Urologic Oncology

An Imprint of Elsevier The Curtis Center 170 S Independence Mall W 300E Philadelphia, Pennsylvania 19106 Urologic Oncol...

Author: Jerome P. Richie | Anthony V. D'Amico

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An Imprint of Elsevier The Curtis Center 170 S Independence Mall W 300E Philadelphia, Pennsylvania 19106 Urologic Oncology

ISBN: 0-7216-0003-4

Copyright © 2005 by Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, PA, USA: phone: (+1) 215 238 7869, fax: (+1) 215 238 2239, e-mail: [email protected]. You may also complete your request on-line via the Elsevier homepage (http://www.elsevier.com), by selecting “Customer Support” and then “Obtaining Permissions.”

NOTICE Urologic oncology is an ever-changing field. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the licensed prescriber, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the publisher nor the author assumes any liability for any injury and/or damage to persons or property arising from this publication.

Library of Congress Cataloging-in-Publication Data Urologic oncology / [edited by] Jerome P. Richie, Anthony D’Amico. p.; cm. Includes bibliographical references. ISBN 0-7216-0003-4 (alk. paper) 1. Genitourinary organs–Cancer. I. Richie, Jerome P. II. D’Amico, Anthony V. [DNLM: 1. Urologic Neoplasms–therapy. 2. Urologic Neoplasms–diagnosis. WJ 160 U7844 2005] RC280.U74U75 2005 616.99¢461–dc22 2004045390

Acquisitions Editor: Rebecca Schmidt Gaertner Editorial Assistant: Suzanne Flint Printed in the United States of America Last digit is the print number:

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CONTRIBUTORS SIDNEY C. ABREU, MD

RICHARD BIHRLE, MD

Fellow, Section of Laparoscopic and Minimally Invasive Surgery Glickman Urological Institute Cleveland Clinic Foundation Cleveland, Ohio 13: Laparoscopic Radical and Partial Nephrectomy

Professor of Urology Indiana University School of Medicine Indianapolis, Indiana 38: Radical Orchiectomy and Retroperitoneal Lymph Node Dissection

ALEX F. ALTHAUSEN, MD

FIONA C. BURKHARD, MD

Associate Clinical Professor (Urology), Department of Surgery Harvard Medical School and Massachusetts General Hospital Cancer Center Boston, Massachusetts 22: Selective Bladder Preservation by Combined Modality Treatment

GERALD L. ANDRIOLE, MD Professor, Department of Surgery Chief, Division of Urologic Surgery Washington University School of Medicine; Director, Prostate Study Center at Barnes-Jewish Hospital St. Louis, Missouri 43: Superficial Carcinoma of the Penis: Management and Prognosis

DARIUS J. BÄGLI, MD, CM, FRCSC, FAAP Associate Professor of Surgery, Division of Urology The University of Toronto Faculty of Medicine Toronto, Ontario, Canada 49: Prepubertal Testicular Tumors

Department of Urology University of Bern Bern, Switzerland 24: Orthotopic Bladder Substitution in the Male and Female

MICHAEL C. CARR, MD, PhD Assistant Professor of Urology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 46: Neuroblastoma

PETER R. CARROLL, MD Professor and Chair, Department of Urology University of California, San Francisco San Francisco, California 23: Noncontinent and Continent Cutaneous Urinary Diversion 26A: Clinically Localized Adenocarcinoma of the Prostate: (Stage T1a-T2c): Surgical Management and Prognosis

GLEN W. BARRISFORD, MD Resident in Urology Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts 32: Complications of Surgical Treatment for Localized Prostatectomy Cancer

WILLIAM J. CATALONA, MD

JAY S. BELANI, MD

XAVIER CATHELINEAU, MD

Resident, Division of Urologic Surgery Washington University School of Medicine St. Louis, Missouri 43: Superficial Carcinoma of the Penis: Management and Prognosis

ARIE BELLDEGRUN, MD, FACS Professor of Urology; Chief, Division of Urologic Oncology David Geffen School of Medicine at UCLA Los Angeles, California 14: Treatment of Advanced Renal Cell Carcinoma

Professor of Urology Northwestern University Feinberg School of Medicine Chicago, Illinois 29: Anatomic Nerve-Sparing Radical Retropubic Prostatectomy

Professor, Department of Urology L’Institut Mutualiste Montsouris Paris, France 31: Laparoscopic Radical Prostatectomy

SAM S. CHANG, MD Assistant Professor, Department of Urologic Surgery Vanderbilt University School of Medicine Nashville, Tennessee 19: Prognosis and Management of Invasive Transitional Cell Carcinoma

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vi Contributors

RICHARD CHILDS, MD

ANDREW J. DRESLIN, MD

Allogeneic Hematopoietic Cell Transplant Unit, Hematology Branch National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, Maryland 5: Immunotherapy: Basic Guidelines

Resident in Urology Brigham and Women’s Hospital Boston, Massachusetts 16: Management of Upper Urinary Tract Transitional Cell Carcinoma

STEVEN J. CHMURA, MD, PhD

Professor of Urology Mount Sinai School of Medicine New York, New York 17: Diagnosis and Staging of Bladder Cancer

Resident, Department of Radiation and Cellular Oncology The University of Chicago Hospitals Chicago, Illinois 3: Principles and Applications of Radiation Oncology

MICHAEL J. DROLLER, MD

DONALD S. COFFEY, PhD

VICTOR FERLISE, MD

Professor, Oncology, Pharmacology and Molecular Sciences; Director, Research Laboratories James Buchanan Brady Urological Institution The Johns Hopkins Medical Institutions Baltimore, Maryland 1: The Molecular and Cellular Biology of Urologic Cancers

Instructor of Urology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 39: Retroperitoneal Tumors: Diagnosis, Staging, Surgery, Management, and Prognosis

MICHAEL S. COOKSON, MD

ROBERT A. FIGLIN, MD, FACP

Associate Professor, Department of Urologic Surgery Vanderbilt University School of Medicine Nashville, Tennessee 19: Prognosis and Management of Invasive Transitional Cell Carcinoma

Professor of Medicine and Urology David Geffen School of Medicine at UCLA Los Angeles, California 14: Treatment of Advanced Renal Cell Carcinoma

MAX J. COPPES, MD, PhD, MBA Head, Division of Paediatric Oncology; Professor, Departments of Oncology and Paediatrics University of Calgary Faculty of Medicine Calgary, Alberta, Canada 47: Wilms’ Tumor

PATRICK J. CREAVEN, MBBS, PhD Research Professor School of Medicine & Biomedical Sciences SUNY Buffalo; Senior Investigator Roswell Park Cancer Institute Buffalo, New York 4: Principles of Chemotherapy for Genitourinary Cancer

ANTHONY V. D’AMICO, MD, PhD

ROBERT C. FLANIGAN, MD Albert J. Speh, Jr, and Clair R. Speh Professor and Chairperson Department of Urology Stritch School of Medicine Loyola University Maywood, Illinois 40: Urethral Cancer

RICHARD S. FOSTER, MD Professor of Urology Indiana University School of Medicine Indianapolis, Indiana 38: Radical Orchiectomy and Retroperitoneal Lymph Node Dissection

Professor, Department of Radiation Oncology Harvard Medical School; Chief, Genitourinary Radiation Oncology Dana-Farber Cancer Institute Brigham and Women’s Hospital Boston, Massachusetts 25: Cancer of the Prostate: Detection and Staging

YVES FRADET, MD, FRCSC

PHILLIPP DAHM, MD

JUDSON R. GASH, MD

Associate Professor, Division of Urology Department of Surgery Duke University Medical Center Durham, North Carolina 30: Radical Perineal Prostatectomy

Associate Professor of Radiology University of Tennessee Knoxville, Tennessee 10: Diagnosis and Staging of Renal Cell Cancer

TRACY M. DOWNS, MD

INDERBIR S. GILL, MD, MCH

Assistant Professor, Division of Urology University of California, San Diego School of Medicine La Jolla, California 23: Noncontinent and Continent Cutaneous Urinary Diversion

Glickman Urological Institute Cleveland Clinic Foundation Cleveland, Ohio 13: Laparoscopic Radical and Partial Nephrectomy

Professor and Chairman, Department of Surgery Faculty of Medicine Université Laval Québec, Canada 20: Transurethral Surgery of Bladder Tumors

Contributors vii

MISOP HAN, MD

FREDERICK A. KLEIN, MD

Assistant Professor, Department of Urology Feinberg School of Medicine Northwestern University Chicago, Illinois 29: Anatomic Nerve-Sparing Radical Retropubic Prostatectomy

Professor and Chairman, Division of Urology University of Tennessee Medical Center Knoxville, Tennessee 10: Diagnosis and Staging of Renal Cell Cancer

