive potential of these cancers is reduced with PD153035, an EGF receptor-speciﬁc kinase inhibitor (60). Several small-molecule inhibitors of the EGF receptor tyrosine kinase ATP binding site have been developed and have entered clinical testing. In non-small cell lung cancer, ZD1839 (Iressa®; Astrazeneca, Macclesfield, UK) is nearing Food and Drug Administration (FDA) approval. In human prostate cancer cell lines it has been shown to induce cell cycle arrest and inhibit proliferation in vitro (61,62). Daily oral administration of ZD1839 in athymic nude mice caused reductions in the growth of HRPC xenografts, and there was clear potentiation of effect when it was combined with paclitaxel (63). Another study demonstrated growth inhibition after ZD1839 treatment in both androgen-dependent and -independent xenografts (64). Phase I studies with ZD1839 have shown activity in patients with advanced prostate cancer (65). Two of 14 evaluable patients demonstrated a response, as deﬁned by a PSA decrease ≥ 50% for at least 6 wk. Additionally, 8 of 12 evaluable patients showed improvement in disease-related symptoms. In another study evaluating the combination of ZD1839/docetaxel/estramustine, a PSA response, as measured by a decline ≥ 50% for ≥ 4 wk, was seen in 11 of 30 patients without signiﬁcant toxicity (66). Ongoing phase I/II trials are also investigating ZD1839 in combination with cytotoxic agents and steroids. Using humanized monoclonal antibodies against the EGF receptor is another approach being explored. C225 is a chimeric monoclonal antibody comprised of a mouse anti-EGF receptor conjugated to a human IgG1 constant region (67). It has speciﬁcity for the external ligand-binding domain of the EGF receptor and has higher afﬁnity than either EGF or TGF-α. Preclinical studies have shown in vitro growth suppression of prostate carcinoma cell lines despite low levels of EGF receptor expression and even regression of pre-established DU-145 xenografts (68). Phase I/II studies have established safety and feasibility in combination with cytotoxic agents in patients with HRPC (69,70). Phase II/III studies are under way in combination with chemotherapy and radiotherapy, although the leading indications are for colon and head and neck cancers. ABX-EFG is a fully human monoclonal antibody against the EGF receptor that has shown efﬁcacy as a single agent (71). In phase I testing, early reports show one prostate cancer patient with a minor response as measured by reductions of PSA and measurable tumors (72).

HER-2/neu The HER-2/neu oncogene encodes a transmembrane glycoprotein with a tyrosine kinase domain that is structurally related to the EGF receptor superfamily (73). Interestingly, there have been no identiﬁed agonistic ligands for the HER2 receptor. Since the receptor heterodimerizes with a variety of other receptors such as the EGF receptor, it may act solely as a co-receptor (74). The possibility exists that overexpression of HER2 may result in spontaneous homodimerization resulting in signal transduction without the need for an activating ligand. Overexpression of HER2/neu in breast cancer is common, and it portends a poor prognosis. The HER2 receptor is also overexpressed in some prostate cancer patients

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(75,76). Ampliﬁcation of HER-2/neu in prostate cancer seems to be reasonably prevalent, ranging from 8 to 44% in several series using ﬂuorescence in situ hybridization (FISH) analysis (77–79). Immunohistochemical studies have also associated exposure to hormone therapy and androgen independence with high levels of expression (80). Additionally, increasing HER-2/neu mRNA and protein expression are seen as tumors progress from the untreated and treated androgen-dependent states to HRPC (81). Interestingly, overexpression of HER-2/neu in an androgen-dependent prostate cancer cell line can stimulate androgen-independent growth (7). AR signaling can be activated in the absence of ligand, and this forced expression cannot be blocked by bicalutamide. Addition of low doses of androgen can even be synergistic with HER-2/neu in activating AR. This ﬁnding makes HER-2/neu inhibition particularly enticing, as it opens up the possibility of reinducing the androgen-sensitive state in HRPC. Humanized murine monoclonal antibodies have also been produced against the extracellular domain of the HER-2 receptor. The FDA has approved trastuzumab (82) as a ﬁrst-line treatment for women with HER-2/neu-positive metastatic breast cancer (83). Investigators at Memorial Sloan-Kettering Cancer Center (MSKCC) have conducted phase II trials of trastuzumab in conjunction with paclitaxel for advanced prostate cancer, and results are forthcoming. Other approaches for targeting HER2/neu have included immunotoxin conjugates with Pseudomonas exotoxin A, and one such conjugate, AR-209 is in early phase I/II clinical trials for multiple malignancies including prostate cancer (84).

Platelet-Derived Growth Factor The platelet-derived growth factor (PDGF) family is another subset of the RTKs that has four isoforms; PDGF-A, PDGF-B, PDGF-C, and PDGF-D pair as homo- or heterodimers. These bind to two receptors; PDGFR-α binds to the PDGF-A, -B, and -C isoforms, and PDGFR-β binds only to PDDG-B and -D with high afﬁnity. Like other RTKs, binding of the ligand causes receptor dimerization, kinase activation, crossphosphorylation, and signal transduction. This signaling occurs through interactions with phosphatidylinositol-3-kinase (PI3K), Src, phospholipase C-γ, Grb2/Sos with activation of the Ras/Raf/MAPK pathway, and other SH-2 domain-containing signaling proteins (85,86). The mechanisms of dysregulated PDGF and PDGFR expression and function have not been fully elucidated, but there is increasing evidence of their role in tumor development, growth, and invasion. PDGF, or c-sis, is closely related to v-sis, the viral oncogene known to cause simian sarcoma by transformation (87). Although the contribution of the PDGFRs to the development of neoplasia is uncertain, more inferences can be drawn by observing the mechanistic activity of the E5 oncoprotein of bovine papillomavirus type 1. The E5 protein causes oligomerization of PDGFR-β, inducing constitutive activation of downstream signaling in the absence of ligand (88). PDGF also blocks the differentiation of prostatic stromal cells by TGF-β (89). Additionally, PDGF-BB dimers and PDGFR-β may regulate angiogenesis through recruitment and differentiation of pericytes, the cells that stabilize immature blood vessels and contribute to their functional integrity (90). Finally, PDGFR activation may indirectly enhance tumor growth by regulating tumor interstitial ﬂuid pressure and transcapillary transport in ﬁbroblasts and pericytes (91). In humans, PDGFR-α and -β are not expressed in normal prostate epithelium and BPH, whereas both isoforms are expressed in high-grade PIN (92) and adenocarcinomas

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(93). Additionally, normal cells and stroma surrounding the tumor lesions do not express PDGF-A or its receptor, PDGFR-α. In metastatic lesions to the bone, PDGFRα is a consistently expressed RTK, as identiﬁed by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry (94). Several small molecules have been developed that inhibit the PDGF RTK. SU101 is a potent inhibitor of the PDGFR/Flk-1 RTK family whose activity against tumor growth correlates with PDGFR expression levels (95). In a multi-institutional phase II study of SU101 in heavily pretreated patients with HRPC, only a limited antitumor effect was seen (96). Treatment resulted in 3 of 39 patients developing a >50% decrease from PSA baseline, 1 of 19 had an actual measurable partial response, and 9 of 35 had improvement of disease symptoms. Most interesting is the fact that PDGFR expression was noted in 80% of bone marrow metastases, whereas 88% of primary prostate tumor archival specimens revealed signiﬁcant expression. This implies one of two things: (1) PDGFR is crucial early in prostate tumorigenesis and is a feasible target for early prostate cancer treatment; or (2) PDGFR expression denotes a subset of prostate neoplasms that confer a poor prognosis and will more likely develop eventual metastatic disease. These hypotheses must be tested ﬁrst with small target populations consisting of high PDGFR expressors before deﬁnitive testing with large randomized studies. Another small-molecule agent developed as an Abl protein kinase inhibitor, imatinib mesylate (STI-571), has been FDA-approved for the treatment of chronic myelogenous leukemia (97). This agent also happens to be a potent inhibitor of the autophosphorylation of PDGFR and c-kit kinases (98). In a nude mouse xenograft model, STI-571 inhibited bone destruction caused by growth of PC-3/MM2 prostate cancer cells implanted in the tibia (99). Addition of paclitaxel to STI-571 was more effective than either agent alone. As a result of these studies, STI-571 has been tested in 40 heavily pretreated patients with advanced prostate cancer (100). The primary endpoint is PSA response; this study closed accrual in May 2001 and results are forthcoming. At the DFCI, patients with newly diagnosed intermediate- or high-risk localized prostate cancer are being treated with neoadjuvant imatinib mesylate prior to surgery (100). This study will help determine the efﬁcacy of STI-571 in prostate cancer as measured by radiologic, pathologic, biologic, and biochemical parameters.

