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.

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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

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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

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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

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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


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

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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.


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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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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).


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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

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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.


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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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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., 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.

Chapter 3 / PSA and Young Men

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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 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.

Chapter 3 / PSA and Young Men

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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 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 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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Levin Table 3 Prostate Cancers With Poor Prognosis Prostatic adenocarcinoma with Gleason score 8, 9, and 10 Mucinous adenocarcinoma Small cell undifferentiated carcinoma Prostatic duct adenocarcinoma Signet ring adenocarcinoma Sarcomatoid carcinoma Data from ref. 24.

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 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 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 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

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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 10.0

a

Pathologic stage

2–4

5–6

3+4=7

4+3=7

8–10


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)


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


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)


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


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)


Chapter 9 / Predicting Outcomes by ANNs and Nomograms

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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

188

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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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.

Chapter 10 / When Is Observation Appropriate?

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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 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

Chapter 15 / Conformal External Beam Radiation Therapy

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

Fig. 4. Biochemical relapse-free survival (bRFS) by 70 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

Chapter 16 / Brachytherapy

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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 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 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 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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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.

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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

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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 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).


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

Hijaz et al.

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)

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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%

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 (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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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, 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.

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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 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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33

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

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