J. MATTHEW HASSAN, MD

ERIC A. KLEIN, MD

Resident Vanderbilt University School of Medicine Nashville, Tennessee 19: Prognosis and Management of Invasive Transitional Cell Carcinoma

NIALL M. HENEY, MD, Clinical Assistant Professor of Surgery Harvard Medical School and Massachusetts General Hospital Boston, Massachusetts 22: Selective Bladder Preservation by Combined Modality Treatment

Glickman Urological Institute The Cleveland Clinic Foundation Cleveland, Ohio 37: Nongerm Cell Tumors of the Testis

BADRINATH R. KONETY, MD, MBA Assistant Professor, Department of Urology University of Iowa Iowa City, Iowa 15: Transitional Cell Carcinoma of the Renal Cell Pelvis and Ureter: Evaluation and Treatment

TRACEY KRUPSKI, MD WERNER W. HOCHREITER, MD Department of Urology University Hospital of Bern Bern, Switzerland 24: Orthotopic Bladder Substitution in the Male and Female

Clinical Instructor David Geffen School of Medicine at UCLA Los Angeles, California 14: Treatment of Advanced Renal Cell Carcinoma

SANJAYA KUMAR, MD

Urologist Lakeshore General Hospital Montreal, Québec, Canada 34: Testis Tumors: Diagnosis and Staging

Assistant Professor, Department of Surgery Harvard Medical School; Division of Urology Brigham & Women’s Hospital Boston, Massachusetts 41: Urethrectomy

MICHAEL A.S. JEWETT, MD, FRCSC, FACS

LOUIS LACOMBE, MD, FRCSC

Professor, Department of Surgery (Urology) University of Toronto Toronto, Ontario, Canada 35: Seminoma: Management and Prognosis

Assistant Professor of Urology, Department of Surgery Faculty of Medicine Université Laval Québec, Canada 20: Transurethral Surgery of Bladder Tumors

AVRUM JACOBSON, MD, CM

MICHAEL W. KATTAN, PhD, MD Associate Professor of Public Health and Biostatistics in Urology Cornell University New York, New York 25: Cancer of the Prostate: Detection and Staging

DONALD S. KAUFMAN, MD

PAUL H. LANGE, MD Professor and Chairman Department of Urology University of Washington Medical Center Seattle, Washington 34: Testis Tumors: Diagnosis and Staging

Clinical Professor of Medicine Harvard Medical School; Director, The Claire and John Bertucci Center for Genitourinary Cancers Massachusetts General Hospital Boston, Massachusetts 22: Selective Bladder Preservation by Combined Modality Treatment

W. ROBERT LEE, MD, MS

HYUNG KIM, MD

HOWARD S. LEVIN, MD

Assistant Professor, Department of Urology Roswell Park Cancer Center Buffalo, New York 14: Treatment of Advanced Renal Cell Carcinoma

Staff, Department of Anatomic Pathology The Cleveland Clinic Foundation Cleveland, Ohio 37: Nongerm Cell Tumors of the Testis

Associate Professor and Vice-Chairman Department of Radiation Oncology Wake Forest University School of Medicine Winston-Salem, North Carolina 26B: Clinically Localized Adenocarcinoma of the Prostate: Radiation Therapy

viii Contributors

W. MARSTON LINEHAN, MD

MAXWELL V. MENG, MD

Chief, Urologic Surgery National Institutes of Health National Cancer Institute/Urologic Oncology Branch Bethesda, Maryland 5: Immunotherapy: Basic Guidelines

Assistant Professor, Department of Urology University of California, San Francisco San Francisco, California 23: Noncontinent and Continent Cutaneous Urinary Diversion; 26A: Clinically Localized Adenocarcinoma of the Prostate: (Stage T1aT2c): Surgical Management and Prognosis

MARK S. LITWIN, MD, MPH Professor of Urology and Health Services David Geffen School of Medicine at UCLA Los Angeles, California 6: Health-Related Quality of Life Issues in Urologic Oncology

KEVIN R. LOUGHLIN, MD, MBA

PETER D. METCALFE, MD Resident in Urology Dalhousie University Halifax, Nova Scotia, Canada 49: Prepubertal Testicular Tumors

Professor of Surgery (Urology) Harvard Medical School; Senior Surgeon Brigham and Women’s Hospital Boston, Massachusetts 42: Squamous Cell Carcinoma of the Penis: Diagnosis and Staging

M. DROR MICHAELSON, MD, PhD

DONALD F. LYNCH, Jr, MD

AARON J. MILBANK, MD

Instructor in Medicine Harvard Medical School Boston, Massachusetts 22: Selective Bladder Preservation by Combined Modality Treatment

Professor and Chairman, Department of Urology Eastern Virginia Medical School and Jones Institute for Reproductive Medicine Norfolk, Virginia 45: Penectomy and Ilioinguinal Lymphadenectomy

Glickman Urological Institute The Cleveland Clinic Foundation Cleveland, Ohio 37: Nongerm Cell Tumors of the Testis

S. BRUCE MALKOWICZ, MD Professor of Urology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 39: Retroperitoneal Tumors: Diagnosis, Staging, Surgery, Management, and Prognosis

Professor of Urology University of Washington School of Medicine; Chief, Division of Pediatric Urology Children’s Hospital & Regional Medical Center Seattle, Washington 46: Neuroblastoma

MURUGESAN MANOHARAN, MD, FRCS

ASHRAF MOSHARAFA, MD

Assistant Professor, Department of Urology University of Miami School of Medicine Miami, Florida 18: Superficial Transitional Cell Carcinoma of the Bladder: Management and Prognosis

MICHAEL E. MITCHELL, MD

Fellow in Urology Indiana University School of Medicine Indianapolis, Indiana 38: Radical Orchiectomy and Retroperitoneal Lymph Node Dissection

ANDREW C. NOVICK, MD FRAY F. MARSHALL, MD Chairman of Urology Emory University School of Medicine Atlanta, Georgia 11: Renal Cell Carcinoma: Localized Disease

MARY FRANCES MCALEER, MD, PhD

Professor of Surgery Cleveland Clinic Lerner College of Medicine; Chairman, Glickman Urological Institute Cleveland Clinic Foundation Cleveland, Ohio 12: Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy

Resident, Department of Radiation Oncology Thomas Jefferson University Philadelphia, Pennsylvania 27: Regionally Advanced Adenocarcinoma of the Prostate: (T3-4N + M0): Management and Prognosis

WILLIAM K. OH, MD

W. SCOTT MCDOUGAL, MD

MICHAEL P. O’LEARY, MD

Walter S. Kerr, Jr. Professor of Urology Harvard Medical School; Chief, Urology Service Massachusetts General Hospital Boston, Massachusetts 44: Invasive Carcinoma of the Penis: Management and Prognosis

Assistant Professor, Department of Surgery Harvard Medical School; Division of Urology Brigham and Women’s Hospital Boston, Massachusetts 32: Management of Complications of Radical Prostatectomy Surgery

Assistant Professor of Medicine Harvard Medical School Boston, Massachusetts 28: Metastatic Adenocarcinoma of the Prostate

Contributors ix

KENNETH OGAN, MD

MARTIN G. SANDA, MD

Assistant Professor of Urology Emory University School of Medicine Atlanta, Georgia 11: Renal Cell Carcinoma: Localized Disease

Visiting Associate Professor at Harvard Medical School, Division of Urology; Beth Israel Deaconess Medical Center Boston, Massachusetts 2: Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations

RISHIKESH PANDYA, MCH, DNB, MS Fellow, Division of Urology University of Toronto Toronto, Ontario, Canada 35: Seminoma: Management and Prognosis

DAVID F. PAULSON, MD Professor of Urology Duke University Medical Center Durham, North Carolina 30: Radical Perineal Prostatectomy

DAVID F. PENSON, MD, MPH Associate Professor of Urology and Preventive Medicine Keck School of Medicine University of Southern California Los Angeles, California 6: Health-Related Quality of Life Issues in Urologic Oncology

WILLIAM U. SHIPLEY, MD Andres Soriano Professor of Radiation Oncology Harvard Medical School; Head, Genitourinary Oncology Unit Department of Radiation Oncology Massachusetts General Hospital Boston, Massachusetts 22: Selective Bladder Preservation by Combined Modality Treatment

WENDLA SILVERBERG, MD Resident, Department of Radiation and Cellular Oncology The University of Chicago Chicago, Illinois 3: Principles and Applications of Radiation Oncology

DONALD G. SKINNER, MD

Assistant Professor of Medicine Keck School of Medicine University of Southern California Los Angeles, California 4: Principles of Chemotherapy for Genitourinary Cancer

Professor and Chairman, Department of Urology Hanson-White Chair in Medical Research Keck School of Medicine University of Southern California Los Angeles, California 21: Partial and Radical Cystectomy