INTRACELLULAR PATHWAYS The functional result of any receptor-ligand interaction can only occur ﬁrst through ampliﬁcation of the signal through multiple protein-protein interactions and/or phosphorylation steps. The myriad of signaling pathways allows much interconnection between different receptor-ligand pathways. Also, activation of some molecules leads to signaling down multiple pathways. Understanding the connections that lead to dysregulated signals in cancer will permit the discovery of crucial pathways whereby an interrupted signal may yield effective antitumor effects (Fig. 2). For instance, the AR can upregulate extracellular signal-regulated kinase-2 (ERK2), a target of MAPK activity, but androgen antagonists are incapable of inhibiting this activation. This observation implies at least two possibilities: (1) androgen binds or interacts with other targets independent of the AR pathway; or (2) androgen binding leads to irreversible changes. Either way, AR signaling leads into the MAPK pathway, as inhibitors of protein kinase C (PKC) and PI3K are effective at reducing AR-induced MAPK upregulation (101).

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Fig. 2. Important signal transduction pathways in prostate cancer. Exogenous signals, such as growth factors, bind to receptor tyrosine kinases (RTKs) and elicit multiple signal cascades. Protein-protein interactions lead to phosphorylation and ampliﬁcation of the signal. Interactions between the separate pathways become important and contribute to the autonomous growth of malignant prostate cells. These ampliﬁed signals lead to nuclear gene transcription and eventual effects on cell proliferation, survival via apoptotic pathways, and migration, which contribute to the development of metastases. Negative regulators, such as PTEN, aid in maintaining homeostasis, overall acting as tumor suppressors. AKT/PKB, Protein kinase B; AP-1, Activator protein 1; DAG, Diacylglycerol; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; IP3, inositol-triphosphate; PDK1, 3-phosphoinositide-dependent protein kinase 1; PI3K, phosphatidylinositol-3-kinase; PIP3, phosphoinositoltriphosphate; PKC, protein kinase C; PLC, phospholipase C; PTEN, phosphatase and tensin homolog; SHC, SRC homolog and collagen protein.

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Cell growth, malignant transformation, and progression have been intimately linked with the MAPK pathway (102–104). The androgen-independent prostate cancer cell line DU-145 harbors constitutive ERK2 activity (8), which is often also seen in highgrade and metastatic prostate cancer, as well as and HRPC (104). MAPK has multiple upstream activators, including RAS and the EGF receptor. The importance of EGF and its relation to the MAPK pathway was demonstrated by inhibiting EGF binding to the EGF receptor with a ﬂavonoid antioxidant, silibinin (105). Treatment with silibinin led to the inactivation of ERK in LNCaP and DU-145 cells, resulting in decreased DNA synthesis and cell growth. ERK2 activation can also be blocked by several other EGF receptor inhibitors, including Tyrphostin AG1748 and MAb-EGFR-528 (8). Thus, autocrine and paracrine growth factors like EGF and others probably provide mechanisms for growth and progression, via the MAPK pathway. Many RTK pathways, in parallel to the MAPK signal transduction cascade, result in activity inducing phosphorylation of PI3K and AKT. These proteins are regulated closely by phosphatase and tensin homolog (PTEN), a tumor suppressor that is a dualspeciﬁcity phosphatase, with both tyrosine phosphoprotein and PI3K phospholipid substrates. In prostate cancer, PTEN expression is frequently lost owing to downregulation by DNA hypermethylation and occasionally from mutation (106–108). In the absence of PTEN expression, phosphoinositol-triphosphate (PIP3), phosphorylated by PI3K, accumulates in cells, activating AKT/PKB kinase as a result (109–111). This constitutively active AKT promotes cell survival and conﬁrms the ability of the negative regulator, PTEN, to act as a tumor suppressor gene.

APOPTOSIS PTEN/PI3K/AKT Unlike MAPK inhibition, which causes a G2/M cell cycle arrest (112), PTEN and the PI3K pathway have been implicated in the regulation of G1 growth arrest (113). This is probably secondary to AKT’s ability to reduce transcription and decrease expression of p27kip1, a cell cycle regulator linked to prostate cancer progression and androgen independence (114). Translational factors controlled by PI3K and AKT, such as p70S6kinase and FRAP (mTOR), are also involved in synthesis of proteins involved in the progression from G1 to S phase. Finally, AKT phosphorylates Forkhead transcription factors, sequestering them in the cytoplasm, fostering cell survival and proliferation (115). PTEN acts through various pathways and at multiple different levels leading to growth arrest, but another important role is apoptosis regulation. The dephosphorylation of PIP3 and focal adhesion kinase (FAK) by PTEN inactivates the PI3K/AKT pathway and has been found to be proapoptotic (110,111), whereas activation of this pathway by loss of PTEN increases the apoptotic threshold (116). In LNCaP cells, AKT upregulation can prevent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis (117). Interestingly, PI3K inhibitor-induced apoptosis in LNCaP cells has been proved to be reversible by the EGF receptor and/or AR activation (118), once again suggesting parallel interactions between various signal transduction pathways in prostate cancer. PTEN and its downstream mediators also have separate roles in tumor development independent of apoptosis and growth arrest. PTEN can inhibit cell motility and migration through PI3K/AKT (119,120), FAK (121,122), and SRC homolog and collagen protein (SHC) (123), thus decreasing metastastic potential. Angiogenesis appears to be

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partially modulated by PTEN as well. Human prostate cancer cell lines expressing ectopically introduced PTEN (124) or downstream inhibitors of PI3K and FRAP (mTOR) (125) exhibit decreased vascular endothelial growth factor (VEGF) production and decreased endothelial cell growth and migration. Thus, it is not surprising that adenoviral-mediated expression of PTEN is not only able to inhibit growth but also prevents metastasis of orthotopically implanted androgen-independent PC-3 cells in mice (126). At the present time no small-molecule inhibitors of the PTEN/PI3K/AKT pathway are available for clinical testing, but the development of signal transduction inhibitors is an ongoing, active process. Inhibition of these signal transduction pathways can occur at several sites, leaving many options for future drug development. To date, most agents have targeted specific ligands competitively, by antibodies or other binding site blocking molecules, or noncompetitively, by sequestering or altering ligand presentation. Another approach utilizes small-molecule strategies that penetrate the cell membrane and bind to ATP-binding sites on the cytosolic portion of RTKs offering reasonable speciﬁcity with the advantage of being able to block propagation of signaling at low nanomolar concentrations. However, inhibiting downstream intermediate proteins, such as members of the PTEN/PI3K/AKT pathway, may also block multiple RTK pathways. For example, both rapamycin and CCI-779 are agents that downregulate mRNA translation by inhibiting mTOR, one of the downstream signals of AKT. Finally, antisense oligonucleotides and gene therapy can affect expression of one or more specific proteins, which may alter the kinetics of these intracellular signals.

Cyclo-oxygenase-2 Traditionally, the role of cyclo-oxygenase has been as an important enzyme in the conversion of arachidonic acid to prostaglandins and other eicosanoids. However, cyclo-oxygenase exists as two different isoforms, the constitutive form (COX-1) and the inducible form (COX-2). Since COX-1 plays a homeostatic role for prostaglandin production in most tissues, inhibition of COX-1 is unlikely to be useful for cancer therapy. However, COX-2 is induced by mitogens, cytokines, and growth factors and is expressed in many malignant tissues, including colorectal carcinoma (127,128). Strikingly, patients taking nonsteroidal anti-inﬂammatory drugs (NSAIDs) were found to have a decreased risk of colon cancer (129), suggesting that inhibition of COX-2 might have a therapeutic effect in cancer therapy. COX-2 may also play an important role in prostate cancer development. Most highgrade PIN cells and their surrounding basal cells demonstrate increased expression of COX-2 protein (130). Additionally, prostate carcinoma cells show marked enhancement of COX-2 expression compared with COX-1 expression by RT-PCR and immunohistochemistry, whereas expression of both isoforms is weak in all cases of BPH and normal prostate (131). These ﬁndings, however, are all correlatives, and the true mechanistic role of COX-2 in prostate cancer must be better deﬁned. There have been many proposed mechanisms hypothesizing the role of COX-2 in human prostate cancer, but the greatest emphasis has been on its role in regulating apoptosis. In vitro studies with both androgen-responsive LNCaP and androgen-nonresponsive PC-3 cell lines revealed a signiﬁcant induction of apoptosis and suppression of growth after treatment with a selective COX-2 inhibitor, N-[(cyclohexyloxy)-4nitrophenyl]-methanesulfonamide (NS-398) compared with a normal prostate stromal