DEREK RAGHAVAN, MD, PhD

JOSEPH A. SMITH, Jr, MD

DAVID I. QUINN, MD

Professor, Lerner College of Medicine; Chairman and Director, Cleveland Clinic Taussig Cancer Center The Cleveland Clinic Foundation Cleveland, Ohio 4: Principles of Chemotherapy for Genitourinary Cancer

MICHAEL L. RITCHEY, MD Professor of Surgery and Pediatrics; Director, Division of Urology University of Texas Health Science Center Houston Medical Center Houston, Texas 47: Wilms’ Tumor

William L. Bray Professor and Chairman Department of Urologic Surgery Vanderbilt University School of Medicine Nashville, Tennessee 19: Prognosis and Management of Invasive Transitional Cell Carcinoma

HOWARD M. SNYDER, III, MD Professor of Urology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 48: Rhabdomyosarcoma of the Pelvis and Paratesticular Structures

MARK S. SOLOWAY, MD

Assistant Professor, Department of Urology The Johns Hopkins University Baltimore, Maryland 2: Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations

Professor and Chairman Department of Urology University of Miami School of Medicine Miami, Florida 18: Superficial Transitional Cell Carcinoma of the Bladder: Management and Prognosis

RANDALL G. ROWLAND, MD, PHD

GRAEME S. STEELE, MD

Professor and Chief, Division of Urology University of Kentucky College of Medicine Lexington, Kentucky 36: Nonseminomatous Germ Cell Tumors: Management and Prognosis

Assistant Professor of Surgery Harvard Medical School and Brigham and Women’s Hospital Boston, Massachusetts 16: Management of Upper Urinary Tract Transitional Cell Carcinoma

RONALD RODRIGUEZ, MD, PhD

x Contributors

JOHN P. STEIN, MD

PAMELA UNGER, MD

Associate Professor of Urology Keck School of Medicine University of Southern California Los Angeles, California 21: Partial and Radial Cystectomy

Associate Professor of Pathology Mount Sinai School of Medicine New York, New York 33: Seminal Vesicles: Diagnosis, Staging, Surgery, Management, and Prognosis

RICHARD G. STOCK, MD

RICHARD K. VALICENTI, MD

Professor of Radiation Oncology Mount Sinai School of Medicine New York, New York 33: Seminal Vesicles: Diagnosis, Staging, Surgery, Management, and Prognosis

NELSON N. STONE, MD

Associate Professor of Radiation Oncology Thomas Jefferson University Philadelphia, Pennsylvania 27: Regionally Advanced Adenocarcinoma of the Prostate: (T3-4N + M0): Management and Prognosis

Professor of Urology and Radiation Oncology Mount Sinai School of Medicine New York, New York 33: Seminal Vesicles: Diagnosis, Staging, Surgery, Management, and Prognosis

GUY VALLANCIEN, MD

URS E. STUDER, MD

CELI VAROL, MD

Chairman University of Bern; Director, Department of Urology University Hospital of Bern Bern, Switzerland 24: Orthotopic Bladder Substitution in the Male and Female

AGNIESZKA SZOT BARNES, MD, MS Research Fellow in Prostate Image-Guided Therapy Program Department of Radiology Brigham and Women’s Hospital Boston, Massachusetts 7: Image-Guided Minimally Invasive Therapy

SHAHIN TABATABAEI, MD Instructor in Surgery Harvard Medical School Boston, Massachusetts 44: Invasive Carcinoma of the Penis: Management and Prognosis

MIAH-HIANG TAY, MBBS, MRCP National Cancer Centre of Singapore Singapore 28: Metastatic Adenocarcinoma of the Prostate

Head, Departments of Urology and Nephrology L’Institut Mutualiste Montsouris Paris, France 31: Laparoscopic Radical Prostatectomy

Department of Urology University Hospital of Bern Bern, Switzerland 24: Orthotopic Bladder Substitution in the Male and Female

E. DARRACOTT VAUGHAN, Jr, MD Professor Weill Medical College of Cornell University New York, New York 8: Adrenal Tumors

JOHANNES VIEWEG, MD Associate Professor of Urology and Immunology Duke University Medical Center Durham, North Carolina 30: Radical Perineal Prostatectomy

DONALD VINDIVICH, MD Senior Researcher, James Buchanan Brady Urological Institution The Johns Hopkins Medical Institutions Baltimore, Maryland 1: The Molecular and Cellular Biology of Urologic Cancers

CLARE M.C. TEMPANY, MB, BAO, BCh

DAVID S. WANG, MD

Professor, Department of Radiology Harvard Medical School; Director, Clinical Magnetic Resonance Imaging Brigham and Women’s Hospital Boston, Massachusetts 7: Image-Guided Minimally Invasive Therapy

PADRAIG WARDE, MB, BCh, BAO

RABI TIGUERT, MD Fellow, Urology–Oncology Université Laval Québec, Canada 20: Transurethral Surgery of Bladder Tumors

Assistant Professor of Urology Boston University School of Medicine Boston, Massachusetts 9: Open and Laparoscopic Surgery of Adrenal Tumors

Professor, Department of Radiation Oncology University of Toronto; Associate Director, Radiation Medicine Program Princess Margaret Hospital Toronto, Ontario, Canada 35: Seminoma: Management and Prognosis

Contributors xi

W. BEDFORD WATERS, MD

HSI-YANG WU, MD

Professor of Urology University of Tennessee Knoxville, Tennessee 10: Diagnosis and Staging of Renal Cell Cancer

Assistant Professor of Urology University of Pittsburgh Pittsburgh, Pennsylvania 48: Rhabdomyosarcoma of the Pelvis and Paratesticular Structures

RALPH R. WEICHSELBAUM, MD

JASON B. WYNBERG, MD, FRCSC

Chairman, Department of Radiation and Cellular Oncology The University of Chicago Chicago, Illinois 3: Principles and Applications of Radiation Oncology

Urologic Oncology Fellow National Cancer Institute Bethesda, Maryland 5: Immunotherapy: Basic Guidelines

RICHARD D. WILLIAMS, MD

ANTHONY L. ZIETMAN, MD

Professor and Head, Department of Urology Rubin H. Flocks Chair University of Iowa Iowa City, Iowa 15: Transitional Cell Carcinoma of the Renal Cell Pelvis and Ureter: Evaluation and Treatment

Professor of Radiation Oncology Harvard Medical School; Director of Residency Training for Radiation Oncology Massachusetts General Hospital Boston, Massachusetts 22: Selective Bladder Preservation by Combined Modality Treatment

HOWARD N. WINFIELD, MD Professor of Urology Director of Endourology and Minimally Invasive Surgery; University of Iowa Iowa City, Iowa 9: Open and Laparoscopic Surgery of Adrenal Tumors

PREFACE Urologic cancer has become a major public health problem in the United States: an estimated 42% of all new cancers in men and 16% of cancer deaths in men are a result of urologic cancers. Although less common in women, bladder and kidney cancer still rank among significant causes of morbidity and mortality. The impact of urologic cancers on the population and the far-reaching advances in urologic oncology have provided the impetus for this new textbook, which covers all aspects of urologic oncology in a concise yet focused fashion. Major strides have been accomplished in the field of urologic oncology, particularly in the area of prostate cancer, where an estimated 220,900 new cases were expected in 2003 and a significant but decreasing number of deaths totaling 31,800. Three sentinel factors have catalyzed the advances in the diagnosis and treatment of prostate cancer: the discovery and application of serum prostate specific antigen and its isoforms for early detection of prostate cancer, the development of effective surgical and radiotherapeutic approaches that increase efficacy and reduce morbidity from prostate cancer, and the utilization of an increasing number of transrectal ultrasound spring loaded needle guided biopsies to more efficiently diagnose prostate cancer in an ambulatory setting. Urologic oncology has matured from case studies to evidence-based medicine. Randomized prospective studies in many arenas of urologic oncology have aided the clinician in decision-making processes. The stratification of patients into various prognostic groups based on pretreatment factors has allowed accurate comparisons of cancer control outcome of different modalities of treatment. Urologic oncology has become a multidisciplinary specialty, with integration of medical oncology and radiation oncology specialists along with urologic oncologist to provide the most comprehensive treatment options for the patient with urologic malignancy. This textbook provides basic principles of medical and surgical urologic oncology. Each urologic cancer tumor type is reviewed with regard to incidence, etiology, clinical presentation, diagnosis and staging, treatment options, prognosis, and future directions. Common surgical procedures for genitourinary cancers are discussed in terms of indications, preoperative preparation, technique, efficacy, and side effects. Both adult and pediatric malignancies, including neuroblastoma, Wilms’ tumor, testis tumors, and rhabdomyosarcoma, are reviewed in detail. Leading authorities in the field have contributed their knowledge and expertise to this compendium of urologic oncology. The text is supplemented with tables and figures, as well as a bibliography containing classic references and recent papers published in the urologic and medical literature. We expect that this textbook will serve as a valuable resource to the oncologist in need of pertinent information in every aspect of urologic oncology, from basic principles to treatment to multidisciplinary approaches. Jerome P. Richie, MD Anthony V. D’Amico, MD, PhD