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cell line (132–134). Bcl-2 was apparently phosphorylated and inactivated in the LNCaP cell line, implying a potential proapoptotic mechanism for the COX-2 inhibitor (132). However, others have found there to be no relationship with Bcl-2, and treatment with another COX-2 inhibitor, celecoxib, instead yielded a block in the phosphorylation of AKT (135). Thus, there is recent evidence to support the fact that COX-2 inhibitors, like celecoxib, may induce apoptosis independent of their ability to inhibit cyclo-oxygenase. In a tetracycline-inducible system of COX-2 antisense clones, COX-2 depletion did not induce cell death (136). However, celecoxib was able to induce apoptosis, independent of the clonal level of COX-2 expression. In a follow-up study, these authors were able to show that particular structural units of COX-2 inhibitors mediate apoptosis by facilitating the dephosphorylation of AKT and ERK2, irrespective of their COX-2 inhibitory activities (137). Other direct effects of COX-2 on malignant growth and development may exist. In the process of COX enzyme catalysis, free radicals are generated, and mutagens such as malondialdehyde can be formed (138,139). Additionally, COX-2 and its derivative, prostaglandin E2, have been implicated in hypoxia-induced tumor angiogenesis (140–142). Overexpression models of COX-2 in LNCaP cells have shown not only increased proliferation, but also increased secretion of VEGF protein (143). Finally, treatment of PC-3 tumor-bearing mice with NS-398 revealed growth suppression and regression of existing tumors (132). Not only did TUNEL stains reveal apoptotic induction, but there was also a decrease in tumor microvessel density. Clinical trials with COX-2 inhibitors in the setting of prostate cancer have just begun. At the DFCI, a randomized, double-blind, placebo-controlled trial of celecoxib vs placebo in men with rising PSA following either prostatectomy or radiation therapy for prostate carcinoma is ongoing. Since there is no standard therapy for men with isolated PSA recurrences alone, and many of these men would have opted for watchful waiting, this represents an excellent population in which to study a novel agent for prostate cancer with little risk of excess toxicity. The primary endpoint for the study will be PSA doubling time, and additional biologic correlates will be drawn from original prostatectomy COX-2 expression levels as well as changes in plasma VEGF levels during treatment.

OTHER TARGETS Endothelin-A Endothelin-1 (ET-1) is the prototype of the endothelin family of peptides, which also consists of endothelin-2 (ET-2) and endothelin-3 (ET-3). It is a potent vasoconstrictor and binds two separate endothelin receptors both of which are G-protein-coupled receptors that signal via second messenger systems stimulating PKC (144). ET-A has preferential afﬁnity for ET-1 and ET-2, and less for ET-3; ET-B has equal afﬁnity for all three ligands. ET-B has an opposing function to ET-A by two separate mechanisms: (1) activation of endothelial nitric oxide synthase (eNOS) causes vasodilation (145–147); and (2) nitric oxide (NO) decreases ET-1 synthesis and receptor binding (148,149). Thus, ET-1 has its own negative feedback loop via the ET-B receptors, best demonstrated by a cell line expressing only ET-B receptors. When exogenous ET-1 is introduced to this cell line, ET-1 secretion is decreased (150). In vivo antagonism of ET-B leads to elevated ET-1 levels in the circulation, providing further evidence of this mechanism of autoregulation (151).

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In prostate cancer, both endothelin ligands and receptors are dysregulated. ET-B receptors are downregulated; this phenomenan may be even more prominent in prostate cancer metastases and is also the case with prostate cancer cell lines (152). This downregulation may be owing to hypermethylation of the regulatory region of ETB resulting in inactivation of gene transcription; meanwhile, ET-A expression remains unchanged (153). ET-A immunostaining is highly prevalent and may be even more so in biopsies from patients with more advanced stage disease at biopsy (154). Additionally, ET-1 is highly expressed in prostate cancer cell lines (155), primary prostatic carcinomas, and most metastases (152), partially as a result of ET-B downregulation. However, there are clearly other factors driving ET-1 upregulation since its gene expression can be induced by multiple factors involved in cancer progression such as interleukin-1 (IL-1). TNF-α, TGF-β, and EGF (156,157). The conversion to the androgen-independent phenotype may partially be driven by ET-1, as ET-1 is downregulated in response to androgens (157). ET-1 has many functions besides vasoconstriction, including a role as a cancer mitogen. ET-1 is able to stimulate DNA synthesis and cell proliferation in direct correlation to receptor density (158). In prostate cancer, it is a direct mitogen in vitro, and its action can be blocked with an ET-A-speciﬁc antagonist (152). In addition to operating via the PKC or PI3-K pathway, ET-1 can phosphorylate and activate the EGF receptor in the absence of ligand (159,160). Although ET-1 demonstrates mitogenic activity on its own, it acts synergistically in vitro as a comitogen with a variety of other polypeptide growth factors, including basic ﬁbroblast growth factor (bFGF), IGFs, and PDGF (152,161). However, its most dramatic effect on prostate cancer growth may be through its ability to activate the AR (162). Since prostate cancer tends to develop characteristic osteoblastic bony metastases, it becomes important that osteoblasts have a high density of ET receptors that stimulate synthesis of osteopontin, osteocalcin, and multiple other collagenous proteins (163–166). ET-1 also inhibits osteoclast action, demonstrated by exogenous introduction and reversal of this effect with an ET-1 neutralizing antibody (167). The overall effect is an environment that favors the development of prostate cancer metastases. There may be other important but less well-established roles for ET-1 in prostate cancer. For instance, ET-1, via the ET-A receptor, may be antiapoptotic. This was demonstrated in a prostatic smooth muscle culture, in which exogenous ET-1 reduced apoptotic induction by paclitaxel by >50% (168). However, other reports from that group of investigators did not support a signiﬁcant role for endothelins on apoptosis (152). Angiogenesis appears to be stimulated by ET-1 via the ET-A receptor by inducing VEGF production (169). VEGF and ET-1 are able to induce neovascularization in vivo, although neither is able to perform this function alone (170). Perhaps one of the most intriguing ﬁndings is the signiﬁcant homology between the endothelin family and the snake venom sarafotoxins. As a result, it has been noted in humans that exogenous ET-1 can induce severe pain (171). This is probably because of stimulation of nociceptive receptors and substance P release (172). This pain can be inhibited by ET-A antagonists (173), implying a potential role for use against metastatic cancer pain. As a result of the promising preclinical data obtained above, a highly potent and selective orally active ET-A receptor antagonist called ABT-627 was developed. The initial phase I dose-ﬁnding study revealed headache as a dose-limiting toxicity (174). Of the 31 patients studied with advanced malignancy, 15 had tumor-related pain, with 5 (33%) experiencing alleviation of symptoms as deﬁned by a ≥25% decrease in a

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numeric pain score or analgesic dose. Fourteen of the patients studied had prostate cancer, and 5 of 11 who had at least two serum PSA levels measured had decreases from 4 to 47%. Preliminary subset analysis data from the phase II extension trial with HRPC patients reveals a signiﬁcant survival beneﬁt for those receiving ABT-627 (175). Thus, phase III clinical trials are under way to elucidate a potential survival beneﬁt further. Additionally, there is a phase II randomized study with ABT-627 in conjunction with zolendronate to determine any potential beneﬁcial effects for men with HRPC metastases to bone.

CONCLUSIONS As the most common cancer diagnosis in men, and the second leading cause of cancer-related deaths, prostate cancer represents one of the most urgent areas for new therapeutic development. A better understanding of the biology that leads to and further drives prostate cancer will facilitate development of such therapies. Although good-risk localized prostate cancer has become readily curable in many cases with either surgery or radiation, we lack effective treatments for patients with a high risk of micrometastatic or grossly advanced disease. Androgen deprivation leads to a reduction in PSA levels for most patients, and an objective tumor response in some, but nearly all these individuals will eventually become refractory to inhibition of this target. We have reviewed some of the major differentiation and growth factors, signal transduction pathways, and inter-relationships between pathways that may participate in the development and further success of the HRPC phenotype. The early clinical trials that are under way may lead to approval of new agents that will hopefully kill or delay growth of malignant cells by targeting these speciﬁc pathways. These agents will probably ﬁrst need to demonstrate signiﬁcant activity in a metastatic setting, enduring a stringent, heavily pretreated test population. The potential then exists for combination androgen deprivation therapy with another molecular targeted agent to yield synergistic results in patients with metastatic disease. With combination therapy of this sort, targeting both androgen-dependent and -independent pathways, there may even be a small cure rate in early PSA recurrent disease after local therapy. Another biologically rational goal will be importing the therapies to an adjuvant setting. Since one of the greatest issues in prostate cancer is the development of the hormonerefractory phenotype, targeting androgen-independent pathways early on in treatment may yield more complete abolition of malignant cells. Perhaps in combination with androgen deprivation therapy or even chemotherapy in a neoadjuvant or adjuvant setting, we will have greater ability to reduce the risk of recurrence after local therapy.

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Index

653

Index combined androgen blockade, 569–571 AAH, see Atypical adenomatous diethylstilbestrol, 565 hyperplasia history of use, 561 ABT-627, prostate cancer trials, 644, 645 intermittent androgen deprivation, ADT, see Androgen deprivation therapy 571 African Americans, prostate cancer, luteinizing hormone-releasing epidemiology, hormone agonists, 565, 566 age risks, 108, 109 mechanism of action, 562, 632 autopsy studies, 113, 114 modes, 563, 564 country distribution, 108 orchiectomy, 564 environmental factors, 116 prognostic factors, 562 incidence, 42, 57, 107, 108, 197 timing, 571, 572 molecular epidemiology, 114–116 prostate-specific antigen recurrence mortality, 107, 108 management, 543–545 prostate-specific antigen levels, side effects, age-adjusted levels, 46 anemia, 569 total levels, 45, 112, 113 hot flushes, 568 screening, 42, 112, 113 osteoporosis, 568, 569, 601, 602 Age, overview, 497, 515, 567, 568 grade at prostate cancer diagnosis, Androgen-independent prostate cancer, 111, 112 chemotherapy, 581–584, 631 prostate cancer risk factor, 74, 108, 109 definition, 579, 580 stage at prostate cancer diagnosis, oncologist referral, 557, 558 109–111 second-line hormonal therapy, 580, 581 AKT, targeting in prostate cancer supportive care, 584, 585 treatment, 641, 642 ANNs, see Artificial neural networks Alendronate, osteoporosis management, Antiandrogen withdrawal syndrome, 602 features, 580 Alprostadil, see Intracavernosal injection; Apomorphine, erectile dysfunction Medicated urethral system for management, 453 erection Apoptosis, targeting in prostate cancer Aminoglutethamide, androgentreatment, independent prostate cancer cyclooxygenase-2 inhibitors, 642, 643 management, 581 kinases, 641, 642 Androgen deprivation therapy (ADT), Artificial neural networks (ANNs), biopsy evaluation, 137–140 architecture, 160, 170 combination therapy with radiation comparison with nomograms, 184–188 therapy, see Hormone therapy limitations, 189 with radiation therapy nodes, 170 localized high-risk disease Partin tables, 171, 172 management, 555, 556 stage prediction based on prostatemetastatic disease management, specific antigen levels and adrenal steroidogenesis inhibitors, Gleason score, 567 T1c, 173 antiandrogens, 566, 567 653 A

654 T2a, 174 T2b, 175 T2c, 176 training, 170, 171 validation, 171 Artificial urinary sphincter, sphincter dysfunction management, 405, 406 Arzoxifene, prostate cancer prevention trials, 90 Atrasentan, bone metastasis management, 601 Atypical adenomatous hyperplasia (AAH), features, 74 B Bicalutamide, androgen deprivation with radiation therapy, 350 androgen-independent prostate cancer management, 581 metastatic disease management, 566, 567 prostate cancer prevention trials, 80, 89 Biopsy, see also Prostatic needle biopsy; Radical prostatectomy specimens; Sextant biopsy; Transurethral resection specimens, positive biopsy prediction from initial prostate evaluation, 162 prostate-specific antigen recurrence patient work-up, 530, 531 Bisphosphonates, androgen-independent prostate cancer management, 585 bone metastasis management, androgen-independent prostate cancer, 585 clinical trials, 600, 601 rationale, 599, 600 mechanism of action, 600 osteoporosis management, 602 types and classification, 599 BMPs, see Bone morphogenetic proteins Bone metastasis, bisphosphonate management, androgen-independent prostate cancer, 585 clinical trials, 600, 601 rationale, 599, 600 bone scintigraphy, 592, 593

Index incidence in prostate cancer, 589 laboratory findings, 594 pathophysiology, 590–592 radiopharmaceuticals for palliative therapy, clinical trials, combination therapy, 598, 599 monotherapy, 596–589 radioisotopes, 594–596 treatment prospects, 601 Bone morphogenetic proteins (BMPs), bone metastasis role, 590, 591 Botulinum toxin, bladder dysfunction management, 398, 399 Bowel dysfunction, brachytherapy with supplemental external beam radiotherapy, 366 risks by treatment mode, 493 Bowman-Birk inhibitor, prostate cancer prevention trials, 93 Brachytherapy, advantages and disadvantages, 495, 496 comparison with surgery, cancer control, 461–468 costs, 475, 487 counseling of patients, 476 early-stage prostate cancer, 485 health-related quality of life, 472, 474 local failure rates, 476 morbidity, 468, 470–472, 486 relative efficacy comparison difficulty, 459–461 salvage therapy, 474 secondary malignancy risks, 474, 475, 487 cystoscopy, 335 efficacy, 336, 338 health-related quality of life outcomes, 382, 383 implantation, 332, 334 loading, 332 patient selection, 329, 330, 362, 363 planning, 331, 332, 360 postoperative care, 335 prostate-specific antigen recurrence prediction, 165, 182–184 salvage therapy following external beam radiation therapy, 542

Index setup, 330 side effects, 335, 336 supplemental external beam radiotherapy, biochemical outcomes, high-risk patients, 363, 364 intermediate-risk patients, 363 low-risk patients, 362, 363 bowel dysfunction, 366 clinical trials, 365 costs, 366, 368 erectile dysfunction, 366 planning, 360–362 prospects, 368 rationale, dose escalation, 360 extracapsular extension, 358, 359 implant inadequacy, 360 overview, 357, 358 urinary incontinence, 366 ultrasonography, 330, 331, 332, 334 BRCA1, prostate cancer susceptibility locus, 62, 63 BRCA2, prostate cancer susceptibility locus, 62, 63 C Carcinogenesis, duration, 71 epigenetic changes in prostate cancer, 74 genetic alterations, 71–73, 75, 76 oncogenes, 73 signal transduction pathways, 73 `-Carotene, prostate cancer prevention trials, 98 Case studies, treatment option selection, 497, 498 Cavermap, erectile dysfunction management, 453, 454 Celecoxib, prostate cancer prevention trials, 80, 94 Chemoprevention, see Prevention trials, prostate cancer Chemotherapy, bone metastasis management, 598, 599 chemoendocrine therapy for metastasis, 572, 573 hormone-refractory disease, 557, 558, 631

655 indications, 556–558 Cialis, erectile dysfunction management, 453 Clodronate, bone metastasis management, 600 Complementary and alternative medicine, effects on prostate-specific antigen levels, 48 Computed tomography (CT), prostatespecific antigen recurrence patient work-up, 531 COX-2 inhibitors, see Cyclooxygenase-2 inhibitors CPA, see Cyproterone acetate Cryotherapy, efficacy, 542 salvage therapy following radiation therapy, 540–542 CT, see Computed tomography Cyclooxygenase-2 (COX-2) inhibitors, prostate cancer prevention trials, 94, 95 prostate cancer treatment, 642, 643 CYP3A4, race differences in poly morphisms, 114, 115 Cyproterone acetate (CPA), metastatic disease management, 566 D DES, see Diethylstilbestrol DFMO, prostate cancer prevention trials, 79, 80, 93, 94 Diagnosis, prostate cancer, family informing and reaction, 503, 504 patient reaction, 501–503 spouse reaction, 503 Diethylstilbestrol (DES), androgen-independent prostate cancer management, 581 hormone therapy with radiation therapy, 342 metastatic disease management, 565 Differentiation therapy, peroxisome proliferator-activated receptor-a ligands, 635, 636 rationale, 632, 633 vitamin D, 633–635 Digital rectal examination (DRE), prostate-specific antigen recurrence patient work-up, 530