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C H A P T E R

1 The Molecular and Cellular Biology of Urologic Cancers Donald S. Coffey, PhD, and Donald Vindivich, MD

The focus of this chapter is to provide an overview of some of the important concepts and discoveries that have recently revolutionized our understanding of cancer. This will be accomplished by giving simple schematics that show the complexity and elegance of the control mechanisms involved in controlling life and how these processes go astray when cancer develops. This will not be an extensive review with detailed references but rather an overview of the most important and complex medical problems. THE ENIGMAS OF GENITOURINARY CANCERS All of our present molecular concepts of the role of inherited genetics as the sole cause of cancers appear to be challenged by the tissue specificity of the genitourinary cancers. Each organ inherits the same genome, but only certain organs, such as the prostate, bladder and kidney, are highly prone to form cancers. In contrast, other organs in close anatomic proximity are essentially devoid of any historic presence of a reported cancer, such as the epididymis, vas deferens, and bulbourethral glands. All of these organs with vast differences in their cancer risk can reside within the same human; thus, they have the same inheritance, genome, environmental exposure, and have aged to exactly the same time (Figure 1-1). For example, the bulbourethral gland and the prostate are both derived from the same developmental anlagen, the urogenital sinus, and they both bud off as adjacent structures from the developing urethra. Both organs are androgen responsive and have a similar blood supply and nerve stimulation and reside within the same host, sharing a common diet, carcinogenic intake, hormonal environments, and identical aging. One would have

anticipated that whatever causes the multimillions of accumulated cases of prostate cancers in the history of the world should have produced at least a dozen bulbourethral cancers, but not one has ever been reported. The same is true for the epididymis. No simple comparative analysis of replication rates, DNA repair, acquired mutation, inherited gene, or lifestyle and environments seems appropriate to explain this paradox of such a marked tissue specificity for cancer risk. Something within the biologic and molecular contexts of the cell type and differentiation would appear to be involved; this nongenetic effect is termed an epigenetic event (Figure 1-2). EPIGENETIC EFFECTS Since the same DNA sequence in two different cell types can produce such drastic differences in cancer risk factors, it is apparent that other factors besides just the DNA sequence (genetics) may affect this carcinogenesis. This epigenetic process is usually thought to be related to the maturation of the stem cell to a specific cell type. What is the molecular basis of epigenetics? The same gene sequence can produce a different messenger RNA in different cell types due to alternative splicing of the RNA. DNA rearrangements can also alter the message. Recent attention has been focused on alterations in chromatin structure, which changes the way DNA is wrapped around the histone cores to form a nucleosome and alter gene expression. One hundred and forty-seven base pairs (bp) of DNA are coiled twice around each histone octamer that is made up of two copies each of H2A, H2B, H3, and H4. This tight interaction of the nucleosome with DNA can be loosened by acetylation of the histone through the action

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Part I Principles of Urologic Oncology

Figure 1-1 Within a human the prostate and bulbourethral gland are similar, yet the risk of cancer is astronomically different. Understanding the molecular basis of this tissue specificity is one of the great riddles of cancer.

of histone acetyl transferases (HAT) or the DNA nucleosome can be tightened by histone deacetylation (HDAC). In addition, some of these histones can be methylated, which usually occurs on the lysine of histone H3. Histone hypoacetylation and H3 methylation both tend to tighten DNA and silent chromatin from being expressed. In addition, the DNA may be silenced by DNA methylation through methylation of the cytosine in the five positions (5 mC). These three types of regulations work closely in coordination, and can be transferred during propagation to the daughter cell, and, therefore, can act like pseudogenetic elements or as termed, an epigenetic event. A fourth element modifying chromatin structure is small molecular weight RNA, such as interference RNA (RNAi). These and other small RNA molecules are not read out into proteins but appear to have powerful regulatory abilities in directing chromatin structure, message availability, cell function, and gene function. One of these small RNAs that are not translated is termed DD3 and is overexpressed in prostate cancer and may be an important control factor or diagnostic agent. DNA topology involves the winding and unwinding of the double helix and can change the super helical density through the actions of topoisomerases and helices that can greatly alter chromatin structure. These factors are usually attached at the base of 60,000 molecular weight DNA loops that are attached to the fixed replication complex on the nuclear matrix. The nuclear matrix is tissue specific in its protein composition. This loop organization represents a much higher order structure of DNA and chromatin and is cell type specific and represents one of the frontiers of understanding epigenetic events. Five to ten percent of the total proteins made within the cell are transcription factors, and it is estimated that

Figure 1-2 An inherited gene that causes cancer is present in every cell, but it only produces cancer in a specific type of cell: this specificity is an epigenetic event dictated by the context of the cell.

there are about 3000 different types of these transcription factors within a human. It now appears that organism complexity, as well as cellular diversity, may arise from the diversity of these transcription complexes that form large cellular machinery in a tissue-specific manner of self-assembly.1 Once a protein is formed by translation of a specific gene, its turnover rate is regulated by a series of posttranslational modifications, such as ubiquination and proteosome interactions, clipping or glycosylation, etc. Certainly, folding of proteins into various dynamic structures is essential for their proper action. Many of these proteins are transported to specific cellular sites and can interact in heterodimers with thousands of other proteins to form complex networks. Understanding these self-assembling networks has now become a major frontier of cell biology.2 CARCINOGENS What causes genitourinary cancers? Is it mostly environment (nurture) or inheritance (nature)? Obviously it is both, but environment has been understudied. In China, prostate and breast cancer incidence is less than onetenth of the incidence rate in the U.S., and this is true of many other parts of Asia. When Asian populations, with low prostate cancer rates, migrate to the U.S., there is a dramatic increase in their incidence of prostate cancer that occurs by the second generation. This alteration risk is different with migration and would appear to involve a change in environmental exposure or a change in lifestyle risk factors that are beyond a simple Mendelian model of genetics. It now appears that genes and environment interact in a system we have not resolved, but it can still

Chapter 1 The Molecular and Cellular Biology of Urologic Cancers 5

only be an effective carcinogenic event when it occurs in a specific type of cell within the body. It is still unclear whether this migration to a higher cancer risk area removes a protective agent that was in the Asian environment or has added a carcinogenic agent in the United States’ environment. With few exceptions, it has been extremely difficult to induce prostate cancer in aging rats. However, if rats are fed with burnt meat, both prostate cancer and breast cancer appear.3 A polycyclic hydrocarbon has been identified from burnt meat and appears to make adducts to the DNA and thus produces mutations. DNA repair cuts out these aberrant bases, and they appear in the urine. The production of these carcinogens in burnt meat is related to the temperature and time of cooking and might easily explain many cultural variations in food processing that alter carcinogens. For example, the Chinese eat meat, but they do not burn it excessively in the same way as we do in the U.S. in our barbecuing and tendencies to sear to the point of burning in the preparation of many of our meats. Obviously, other cultural aspects of diet might also be involved, such as the absence of milk and cheese in the diet of Asia in contrast to its heavy use in the U.S. and Northern Europe, or the addition of tea and soy in the Asian diet. INFLAMMATION Chronic inflammation has recently received tremendous interest as an etiologic factor associated with many diseases appearing during aging, including arteriosclerosis, arthritis, and now cancer. It has long been recognized that schistosomiasis infections in Egypt were associated with a high incidence of bladder cancer. Now a new mechanism for inflammation in the formation of prostate cancer is becoming evident.4 This new mechanism may combine many aspects of genetics and epigenetics defined by lifestyle and risks. In the aging prostate, there appear to be many small foci of atrophy. Usually, atrophy indicates a dormant state or DNA synthesis that is often seen when androgens are withdrawn. Following androgen ablation the entire prostate becomes atrophied in relation to its epithelial cells and DNA synthesis and replication essentially cease.5 The paradox was that in some prostates in humans these small foci of atrophy could be seen in juxtaposition to acini with highly stimulated luminal epithelial cells that appeared to be under strong androgen stimulation. The paradox of atrophy next to stimulation was resolved in part when it was observed that these atrophied epithelial cells seen in the small foci were actually not dormant for DNA synthesis but were highly stimulated and were undergoing rapid DNA synthesis. This proliferative type of atrophy was often associated with areas of prostate inflammation. Prostate inflammation is

very common and is often not associated with any symptoms, and it must be distinguished from prostatitis, which frequently can be symptomatic. The cause of this hidden prostate inflammation is unknown. It may be related to pathogens, it could also be associated with autoimmunity. Nevertheless, this close proximity of highly replicating prostate cells in focal proliferative atrophy juxtaposition with inflammatory cells that could produce high levels of reactive oxygen species (ROS) could be highly detrimental to the DNA of the prostate epithelial cells unless they can protect themselves against this oxidative onslaught. One of the common mechanisms of protecting against this type of oxidative damage is to induce a stress response that up-regulates glutathione-S-transferase pi (GSTPi) that provides a strong protection against carcinogens and ROS. These prostate cells that are under stress near the inflammation have indeed induced their defenses by the induction of this GSTPi, however, a few isolated epithelial cells appear to be unable to produce this protective effect. These cells are highly prone to DNA damage, and when replicated would then accumulate and be the early events in prostatic interepithelial neoplasia (PIN), a precursor to prostate cancer. This model has been proposed and tested by Angelo De Marzo, and a recent review discusses details of the molecular mechanism.4 How is GSTPi regulated? As stated, the DNA promoter region of GSTPi is in a CpG-rich island domain located within the promoter region. This promoter is silenced by the methylation of the cytosine residues in these CpG islands, thus turning off the expression protective effect of GSTPi for the replicating cells located in the reactive oxygen environment of the inflammation. The final prostate cancer cells that form have a hypermethylated CpG island region in the promoter of GSTPi, and this is the most common molecular and genome change (>90%) that has been reported to be associated with all forms of prostate cancer. The cellular and molecular events that can be correlated with the early pathology pathway to prostate cancer have been defined and named proliferative inflammatory atrophy (PIA).4 It is also of interest that in animal models of prostate inflammation in the rat, that the inflammation can be suppressed by high levels of soy in the diet; a possible clue to a protective factor in the Asian diet.5 Two genes that have been implicated as candidates in familial human prostate cancer studies and by microarray studies are the macrophage scavenger receptor (MSR-1) and RNASEL6 (Table 1-1). These genes have been shown to increase infections in knock out animals devoid of these genes. Thus, the role of pathogens might be implicated in this process, but equal attention should be given at this time to the possibility that this type of inflammation may be produced by autoimmune reactions. Estrogen imprinting in the early neonate life of the rat can result in later

6


Table 1-1 Selected Genes Proposed to be Involved in Prostate Cancer Initiation or Progression, or in Modifying the Risk of Prostate Cancer Development Gene

Proposed Function

Mutations causing decreased activity MS (MSR-1) RNASEL ELAC2

Antiinfectious, macrophage scavenger receptor Antiinfectious, apoptosis, RNASE Metal-dependent hydrolase

Promoter hypermethylation resulting in gene silencing GSTP1 Carcinogen detoxification EDNRB Endothelin receptor ER (alpha and beta) Estrogen receptor LOH and point mutation PTEN TP53 (also p53) LOH and haploinsufficiency NKX3-1 CDKN1B (P27KlP1) Point mutations COPEB (also KLR6) Androgen receptor (AR) Amplification AR

Cell survival and proliferation, phosphatase Cell survival and proliferation, genome stability Cell differentiation and proliferation Cell proliferation, brake for proliferation

Transcription regulation Cell proliferation, survival and differentiation Cell proliferation, survival, and differentiation

Overexpressed at mRNA and protein level HTERT (telomerase) Cell immortality HPN (Hepsin) Transmembrane protease FASN Fatty-acid synthesis AMACR (racemase) Fatty-acid metabolism, branched chain EZH2 Transcription repressor, cell proliferation MYC Cell proliferation BCL2 Cell survival Polymorphisms affecting prostate cancer risks AR (CAG and GGC repeats) Cell proliferation, survival, and differentiation CYP17 Androgen metabolism SRD5A2 (5 Alpha reductase) Androgen metabolism Metastasis suppressor (down-regulated) KAI1 CD44 NME23 KISSI BRMS1 MAP2K4

development of marked inflammation in the adult rat’s prostate if they are carried out in strains that have a high propensity for autoimmune disease. The body’s defense against many infectious insults is to produce reactive oxygen, which is primarily produced by macrophages. Reactive oxygen can also occur from normal metabolism within the cell and has often been suggested as part of the aging process. As hydrogen from food metabolism interacts with oxygen to make water, they go through a series of oxidation states

involving single electron transfer resulting in free radicals that can be highly deleterious to DNA resulting in specific types of DNA oxidative damage. In addition, nitric oxide (NO), which is formed by NO synthetase activity in the metabolism of arginine, produces NO, a powerful oxidizing agent when combined with ROS. GSTPi is a powerful defender against these types of oxidative agents produced by inflammation, as well as protecting against adduct formation on the DNA caused by carcinogens. These free radicals can also be


squelched in the presence of vitamin E. Thus, vitamin E as a free radical scavenger has received popularity as a chemoprotective agent and is being tested in large clinical trials. Lipid peroxidation is another mechanism for protecting DNA, and it utilizes selenium in its action. Inflammation may be involved in the tissue specificity of cancer. Seminal vesicles, which rarely get cancer, have no inflammation like the prostates do. Furthermore, inflammation is greatly reduced in the prostates of people in Asia, and this reduction can be mimicked in animals fed diets high in soy. The role of estrogens in inflammation is also an intriguing possibility, particularly since the soy diet contains high levels of phytoestrogens that could serve as antiestrogens and block these effects.5 Much is left to discover in these new developing fields of carcinogenesis of the prostate, but there is little doubt that major inroads have been realized in the last 4 years by combining genetic and epigenetic concepts.4 We now have models that might help explain why only humans and dogs get prostate cancer, why the seminal vesicles are not at risk, and why the risks are so different in Asia and change with migration.5 Molecular targets are being identified by new microarray techniques, and clinical prevention trails are now underway in many centers. FAMILIAL CANCER Cancer clusters in some families could be the result of inherited genetic alterations or shared environmental factors. Single or multiple genes could be causing predisposition to cancer. Sporadic occurrence suggests aggregation by the adverse effects of the environment, such as pollutants and carcinogens, as well as socioeconomic differences and cultural habits, such as work, sexual, and dietary factors. It is now possible to apply statistical analysis to these inherited patterns, trying to correlate these with the time of diagnosis in order to determine if there is a genetic predisposition, inherited primarily through genes from either the mother or the father, termed autosomal. In this regard, Patrick C. Walsh and his colleagues have reported that there is a hereditary form of prostate cancer (HPC) with an early onset and a 3- to 9-fold increased incidence, depending on the number of first-degree relatives involved. Indeed, hereditary prostate cancer appears to be inherited in a Mendelian manner and is autosomal dominant, with a penetrance of approximately 85%. Intense efforts have been underway in many centers to find chromosomal linkage to this hereditary form of cancer and to identify the gene(s) involved in this increased cancer risk.7 It is hoped that these high-risk genes can be sequenced as they have been in breast cancer. In breast cancer, BRCA1 and BRCA2 have been identified as hereditary genes. Also, in colon cancer, 4 genes have been identified and, 3 of which are

mismatch DNA repair genes, termed MSH2, MLH1, PMS1, PMS2, as well as the APC tumor suppressor gene. Two kidney cancer genes have been identified to be WT1, in the Wilms’ tumor, and the VHL gene associated with von Hippel-Lindau syndrome, identified by Marston Linehan and his colleagues. It is most interesting that there is a familial tendency in both prostate and renal cell cancers but no such familial tendency has yet been identified for bladder cancer. However, only 10% of many types of cancers are inherited through a predisposing gene or genes, but 90% of cancers are acquired through living or by environmental insults; these later types are termed sporadic cancers. It is believed that if we identify the inherited genes that predispose to familial cancer, these genes will be the same targets that are altered by carcinogens, aging, or biologic damage in sporadic cancers. This is the basis for Knudson’s hypothesis, which has been proven in retinoblastoma. Since we inherit two genes, one each from our mother and father, we therefore have two alleles for every gene that can be slightly different in sequence (polymorphism) or in methylation (imprinting). If both genes are required to be knocked out to produce cancer, which is the case when a suppressor gene is eliminated, then inheriting the loss of one gene (loss of heterozygosity [LOH]) would increase your chances of getting cancer, because now an environmental insult only needs to eliminate the second allele to inactivate the suppressor gene. This increase in probability results in the early onset of cancer, because one of the two suppressor genes had already been inactivated at birth. The similarity that approximately 10% of all colon, breast, and prostate cancers are inherited, although the overall frequency of these genes in the population is about 0.3%, is one of the mysteries in cancer research. Is this similarity by chance or does it have a meaning? In addition, in each case when you inherit these predisposing genes you have an approximately 85% chance of getting the cancer, but 15% will not get cancer. One of the difficulties in locating cancer-causing genes is that once you have developed cancer, it is often accompanied by a genetic instability, which produces a series of changes in the genome that alter the cancerous properties of the cell. This temporal change in the cancer cell clones is called progression and produces a marked tumor cell heterogeneity. These genetic changes that ensue because of this instability can produce a cell with an increased growth rate, and then this clone will expand and dominate in the tumor. This phenomenon is termed “clonal selection,” and since it occurs with time, it is called tumor progression. Ultimately, cells may be selected with not only increased growth rate but also with more aggressive properties, and alterations in many cancer genes, such as p53, appear to be related to more aggressive tumors. Therefore, when a tumor is removed