656 Docetaxel, androgen-independent prostate cancer management, 583, 584 Doctor–patient relationship, comfort level, 513, 514 DRE, see Digital rectal examination Duloxetine, bladder dysfunction management, 398 Dutasteride, prostate cancer prevention trials, 90 E ECE, see Extracapsular extension ED, see Erectile dysfunction EGF, see Epidermal growth factor Ejaculation, effects on prostate-specific antigen levels, 47, 48 ELAC, prostate cancer susceptibility locus, 59 Endothelin-1 (ET-1), bone metastasis role, 591 functions, 644 targeting in prostate cancer treatment, 643–645 Epidermal growth factor (EGF), receptor targeting in prostate cancer treatment, 636, 637 Erectile dysfunction (ED), apomorphine management, 453 brachytherapy outcomes, 366 Cavermap management, 453, 454 Cialis management, 453 early postoperative rehabilitation importance, 454, 455 growth factor therapy, 455 intracavernosal injection, compliance, 440–442 drugs, 440 early postoperative use, 442, 443 efficacy, 440–442 prospects, 444, 445 sildenafil conversion, 443, 444 laparoscopic radical prostatectomy outcomes, 259, 260 medicated urethral system for erection, early postoperative use, 438, 439 intraurethral alprostadil administration, 436 long-term efficacy, 436, 437 prospects, 439, 440

Index sildenafil combination therapy, 437, 438 perineal radical prostatectomy outcomes, 291, 292 postoperative education of patient, 509–511 prevalence following radical prostatectomy, 431, 432, 455 risks by treatment mode, 493 sildenafil, factors affecting efficacy, age, 451, 452 neurovascular bundle status, 449–451 postoperative timing, 452 preoperative erectile function, 451 long-term efficacy, 447, 448 nerve-sparing surgery and response, 445–447, 449 patient satisfaction, 447, 448 self-assessment of response, 453 sural nerve grafting for potency preservation, see Sural nerve grafting vacuum constriction device, efficacy, 433, 434 patient compliance and satisfaction, 433, 434 principles, 432, 433 sildenafil combination therapy, 434–436 Vardenafil management, 453 Estramustine, androgen-independent prostate cancer management, 582–584 ET-1, see Endothelin-1 Exercise, effects on prostate-specific antigen levels, 48 External beam radiotherapy, advantages and disadvantages, 495, 496 biopsy evaluation, 137 brachytherapy supplementation, see Brachytherapy combination therapy with androgen deprivation, see Hormone therapy with radiation therapy comparison with surgery, age-dependent factors, 482, 483 cancer control, 461–468

Index costs, 475, 487 counseling of patients, 476 early-stage prostate cancer, 482–485 health-related quality of life, 472, 474 local failure rates, 476 morbidity, 468, 470–472 relative efficacy comparison difficulty, 459–461 salvage therapy, 474 secondary malignancy risks, 474, 475, 487 survival, 481, 482 disease control endpoints, 312, 313 dose escalation, 314, 317 health-related quality of life outcomes, 381, 382 intensity-modulated radiation therapy, 312 limitations, 311 lymph node irradiation, 310, 311 morbidity, 486 outcomes, conformal radiation therapy, 317–319 conventional external beam radiotherapy, 313, 314 intensity-modulated radiation therapy, 319, 320 particle beam therapy, 320, 322 palliative care, 584 particle beam therapy, 312 planning, 309, 310 prospects, 326 prostate motion, 310 prostate-specific antigen recurrence prediction, 164, 179–182 salvage therapy, following cryotherapy, 543 following radical prostatectomy, 534–539 surgery following failure, 497 target volume, 310 three-dimensional conformal radiation therapy, 311, 312 toxicity outcomes, acute toxicity, 322, 325 chronic toxicity, 325, 326 Extracapsular extension (ECE), biopsy specimens, 128, 132, 135

657 supplemental external beam radiotherapy, 358, 359 F Fat intake, prostate cancer risks, 116, 197 Filamin A, prostate-specific membrane antigen binding, 611 Finasteride, effects on prostate-specific antigen levels, 48 prostate cancer prevention trials, 84, 90, 96 Flutamide, metastatic disease management, 566, 567 prostate cancer prevention trials, 78, 89 G Genistein, prostate cancer prevention trials, 81, 92, 197, 198 Gleason score, biopsy interpretation, 125–127, 129, 132 mortality outcome effects, 199 risk stratification, 494, 495 Goserelin, metastatic disease management, 565, 566 GTX-006, see Toremifene H Health-related quality of life (HRQOL), advanced prostate cancer, 387 assessment, 374, 375 brachytherapy outcomes, 382, 383 cancer recurrence effects, 387 comparison of outcomes with different therapies, 383–387 components in prostate cancer, 375 definition, 373 external beam radiotherapy outcomes, 381, 382 instruments, reliability and validity, 375 selection, 378–380 types, 376–378 morbidity, 486 prospects for study, 387, 388 radiation therapy comparison with surgery, 472, 474

658 radical prostatectomy outcomes, 292, 380, 381 watchful waiting outcomes, 383 HER-2/neu, targeting in prostate cancer treatment, 637, 638 Hereditary prostate cancer (HPC), aggressiveness loci, chromosome 7q32-q33, 63, 64 chromosome 19q12-q13.1, 63, 64 incidence, 196 linkage analysis, 58, 59 prospects for study, 64 risks, 57, 196 screening in young men, 42 segregation analysis, 58 susceptibility loci, BRCA1, 62, 63 BRCA2, 62, 63 CAPB locus, 62 chromosome 16q23, 62 HPC1/RNASEL, 59, 60 HPC2/ELAC, 59 HPC20 locus, 61 HPCX locus, 61 MSR1, 60, 61 overview, 75, 196 PCAP locus, 61 hK2, see Human glandular kallikrein-2 Hormone-refractory disease, see Androgen-independent prostate cancer Hormone therapy with radiation therapy, androgen deprivation, agents, 350 duration, 351, 352 hormone therapy effects on outcome endpoints, 346 interaction of radiation with androgen deprivation, 346, 347 patient selection, 347–350 radiation dose, 353 randomized studies, diethylstilbestrol study, 342 EORTC 22863, 343, 344 MRC trial, 342, 343 RTOG 85-31, 343 RTOG 86-10, 344, 345 RTOG 92-02, 345

Index RTOG 94-13, 345, 346 Umea trial, 343 recommendations, 354 retrospective studies, 341, 342 sequencing of therapies, 352, 353 HPC, see Hereditary prostate cancer HRQOL, see Health-related quality of life Human glandular kallikrein-2 (hK2), immunoassay, 25 prostate cancer diagnostic utility, 26–28 prostate-specific antigen homology, 25, 26 staging of prostate cancer, 30 Human glandular kallikrein-3, see Prostate-specific antigen Hydrocortisone, androgen-independent prostate cancer management, 581, 584 I IGF, see Insulin-like growth factor Imatinib, prostate cancer trials, 639 Imipramine, bladder dysfunction management, 398 Incidence, prostate cancer, mortality-to-incidence ratio and evidence for overdiagnosis and overtreatment, 8–10 projection from pre-prostate-specific antigen era, 11 prostate-specific antigen impact, 3, 4, 11, 12, 15, 38 recent figures, 37, 159, 501 treatment modalities, 6, 7 trends, 4, 5 TURP diagnosis impact, 11, 12 Incontinence, see Urinary incontinence Insulin-like growth factor (IGF), bone metastasis role, 592 Intensity-modulated radiation therapy, see External beam radiotherapy Intracavernosal injection, compliance, 440–442 drugs, 440 early postoperative use, 442, 443 efficacy, 440–442 prospects, 444, 445 sildenafil conversion, 443, 444