8


from a patient and the karyotype or DNA is examined, it is possible to see tremendous changes in the chromosomes. There are cases of chromosomal deletions, amplifications, rearrangements, and duplications, which can result in changes in ploidy and abnormal amounts of DNA in the cancer cell nuclei. This was seen earlier in what we call karyotyping, but this only looked at the shapes and forms of chromosomes and their banding. Later it was possible to differentially stain cancer and normal DNA using either red or green markers as probes to stain and differentially compare the chromosomes. By looking at the presence or absence of the red and green markers on cancer chromosomes, it is possible to visualize changes in their karyotype. This technique has been termed comparative genome hybridization (CGH). Recently, all chromosomes can be painted a different color; a process termed spectral karyotyping (SKY). With this, it has been possible to find that in certain cancer chromosomes there is a gain in areas on one arm, and a simultaneous loss in areas on the other arm. In prostate cancer, this occurs with loss of material in the short arm (p) and a subsequent gain in the long arm (q) of the eighth chromosome; this is not a simple transposition. Some of these changes may be causal for cancer, but many are just associated with the properties of the tumor as it progresses and are simply epiphenomena. This produces the complex problems that the geneticists face when analyzing tumor cell chromosomes and DNA. Therefore, this requires the meticulous linking of the inherited chromosome changes within the lineages of the families with the tumor types. These linkage studies are most difficult and usually require years of work. New molecular probes and information from the Human Genome Project are speeding this process, and certainly automated and highthroughput systems are accelerating this search, which has been a most difficult problem for cancer research. Certainly, many candidate genes have been identified and are being verified or eliminated by painstaking work. The problem then will be to link specific sequences to gene functions, gene control, and disease. There will be much variation and polymorphism within the population, genetic types, and races. Several different types of each inherited cancer may exist. The genome can also change through aging, replication errors, and failures in DNA repair. This is a complex but critical problem in understanding genetic changes associated with cancer. Large populations will be required in these studies to assure accuracy.7

2.

3.

4.

CANCER GENES Cancer susceptibility is driven primarily by six types of genes: 1. Oncogenes. A series of over 60 genes have been identified that are activated or overexpressed and that

5.

have a positive effect in the induction of growth. These constitutive genes have a prefix like c-myc. If they are mutated and inserted by viruses this prefix changes to v, like v-src. Suppressor genes. Loss of the function of a suppressor gene essentially removes a brake on cell growth, thus permitting it to become up-regulated (examples are p53, Rb, and p16). DNA repair genes. Normal or induced errors in DNA copying, DNA damage from the environment, or oxidative damage must be corrected or the gene will be mutated or silenced. In colon cancer, a group of mismatch repair genes (MSH2, MLH1, PMS1, and PMS2) have all been shown to be inherited and to induce cancer by accumulation of DNA damage. We know little about how telomere damage is repaired or how repetitive DNA transposons are regulated. DNA defense genes. These genes protect the DNA from oxidative damage or electrophiles that can form adducts to the bases that are detrimental. There are enzymes that protect the cell against ROS that form free radicals and produce oxidative damage to the cell. As the mitochondria carry out their aerobic oxidation, 4 electrons are required to reduce molecular oxygen to water. In this process, partially reduced intermediates of oxygen produce superoxide, hydrogen peroxide, and hydroxyl radicals that are collectively known as ROS. ROS can also be caused by ionizing radiation, UV light, or certain chemicals in the environment. ROS converts guanine in DNA to 8-oxoguanine, which is highly mutagenic and preferentially mispairs with adenine during replication. There are enzymes, such as glutathioneS-transferase (GST), glutathione reductase, quinone reductase, superoxide dismutase, catalase, and other protective enzymes that inactivate electrophiles, carcinogens, and ROS. Carcinogens in our environment are often in a pro-form and need to be activated by type 1 enzymes or the active carcinogen needs to be inactivated by type 2 enzymes. For example, procarcinogens like benzpyrene are inactive and must be metabolized by epoxidases to form the active carcinogen that reacts with DNA; this represents a type 1 reaction. Type 2 reactions are represented by the family of glutathione transferases, glucuronosyltransferases, and quinone reductases, all of which can inactivate carcinogens or ROS. Types 1 and 2 enzymes can be induced or altered by environment, diet, or inheritance, altering the rate of cancer formation. There are several isoforms and polymorphisms; for example, GST-M is related to bladder and glutathione-S-transferase isoforms (GST-π) methylation to prostate cancer. Viral genes. Retroviruses, polyoma, adenoma, and papilloma viruses can also introduce genes into the


mammalian cell, which when expressed induce malignant transformation. This includes large T-antigen, E1, E6, and oncogenes. 6. DNA methylation genes. DNA methylation is altered in many cancers and for unknown reasons. Hypermethylation of CpG islands in promoter regions can silence genes. DNA methylation can vary in maternal and paternal genes, termed imprinting. Loss of imprinting (LOI) is a common change in cancers. At present, all of the above six mechanisms are being studied to determine what causes urologic cancers. At the moment, there is only definitive evidence that the VHL gene is associated with von Hippel-Lindau syndrome, and the WT1 gene is associated with Wilms’ tumor. The p53 gene is associated with bladder cancer but it may only be a progression marker, as it is in prostate cancer. No specific gene has yet been shown to be inherited in prostate cancer, although practically all of these tumors are associated with inactivation of one of the GST-π. As stated, this inactivation of expression is accomplished through methylation of the CpG islands in the promoter region, which down-regulates the gene. This genomic change is almost universal in both familial and sporadic prostate cancers but is not believed to be the inherited gene that causes the cancer, but we do not know what controls DNA methylation. Since both aging and cancer produce heterogeneity in the stability of various chromosomes, it is hard to eliminate this form of noise in the system, without careful study. In addition, many normal genes have different DNA sequences, which are called polymorphism. These polymorphisms are inherited and can produce different types of isozymes or genetic patterns that may or may not have effects on how these genes function. Some of these polymorphisms are certainly going to increase tendencies towards malignant transformation that would enhance the chances of acquiring cancer, which will add to the complexity. Many suppressor genes not only will be lost through mutation or genetic inactivation but can also be down-regulated and turned off by nongenetic or epigenetic means, such as DNA methylation. Many traits within the human body, resulting in specific phenotypes, do require many genes operating in concert to produce their specific phenotype. This polygenic phenomenon can be operating in some cancers. Indeed, there are multiple steps involved in the evolution of cancer. It is well known that multiple hits are required, resulting in multiple changes, which occur with time. It has been estimated that 3 to 6 changes may be the minimum requirement to produce a clone of cells with the properties to propagate the cancer to a lethal stage. It has been suggested that these hits are cumulative and may

not have to occur in a specific order, although this model has not been completely confirmed. Certainly, just inheriting one familial cancer gene seems to guarantee the rest of the hits, since there is often an 85% chance of developing cancer when an inherited gene is involved, an effect termed penetrance. How do the aforementioned oncogenes and suppressor genes function within the cell to cause cancer? They appear to regulate cell replication, death, and growth. There are about 60 oncogenes of primarily four types: 1. Genes for growth factors or their receptors (e.g., platelet-derived growth factor [PDGF], erb-B, and RET). 2. Genes affecting cell-signaling pathways, such as ras and src. 3. Genes acting as transcription factors that activate early growth genes, such as the myc oncogenes. 4. Genes affecting the cell cycle: Bcl-2 is an inhibitor of cell death that when overexpressed, blocks apoptosis and allows cells to survive and accumulate. Overexpressing factors that bind to suppressors can remove the brake. For example, MDM-2 removes the suppressor brake p53 by binding to it and inactivating it. Many virus proteins are expressed in an infected cell, such as large T, E1A, and E7, and have the ability to complex suppressor molecules, such as p53 and Rb. In summary, turning these genes on turns on cell growth. Suppressors are brake molecules that turn growth off. Removing the brake, of course, turns on the growth. These brakes can be removed either by inheriting the loss of this gene, by mutating the gene and activating it, or by turning off the gene through regulation, which is the case when the DNA in its promoter region is methylated. How do the suppressor genes function as brakes? Many of these genes are located in the nucleus and affect the cell cycle regulation. The Rb gene is present in all cells and codes for a master brake on the cell cycle that is discussed in the following. The p53 is one of the bestknown suppressors and is abnormally regulated in most cancers. It blocks the cell cycle by inducing a series of cell cycle kinase inhibitors. This p53 protein is activated when the cell detects damage, such as DNA breakage, and blocks the cell cycle at the G1/S checkpoint to allow time for DNA repair. If the damage is extensive the p53 induces abnormal cells to undergo a suicide through apoptosis. The p53 can also affect the mechanism of mitosis; abnormalities may result in mitotic dysjunction (Figure 1-3). MTS-1, also called p16, is another suppressor involved in the braking components of the cell cycle. Other suppressor genes function in the cytoplasm, such as APC, which is involved in colon cancer. APC may affect the cell adhesion molecule mechanisms by interacting

10


PDGF, myc, and Bcl-2. However, none of these have been shown to be involved in cancer as inherited factors. There are many candidate genes for familial prostate cancer, such as RNASEL for HPC-1 on 1q25-25; ELAC2 for HPC-2; and MSR-1 but as yet none have been confirmed to a point of certainty. Certainly these genes play a major role in urologic cancers in controlling growth and progression, but what is the inherited gene that sets off prostate cancer? This will soon be resolved, as many groups are rapidly mapping in on the target of candidate genes.6 MICROARRAYS AND PROTEOMICS

Figure 1-3 Schematic of how cyclin-dependent kinases (CDKs) are activated or inactivated in the cell cycle. The active kinases are bound to variable cyclins and phosphorylate Rb, thus releasing the Rb brake on the cell cycle.

with catenin-like molecules. DPC4 is involved in pancreatic cancer and interacts with the cell signaling mechanisms.1 NF-1 and NF-2 are suppressor genes involved in cell signaling pathways. Of great interest to the urologist is the WT1 gene, which is involved in the Wilms’ tumor of the kidney, and the VHL gene, which is involved in renal cell cancer accompanying von Hippel-Lindau syndrome. VHL can either be lost by inheritance or inactivated by methylation of the cytosine residues of the DNA located in the promoter region of this gene. The VHL gene appears, at the moment, to be involved in the regulation of transcription. Transcription is the conversion of the information of DNA into RNA through the action of RNA polymerase II that forms messenger RNA (mRNA). An important protein binds to the RNA polymerase II and controls the elongation of the mRNA. This transcription and elongation factor is termed elongin or S III. It appears that in normal cells, VHL forms a protein that binds to the elongin and is involved in the control of transcription elongation. When the VHL gene is missing or mutated, it loses its ability to complex to the elongin and, therefore, allows elongin to interact with RNA polymerase II, deregulating the process of mRNA elongation. VHL is the first suppressor gene that has been identified to control the level of transcriptional elongation. This raises the question: Why does the elongation result in cancer? It is believed that this may increase the expression of certain genes involved in growth control, such as myc or fos. In summary, the only two genes so far identified for urologic cancers that can be inherited and increase our incidence of cancer are VHL and WT1, which cause renal cell cancers. In urologic cancers, other suppressors have been implicated, such as Rb, p53, p16, and the oncogenes

DNA expressed as RNA can be reversed transcribed to obtain a c-DNA sample that can be hybridized to the specific DNA of the gene that was transcribed to make the original messenger RNA. By placing from 10,000 to 40,000 small snippets of DNA from identified genes onto a chip or a microscope slide, it is possible to hybridize the c-DNA made from the messenger RNA to the specific genes it represents. The gene targets are located on each small dot placed on the chip. With these high throughput techniques, it is possible to analyze thousands of gene expression patterns in one sample in a quantitative manner. This is possible by coloring these gene (c-DNA) expression products with red for the control cell, which can be normal, or by coloring green for the cancer cell (cDNA) and then by combining the red and green messenger RNA, the appearance of a red dot would indicate a gene that was expressed only in the normal cell. Likewise, the green dot would represent genes turned on only in the cancer cell. The expression of both red and green would form a yellow dot and would indicate expression in both cell types. With this type of microarray or with other forms of differential displays, it has been possible to implicate a series of genes that are turned off or on that may be involved in prostate cancer in comparison to normal as is shown in Table 1-1.6 Many of these genes have been activated or knocked out in transgenic mice, and their functions have been studied in many cases. For example, NKX3-1 is expressed in normal prostates and is decreased in prostate cancers. In mice that have lost one or more of these NKX3-1 genes abnormal duct development and hyperplasia occurs. It then goes on to form PIN. Likewise PTEN on 10q23 mutated in about onethird of human prostate cancers and correlates with high Gleason grade. PTEN is a phosphatase that inactivates PIP3 that is a signal of several growth factors, including IGF-1. PIP3 activates protein kinase AKT, which leads to inhibition of apoptosis causing increasing cell survival and a tumor. Increasing both PTEN and NKX3-1 increases the severity of high-grade PIN in animal models. The most consistent of these genomic alterations associated with cancer may be the GSTP1 gene, which is inactivated by hypermethylation of the promoter region


that occurs in over 90% of primary lesions of prostate cancer. The functions of the other genes in Table 1-1 are discussed in more detail in a recent review.6 Certainly the increased expression of a gene in the form of messenger RNA does not necessarily reflect the amount of protein or its posttranslational modification. In this regard, rapid development of proteomic techniques that give two-dimensional electrophoretic patterns of protein content based on their molecular weight and charge is providing additional means of identifying proteins that change during various stages of cancer and treatment. These isolated proteins can then be identified in sequence using new techniques utilizing mass spectrometry. Time of flight and fragmentation of proteins in mass spectrometers have been extremely useful especially when the proteins are first trapped by baiting them to specific binding elements on commercially developed probes. Certainly as these techniques become defined and standardized they will add a new armamentarium to the identification of new markers and targets. THE CONTROL OF THE CELL CYCLE, CELL DEATH, AND TUMOR GROWTH In normal tissues, the rate of cell replication and the rate of cell death are in a tightly controlled balance, but it is unknown how this balance is maintained. However, when an imbalance occurs, either through an increase in cell replication or a decrease in cell death, there is an accumulation of cells that forms the tumor. This balance involves growth factors, cell signaling, and control of the cell cycle, as well as apoptosis. DNA damage, aging, and senescence activate certain signals, which we believe to be “death” genes that cause the cell to commit suicide. Signaling of the cell cycle for growth and cell death is one of the most active areas of science. First we will review how the cell cycle functions. The cell is usually quiescent in the nongrowing phase, which is termed G0. Growth factors, steroids, and hormones can stimulate the cell to grow and undergo an active phase of biochemical events, termed G1 or the gap period that occurs before DNA synthesis. After the biochemical preparation in G1, the cell undergoes DNA synthesis, termed the S phase. Following the replication of the complete DNA, there is a second gap called G2, where the cell prepares itself for mitosis. Then the mitosis (M phase) ensues, in which the mitotic spindle separates the two sets of chromosomes. Then the nucleus reorganizes and the cell cycle is completed. Recently, there has been a tremendous amount of research delineating the biochemical controls of the cell cycle. There are specific checkpoints at the interface between each of these phases, in which the cell stops to determine its next decision. These decisions in the cycle are primarily controlled by the interaction of regulatory proteins to form

heterodimers with kinases that are either active or inactive. This in turn regulates their state of phosphorylation of growth suppressors. A kinase is an enzyme that phosphorylates a protein. In the cell cycle, these kinases are termed cyclin-dependent kinases (CDKs); there are approximately 7 of these enzymes (CDK2, CDK4, etc.). They are usually at a constant level and inactive as shown in Figure 1-3. These CDKs are activated at specific phases of the cell cycle by binding to a second type of molecule, called cyclins (termed cyclin A to H). These are termed cyclins because their concentration varies through the cycle, and it is these transient molecules that regulate the cell cycle. Therefore, you can activate cyclin kinases in a controlled manner by turning on the synthesis and degradation of the cyclins. Once the CDKs are activated by binding cyclins, they appear to regulate the cell cycle by phosphorylating and turning off the brakes within the nucleus that prevent cell growth. One of the primary brakes or suppressors in the nucleus is Rb, which, when unphosphorylated, is a checkpoint at G1/S and prevents the cycle from proceeding. When the cyclin kinase is activated, it phosphorylates the Rb, thus removing the brake and allowing the cell cycle to initiate DNA synthesis and to continue to complete growth to the daughter cell. CDKs can also be inactivated by binding to a group of CDK inhibitors (CDKIs). Examples of this type of inhibitor are p16, p21, and p27. If these inhibitors are induced, the cell cycle stops, growth is suppressed, and so a checkpoint is formed. How are these inhibitors induced? This occurs in part through the normal function of p53, which acts like an inducer and can upregulate these inhibitors. The p53 is usually turned on when cells are damaged. In this case, the cell wishes to make the decision not to proceed through cell cycle and to repair itself. In summary, expression of p53 is increased during cell and/or DNA damage and induces a braking system on the cell cycle to prevent defective cells from being made. If the p53 is damaged, lost, or down regulated, this checkpoint is eliminated. This results in damaged DNA proceeding and accumulating through each cell cycle and may result in the large amount of genetic instability and DNA damage that occur in cancer. We have just discussed most briefly how the cell cycle is regulated, but how does a cell determine to undergo cell death or apoptosis? Damage to the DNA is detected in part by a series of checkpoint including AMT, ATR, KU 70, and poly-ADP ribosylation. Broken ends of the DNA often bind KU 70 or have a special polymer added to them that is made from a breakdown product of nicotinamide-adenine dinucleotide (NAD). The polyADP ribosylation of the ends of damaged DNA appears to set off a signal that can induce cell death. Other ways to induce cell death are to remove the cell from its extracellular matrix (ECM) anchorage or to disturb