Index Iressa, prostate cancer trials, 637 K Kallikrein, see Human glandular kallikrein-2 Ketoconazole, androgen-independent prostate cancer management, 581, 584 metastatic disease management, 567 L Laparoscopic radical prostatectomy (LRP), advantages, 243 anesthesia, agents, 301, 302 general anesthesia, 301 monitoring, 301 anterior transperitoneal approach, 246 apical dissection, 255, 256 bladder neck reconstruction, 256 bladder neck transection, anterior bladder neck, 250 posterior bladder neck, 250, 251 dorsal vein complex, ligation, 249 transection, 255 endopelvic fascia incision, 248, 249 intraoperative data, 257, 258 laparoscopic exit, 256 nerve-sparing surgery, 253, 254 non-nerve-sparing surgery, 252 outcomes, complications, 302 continence, 259 oncologic outcome, 258, 259 potency, 259, 260 patient positioning, 244 patient selection, 243, 244 pneumoperitoneum effects, cardiovascular, 299 respiratory, 299, 300 port placement, 244 posterior Denonvilier’s fascia incision, 252 preoperative preparation, 244, 300 Retzius space exposure, extraperitoneal approach, 247, 248 transperitoneal approach, 246, 247

659 seminal vesicles, 251, 252 transperitoneal posterior approach, 245 urethral dissection, 255, 256 urethrovesical anastomosis, 256 vas deferens, 251 Leuprolide, metastatic disease management, 565, 566 prostate cancer prevention trials, 89 LRP, see Laparoscopic radical prostatectomy Lycopene, prostate cancer prevention trials, 82, 91 Lymphadenectomy, see Pelvic lymphadenectomy Lymph node metastasis, incidence, 136 management, 136 M Magnetic resonance imaging (MRI), prostate-specific antigen recurrence patient work-up, 531, 532 Male slings, sphincter dysfunction management, 402–404 MAPK, see Mitogen-activated protein kinase Meat intake, prostate cancer risks, 116, 197 Medicated urethral system for erection (MUSE), early postoperative use, 438, 439 intraurethral alprostadil administration, 436 long-term efficacy, 436, 437 prospects, 439, 440 sildenafil combination therapy, 437, 438 Megestrol acetate (MGA), androgen-independent prostate cancer management, 581 metastatic disease management, 566 Metastasis, see also Lymph node metastasis, androgen deprivation therapy, adrenal steroidogenesis inhibitors, 567 antiandrogens, 566, 567

660 combined androgen blockade, 569–571 diethylstilbestrol, 565 history of use, 561 intermittent androgen deprivation, 571 luteinizing hormone-releasing hormone agonists, 565, 566 mechanism of action, 562 modes, 563, 564 orchiectomy, 564 prognostic factors, 562 timing, 571, 572 bone, see Bone metastasis chemoendocrine therapy, 572, 573 hormone-refractory disease, see Androgen-independent prostate cancer incidence at diagnosis, 561 survival prediction, 166 MGA, see Megestrol acetate Mitogen-activated protein kinase (MAPK), targeting in prostate cancer treatment, 639, 641 Mitoxantrone, androgen-independent prostate cancer management, 582, 584 Mortality, prostate cancer, death attribution bias, 6, 7 death from competing medical hazards, 198 Gleason score effects, 198, 199 mortality-to-incidence ratio and evidence for overdiagnosis and overtreatment, 8–10 recent figures, 37, 159, 579 trends, 4–6 MRI, see Magnetic resonance imaging MSR1, prostate cancer susceptibility locus, 60, 61 MUSE, see Medicated urethral system for erection N Natural history, prostate cancer, death from competing medical hazards, 198 lead time estimates using prostatespecific antigen, Carter study, 207

Index Gann study, 207, 208 observation patient identification, 211, 212 studies, Albertsen study, 203, 204 Chodak study, 201, 202 Johansson studies, 200, 201 Lu-Yao study, 202, 203 prostate-specific antigen era studies, 204, 206, 207 treatment effect studies, 208–211 NED, see Neuroendocrine differentiation Neuroendocrine differentiation (NED), biopsy specimens, 127 Nilutamide, metastatic disease management, 566, 567 Nomograms, accuracy, 172, 177 cancer recurrence prediction, 160, 161, 529 comparison with artificial neural networks, 184–188 continuity of prostate cancer disease states, 177 counseling of patients, 491, 492 limitations, 189 linearity, 172 types and availability, 178–184 Nutritional Prevention of Cancer Study, 98 O Observation, see Watchful waiting Oncogene, carcinogenesis role, 73 Oncologist referral, chemotherapy indications, 556–559 hormone-refractory disease, 557, 558 localized high-risk disease, 554–556 localized low-risk disease, 553, 554 oncologist role in treatment, 553 terminal patients, 558, 559 OPG, see Osteoprotegerin Orchiectomy, metastatic disease management, 564 Osteoporosis, androgen deprivation therapy induction, 568, 569, 601, 602 management, 602 Osteoprotegerin (OPG), bone metastasis role, 591

Index Outcome prediction, artificial neural networks, architecture, 160, 170 comparison with nomograms, 184–188 limitations, 189 nodes, 170 Partin tables, 171, 172 stage prediction based on prostatespecific antigen levels and Gleason score, T1c, 173 T2a, 174 T2b, 175 T2c, 176 training, 170, 171 validation, 171 brachytherapy and prostate-specific antigen recurrence, 165, 182–184 external beam radiotherapy and prostate-specific antigen recurrence, 164, 179–182 importance, 159 metastasis and survival prediction, 166 model design considerations, calibration, 161, 168 discrimination, 161, 167, 168 generalizability, 161 linearity of relationships, 166 missing data handling, 161, 163 multivariable models, 163, 165 overfitting, 161, 165 risk factor counting, 166, 167 user-friendliness, 169, 170 validation, 161, 168, 169 nomograms, accuracy, 172, 177 comparison with artificial neural networks, 184–188 continuity of prostate cancer disease states, 177 limitations, 189 linearity, 172 recurrence prediction, 160, 161, 529 types and availability, 178–184 pathology prediction for clinically localized cancer, 163 positive biopsy prediction from initial prostate evaluation, 162

661 radical prostatectomy and prostatespecific antigen recurrence, postoperative variables, 165, 179 pretreatment variables, 164, 178, 179 Overdiagnosis/overtreatment, prostate cancer, factors affecting, 4 mortality-to-incidence ratio evidence, 8–10 prostate-specific antigen impact, 3, 4, 11, 12, 15 Oxybutynin, bladder dysfunction management, 398 P Paclitaxel, androgen-independent prostate cancer management, 583 Pamidronate, bone metastasis management, 600 osteoporosis management, 602 Partin tables, see Artificial neural networks Patient perspective, prostate cancer, 513–518 PCPT, see Prostate Cancer Prevention Trial PDGF, see Platelet-derived growth factor Pelvic lymphadenectomy, perineal radical prostatectomy, 263, 264 retropubic radical prostatectomy, 219, 220 Perineal radical prostatectomy, advantages, 263 anatomy, anorectal anatomy, 265, 266 neurovascular bundles, 264 pelvic fascia, 264 anesthesia, 297, 298 apical dissection, 278, 279 bladder neck division, 279, 282, 283 closure, 285, 286 extended radical dissection, 276, 277 incision, 271, 272 large prostate considerations, 286–288 nerve-sparing dissection, 275, 276 nerve-sparing surgery vs extended dissection, 266–269 outcomes, cancer control, 292, 293

662 continence, 290 morbidity, 289, 290 potency, 291, 292 quality of life, 292 patient positioning, 269 pelvic lymphadenectomy, 263, 264 postoperative care, 288, 289 preoperative preparation, 269 puboprostatic ligament division, 279 rectal mobilization, 274, 275 salvage therapy, 293 seminal vesicle dissection, 284 vascular pedicle division, 277, 278 vesicourethral anastomosis, 284, 285 Peroxisome proliferator-activated receptor-a (PPARa), therapeutic targeting, 635, 636 PET, see Positron emission tomography Phosphatidylinositol 3-kinase, targeting in prostate cancer treatment, 641, 642 PIA, see Proliferative inflammatory atrophy PIN, see Prostatic intraepithelial neoplasia Platelet-derived growth factor (PDGF), receptor targeting in prostate cancer treatment, 638, 639 PNBX, see Prostatic needle biopsy Population-based screening, prostate cancer, opposition, 40, 41 prostate-specific antigen screening, age at diagnosis impact, 38, 39 incidence impact, 3, 4, 11, 12, 15, 38 stage at diagnosis impact, 39, 40 survival impact, 40 rationale, 37, 38 young men screening, biopsy refusal, 50 free prostate-specific antigen, 49 high risk groups, African Americans, 42, 45 familial predisposition, 42 prospects, 50, 51 prostate-specific antigen, factors affecting levels, 47, 48 normal levels, 43–45, 47 threshold levels in cancer, 46, 47 velocity, 49, 50

Index Positron emission tomography (PET), prostate-specific antigen recurrence patient work-up, 532, 533 Potency, see Erectile dysfunction PPARa, see Peroxisome proliferatoractivated receptor-a Prednisone, androgen-independent prostate cancer management, 581 Prevention trials, prostate cancer, androgen hypothesis and androgen targeting, 88–90 antioxidants, 90–92 arzoxifene, 90 bicalutamide, 80, 89 Bowman-Birk inhibitor, 93 `-carotene, 98 celecoxib, 80, 94 cohorts, agent studies by cohort, 78–85 elevated prostate-specific antigen with negative biopsy, 86 high-grade prostatic intraepithelial neoplasia, 86 overview, 77, 86 positive family history, 86 preprostatectomy, 87 watchful waiting, 86, 87 combination therapy rationale, 95, 96 cyclooxygenase-2 inhibitors, 94, 95 DFMO, 79, 80, 93, 94 dutasteride, 90 endpoints, 75, 77 estrogen hypothesis and estrogen targeting, 90 finasteride, 84, 90, 96 flutamide, 78, 89 genistein, 81, 92 leads for agent development, 87, 88 leuprolide, 89 lycopene, 82, 91 Nutritional Prevention of Cancer Study, 98 Prostate Cancer Prevention Trial, 96 raloxifene, 90 selenium, 78, 91, 96–98 Selenium and Vitamin E Prevention Trial, 96–98 selenomethionine, 79, 82, 84, 85 soy isoflavones, 78, 82, 92

Index soy protein, 78 sulindac sulfone, 83, 95 toremifene, 83, 90 vitamin D, 79, 93 vitamin E, 82, 84, 85, 91, 96–98 Proliferative inflammatory atrophy (PIA), features, 74 ProstaScint scan, metastasis prediction, 617, 618 multimodality scanning, 618–620 prostate-specific antigen recurrence patient work-up, 532, 533 prostate-specific membrane antigen, antibody, 609, 617 second-generation antibodies, 620, 624 Prostate Cancer Prevention Trial (PCPT), 96 Prostatectomy, see Radical prostatectomy Prostate-specific antigen (PSA), age-specific ranges, 24, 25, 46 baseline value as prostate cancer risk factor, 43 brachytherapy response, 336, 338 complex antigen levels, clinical significance, 19, 20 staging of cancer, 29, 30 early cancer detection advantages, 15 factors affecting levels, 16, 47, 48 free antigen levels, clinical significance, 17, 19 staging of cancer, 29 young male screening, 49 impact on prostate cancer incidence rate, 3, 4, 11, 12, 15, 38 isoforms, BPSA, 22 intact PSA, 23 overview, 20(-2), pPSA, 20, 22 lead time estimates, Carter study, 207 Gann study, 207, 208 metastasis marker, 140 population-based screening, see Population-based screening, prostate cancer radical prostatectomy monitoring, 31 risk stratification, 494, 495

663 sensitivity, 20, 21 specificity, 4, 16, 20, 21 total antigen levels and clinical significance, <4 ng/ml, 16 4–10 ng/ml, 16, 17 >10 ng/ml, 17 staging of cancer, distant staging, 28 local staging, 28 Prostate-specific antigen density, limitations, 23 rationale, 23 transition zone density, 23 Prostate-specific antigen recurrence, definitions, 526, 527 dependence on treatment mode, 526 incidence, 525 prediction, brachytherapy, 165, 182–184 external beam radiation therapy, 164, 179–182 nomograms, 160, 161, 529 radical prostatectomy, postoperative variables, 165, 179 pretreatment variables, 164, 178, 179 recurrent cancer prediction, 528, 529 treatment, androgen deprivation therapy, 543–545 chemotherapy, 557 prospects, 545 salvage therapies, brachytherapy following external beam radiation therapy, 542 cryotherapy following radiation therapy, 540–542 external beam radiation therapy following cryotherapy, 543 radiation therapy following radical prostatectomy, 534–539 radical prostatectomy following cryotherapy, 543 radical prostatectomy following radiation therapy, 539, 540 timing, 533, 534 work-up of patients,

664 biopsy, 530, 531 computed tomography, 531 digital rectal examination, 530 magnetic resonance imaging, 531, 532 positron emission tomography, 532, 533 prostate-specific antigen velocity, 529, 530 transrectal ultrasonography, 530, 531 Prostate-specific antigen velocity, calculation, 24 limitations, 24 prostate-specific antigen recurrence patient work-up, 529, 530 young male screening, 49, 50 Prostate-specific membrane antigen (PSMA), N-acetylaspartylglutamate peptidase activity, 610, 611 discovery, 609, 610 filamin A binding, 611 folate hydrolase activity, 610 gene, cloning, 610 expression regulation, 612 immunostaining, malignant tissue neovasculature, 616 normal nonprostate tissue, 615, 616 prostate specimens, 614, 615 internalization signal, 611 isoforms, 612 knockout mouse phenotype, 612, 613 monoclonal antibodies and epitopes, 613, 614 ProstaScint scan, antibody, 609, 617 second-generation antibodies, 620, 624 serum assays, 616, 617 therapeutic prospects, gene therapy constructs, 626, 627 immunotherapy, 621, 625, 626 radioactive and cytotoxic agent targeting, 621 transgenic mouse studies, 613 Prostatic intraepithelial neoplasia (PIN), biopsy interpretation, 127, 128

Index features, 74 Prostatic needle biopsy (PNBX), core number, 121, 122 DNA ploidy studies, 126 eleven-core biopsy scheme, 148 five-region biopsy scheme, 146 fixation, 122 interpretation and reporting, 125–128 local anesthesia, 154 needle size, 121 repeat biopsy strategies, 151–153 site of biopsy reporting, 122 slide preparation, 122–125 ten-core biopsy scheme, 146, 147 transrectal biopsy, 121 twelve-core biopsy scheme, 149–151 PSA, see Prostate-specific antigen PSMA, see Prostate-specific membrane antigen PTEN, targeting in prostate cancer treatment, 641, 642 Q Quality of life, see Health-related quality of life R Radiation therapy, see Brachytherapy; External beam radiotherapy Radical prostatectomy (RP), advantages and disadvantages, 495 comparison with radiation therapy, age-dependent factors, 482, 483 cancer control, 461–468, 481 costs, 475, 487 counseling of patients, 476 health-related quality of life, 472, 474 local failure rates, 476 morbidity, 468, 470–472, 486 relative efficacy comparison difficulty, 459–461 salvage therapy, 474 secondary malignancy risks, 474, 475, 487 survival, 481, 482 erectile dysfunction management, see Erectile dysfunction health-related quality of life outcomes, 292, 380, 381

Index laparoscopic approach, see Laparoscopic radical prostatectomy patient education, 504, 505 perineal approach, see Perineal radical prostatectomy postoperative support of patient and family, education, 505 home routine, 506 office visit, 508–510 ongoing issues, 510, 511 removal of staples and catheter, 506–508 single patients, 508 support groups, 511 unfavorable pathology report, 510 prostate-specific antigen monitoring, 31 prostate-specific antigen recurrence prediction, postoperative variables, 165, 179 pretreatment variables, 164, 178, 179 radiation failure salvage, 497 retropubic approach, see Retropubic radical prostatectomy salvage therapy, following cryotherapy, 543 following radiation therapy, 539, 540 sural nerve grafting for potency preservation, see Sural nerve grafting Radical prostatectomy specimens, apex findings, 132 bladder neck margin, 132 capsular invasion, 132 extracapsular extension, 128, 132, 135 perineural invasion, 126, 127 processing, 128, 129 reporting, 129, 131–135 Radiopharmaceuticals, palliative care, clinical trials, combination therapy, 598, 599 monotherapy, 596–589 overview, 584, 585 radioisotopes, 594–596 Raloxifene, prostate cancer prevention trials, 90 RANK ligand, bone metastasis role, 591

665 Recurrence, see Prostate-specific antigen recurrence Retropubic radical prostatectomy (RRP), anesthesia, 217, 218, 297, 298, 304, 305 anesthesia, 297, 298 apical dissection, 220–224, 226, 228 bladder neck dissection, 236 blood conservation techniques, 297, 302, 303 complications, 241 continence preservation, 221, 222, 241 dorsal vein complex, 226, 228 endopelvic fascia, 221, 223 incision and retractor replacement, 218, 219 lateral pelvic fascia, 224 margin status, 232 neurovascular bundle release, 228, 229, 232 patient positioning, 218 pelvic lymphadenectomy, 219, 220 posterior vascular pedicle dissection, 234, 236 postoperative care, 237, 241 postoperative pain control, 303, 304 preoperative preparation, 217 urethra division, 232–234 urethrovesical sutures, 232–234, 236, 237, 240 RNASEL, prostate cancer susceptibility locus, 59, 60, 75 RP, see Radical prostatectomy RRP, see Retropubic radical prostatectomy S Sacral nerve stimulation, bladder dysfunction management, 398, 399 Screening, see Population-based screening, prostate cancer SELECT, see Selenium and Vitamin E Prevention Trial Selective estrogen receptor modulators (SERMs), prostate cancer prevention trials, 90 Selenium, prostate cancer prevention trials, 78, 91, 96–98 Selenium and Vitamin E Prevention Trial (SELECT), 96–98

666 Selenomethionine, prostate cancer prevention trials, 79, 82, 84, 85 SERMs, see Selective estrogen receptor modulators Sextant biopsy, eleven-core biopsy scheme, 148 lateral biopsy combination, 147, 148 local anesthesia, 154 prostate size effects on cancer detection rate, 143–145 repeat biopsy strategies, 151–153 sampling error, 143–145 sites, 143 technique, 143 ten-core biopsy scheme, 146, 147 twelve-core biopsy scheme, 149–151 Sildenafil citrate, conversion from intracavernosal injection, 443, 444 factors affecting efficacy, age, 451, 452 neurovascular bundle status, 449–451 postoperative timing, 452 preoperative erectile function, 451 long-term efficacy, 447, 448 medicated urethral system for erection combination therapy, 437, 438 nerve-sparing surgery and response, 445–447, 449 patient satisfaction, 447, 448 self-assessment of response, 453 SNG, see Sural nerve grafting Soy isoflavones, prostate cancer prevention trials, 78, 82, 92, 197 protective mechanisms, 198 Spouse, education importance, 514, 519 prostate cancer diagnosis reaction, 503 support group participation, 520–522 support needs, 513, 515 SRD5A2, race differences in polymorphisms, 115 Staging, prostate cancer, algorithms and nomograms, 309 artificial neural network prediction based on prostate-specific antigen levels and Gleason score, T1c, 173

Index T2a, 174 T2b, 175 T2c, 176 complex prostate-specific antigen, 29, 30 free prostate-specific antigen, 28, 29 human glandular kallikrein-2, 30 risk stratification, 494, 495 total prostate-specific antigen, distant staging, 28 local staging, 28 SU101, prostate cancer trials, 639 Sulindac sulfone, prostate cancer prevention trials, 83, 95 Support groups, goals and objectives, 517 importance, 511, 516 spouse participation, 520–522 treatment education, 517 Sural nerve grafting (SNG), benefits, 426, 427 feasibility, 427 graft placement, 420 historical perspective, 413 indications, 427 margin considerations, 426 mechanism of potency preservation, 411 nerve harvesting, morbidity, 426 technique, 417 nerve regeneration stages, 412 neurovascular bundle resection, 414 outcomes, bilateral grafts, 423, 424, 454 overview, 421–423 potency recovery time, 425, 426 unilateral grafts, 424, 425 parasympathetic reinnervation, 412, 413 patient selection, 413 postoperative care, 420, 421 prospects for study, 427, 428 rationale, 412 surgical technique, 413, 414 vesicourethral anastomosis, 420 T Taxanes, androgen-independent prostate cancer management, 583, 584

Index Testosterone, race differences in levels, 114 TGF-`, see Transforming growth factor-` Tolterodine, bladder dysfunction management, 398 Toremifene (GTX-006), prostate cancer prevention trials, 83, 90 Transforming growth factor-` (TGF-`), bone metastasis role, 591 Transurethral resection specimens, diagnosis impact on prostate cancer incidence, 11, 12 staging, 135, 136 Treatment outcomes, see Outcome prediction Triptorelin, metastatic disease management, 565, 566 Troglitazone, clinical trials, 635, 636 Tumor suppressor gene, mutation in cancer, 73 Tumor volume, effect on outcome, 199 U Ultrasonography, brachytherapy guidance, 330, 331, 332, 334 transrectal ultrasonography for prostate-specific antigen recurrence patient work-up, 530, 531 Urinary incontinence, anatomy, 393, 394 bladder dysfunction management, 398, 399 brachytherapy outcomes, 366 etiology in prostatectomy, 395 evaluation, history and physical examination, 396 laboratory tests, 396 urodynamic evaluation, 397, 398 laparoscopic radical prostatectomy, 259 perineal radical prostatectomy, 290 postoperative education of patient, 509

667 retropubic radical prostatectomy preservation, 221, 222, 241 risks by treatment mode, 492, 493 sphincter dysfunction management, artificial urinary sphincter, 405, 406 injectable therapy, 399–402 male slings, 402–404 surgical technique effects on outcomes, 394, 395 voiding symptoms and treatment selection, 496 V Vacuum constriction device (VCD), efficacy, 433, 434 patient compliance and satisfaction, 433, 434 principles, 432, 433 sildenafil combination therapy, 434–436 Vardenafil, erectile dysfunction management, 453 VCD, see Vacuum constriction device Viagra, see Sildenafil citrate Vinblastine, androgen-independent prostate cancer management, 582, 583 Vitamin D, differentiation therapy, 633–635 prostate cancer prevention trials, 79, 93 Vitamin E, prostate cancer prevention trials, 82, 84, 85, 91, 96–98 W Watchful waiting, advantages and disadvantages, 495 health-related quality of life outcomes, 383 natural history considerations, see Natural history, prostate cancer Z Zoledronic acid, bone metastasis management, 600, 601 osteoporosis management, 602

Management of Prostate Cancer SECOND EDITION Edited by

Eric A. Klein,

MD

Cleveland Clinic Foundation, Cleveland, OH

From Reviews of the First Edition… “…a balanced and comprehensive review…covers the gamut of topics, from epidemiology and molecular genetics to treatment options for localized disease and disease that is refractory to hormone therapy.” —NEW ENGLAND JOURNAL OF MEDICINE “…A must read for any physician desiring a complete and up-to-date understanding of prostate cancer…provides the clinician with a current, complete snapshot of all issues involved in the diagnosis and management of the disease…should be part of the library of all urologists.” —CURRENT SURGERY “…Dr. Klein has assembled an outstanding group of clinicians who have written in detail on many aspects of the disease…provides an excellent resource for practitioners.” —ONCOLOGY “…gives a step by step overview of all available therapeutic options, adapted to the diagnostic evaluation of the patient. This is an interesting publication.” —EUROPEAN UROLOGY

In this second edition of his popular and widely acclaimed book, Eric Klein, MD, and a panel of leading authorities have thoroughly updated and revised its contents to include all the latest observations and developments that will shape the direction of clinical practice and research over the next 5–10 years. Here, the reader will find in concise form accounts of the latest trends in diagnosis and mortality, new PSA isoforms for diagnosis, PSA screening, chemoprevention, biopsy techniques, sural nerve grafting, and hereditary prostate cancer. Additional chapters reflect progress in the management of locally advanced disease, the use of nomograms to predict outcomes, the medical management of erectile dysfunction, brachytherapy, and deciding between surgery and radiation. The chapters on open and laparoscopic techniques, the selection of candidates for observation, pathological analysis, quality of life, and the management of rising PSA after definitive therapy have been extensively updated. A compact disk accompanies the book for downloading an ebook to the reader’s PC or PDA. Up-to-date and eminently practice-oriented, Management of Prostate Cancer, Second Edition, offers every physician—especially front-line urologists, radiation therapists, and medical oncologists—concise and authoritative guidance on today’s best therapeutic regimens for the diagnosis and treatment of prostate cancer. 䊏 State-of-the-art guidance on the diagnosis and treatment of prostate cancer 䊏 Analysis of trends in diagnosis and mortality 䊏 New PSA isoforms for diagnosis and PSA-based screening 䊏 Recent advances that will shape clinical practice and research in the next 5–10 years

䊏 Advances in chemoprevention, biopsy techniques, and sural nerve grafting 䊏 Updated chapters on open and laparoscopic techniques and pathological analysis 䊏 New insights into deciding between surgery and radiation and managing bone metastases

90000 Current Clinical Urology™ Management of Prostate Cancer ISBN: 1-58829-304-1 E-ISBN: 1-59259-776-9 humanapress.com

9 781588 293046