12


the cytoskeleton. This is termed anoikis; unknown signals from the cell periphery and integrin disruption are being signaled to the nucleus to induce cell death. In addition, there are large protein molecules like tumor necrosis factor (TNF), Fas-ligand and trail ligands that act conversely to growth factors and could be termed death factor. Their action is cell type specific. The TNF binds to two types of cell surface receptors and the Fasligand binds to its receptor. These complexes then involve the activation of a series of caspases (2, 3, 6, 7, and 9) and the release of cytochrome c from the mitochondria all in dynamic concert with either proapoptotic factor induction (Bid, Bad, Bax) or antiapoptotic factor suppression (Bc1-2, Bcl-xl). Sometimes growth factors can induce cell death in certain cell types. For example, tumor growth factor-β (TGF-β) can activate cell death in some epithelial cells. Other growth factors appear to induce cell death when they are absent; these include EGF and FGF2 and FGF7. Of great importance to the urologist is the fact that the absence of androgen on its receptor can induce cell death in the prostate. Therefore, when the androgen withdrawal occurs following castration, this absence of androgens induces rapid cell death in the prostate epithelial cells. This is, of course, the basis for the hormonal treatment of prostate cancer. In apoptosis, the fragmentation of the DNA produces a characteristic pattern of small DNA fragments that can be observed on gel electrophoresis to form the multiple pieces of short DNA of 170 bp surrounding the nucleosomes. These multiples of 170 produces a stepladder effect on DNA gel analysis. Once the DNA fragmentation occurs, it is irreversible and accompanied by the pro-

teolytic degradation of the nuclear architecture, destroying the lamins around the nuclear periphery and the internal nuclear matrix components. The cell then disintegrates under protease activity, and phagocytosis of the remaining components occurs, destroying the cell. This entire event of cell death has been termed “apoptosis” and is characterized by these morphologic and series of biochemical events. As there are brakes or suppressors of growth on the cell cycle, such as p53 and Rb, there are also brakes to stop cell death. One of the leading brakes, for example, is Bcl-2. When Bcl-2 is available, it blocks the process of cell death and therefore is termed a survival factor. How is the brake Bcl-2 removed? It can bind to a series of proteins and form a heterodimer. One of these Bcl-2-binding molecules is termed Bax, and now a family of these deathinducing molecules has been identified. Combining the Bcl-2 with Bax removes the brake and allows cell death to occur. CELL GROWTH FACTORS There is much direct and indirect signaling that occurs between cells and organs. As shown in Figure 1-4, this signaling can be broken down to various types or categories. Growth factors (GF) are of many types, and they bind to specific transmembrane receptors on the cell surface, setting off kinase cascades and structural information to induce cell growth or death. If the growth factor is made and operates on the cell in which it was manufactured, it is called an autocrine factor. Usually, the autocrine factors are secreted from the cell and then bind to their specific cell surface receptors. If the growth

Figure 1-4 Examples of the types of cell signaling. (Adapted from Partin AW, Coffey DS: In Walsh PC, Retik AB, Stamey TA, Vaughan ED Jr (eds): Campbell’s Urology, 7th edition. Philadelphia, WB Saunders, 1997, with permission.)


factor operates within the cell, it is called an intracrine mechanism. If the growth factor diffuses to a neighboring cell, it is termed a paracrine stimulation. If the growth factor is transported through the circulation to distant cells, it is termed an endocrine effect. Other special factors can be transported by the nerves (neurocrine), or they may come from immune like cells (cytokine). Cells can also signal by direct communication through linkages of their structural elements. The ECM makes direct contact with the cell by binding to integrins, which are molecules that extend through the cellular membrane and link to the cytoskeleton within the cell. Cells can also “hold hands” with their neighbors by direct linkage of the cell adhesion molecules (CAMS), which form homodimers. These direct structural linkages, which transfer information in a vectral manner, allow the cell to sense its neighbors. This linkage is like a telephone area code and is one of the most active areas of research in cell biology. These combined units of structural elements form a tissue matrix system, as is shown in Figure 1-5. The CAMS

form a homopolymer with their neighbors. One of the most prominent of these is E-cadherin, which is a cell surface CAM and extends through the membrane of the cell and organizes cytoskeleton components, such as actin. It does that by interacting with an important molecule called catenin, which appears in several forms called α and β. In cancers, there is aberration in the expression of E-cadherin, whose expression can be regulated by methylation of the DNA in the promoter region for this gene. The linkage to actin can also be disrupted by components that can bind to the catenin, such as the suppressor APC, which has been delineated in colon cancer. The cytoskeleton can also be regulated in its organization by binding to receptors called integrins that detect ECM components, such as fibronectin. Aberrations in this linking system, which involves vinculin, tailin, and αactinin, disrupt the organization of the cytoskeleton components, such as actin. The cytoskeleton is made up of microtubules, actin, and keratins, which give the shape to the cell and a different structure to each cell type. The recognition of the cell

Figure 1-5 The dynamic tissue matrix system is composed of interlocking structural components that hardwire the cell to the nucleus and DNA. The proteins of the matrix are tissue specific.

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structure, shape, and organization is the basis of histology. The cytoskeleton links directly to the nuclear matrix, which organizes the DNA into 50,000 loop domains, termed replicons. These loops of about 60,000 bp of DNA are anchored at their base onto the nuclear matrix, where DNA synthesis and DNA methylation can occur. Steroid hormone receptors bind to this nuclear matrix in a tissue-specific manner dictated by the receptors dimerization and interaction with coactivators on corepressors. It is this nuclear matrix protein pattern that makes up the tissue specificity. The nuclear matrix protein pattern is altered in cancer. This dynamic tissue matrix system is shown in its interactive form in Figure 1-5. In summary, what a cell touches determines what a cell does, and the disturbance in the tissue matrix system and its dynamic components cause the variation in shape that we term pleomorphism that is a hallmark of cancer. Only the pathologist can diagnose cancer, which is done by recognizing aberrations and variations in the nuclear structure and in the tissues and cell structure. Cancer is a disease of cell structure. CELL SIGNALING As mentioned, many factors can regulate cell growth and cell death. They do so by interacting with specific transmembrane receptors on the cell surface. Their ligands involve growth factors, cytokines, stress signals, ECM, and death signals, such as TNF. Once these ligands bind

to their cell surface receptors, which span the membrane and activate a series of kinases on the cytoplasmic portion of the receptor, they set off a cascade of phosphorylation that proceeds to the nucleus. The kinases can either be tyrosine kinases, which put phosphate groups on tyrosine, or serine kinases, which put phosphate groups on the serine molecules of the target substrate. Many of these kinases are opposed by phosphatases. Figure 1-6 demonstrates a few of these cascades of protein phosphorylations that are directed to the nucleus. Each large K indicates a kinase that is activated as the receptor signals down to the nucleus. A selection of five of the major kinase cascades involve a series of phosphorylations of kinase molecules that activate other kinase molecules to phosphorylate, finally reaching phosphorylation of nuclear factors. These four prominent kinase pathways are the jak/stat, MAP kinase, and the jnk/erk pathways and the PI-3 kinase. These phosphorylation pathways finally terminate in the nucleus to activate a series of transcription factors that induce the expression of specific genes of either growth and death or survival and senescence. The receptor tyrosine kinase receptor molecule can also link itself to a series of G-protein systems to activate these kinases or can act through another important mechanism that converts the lipids of the membrane into signaling molecules. For example, phospholipase C (PLC) can hydrolyze the lipid molecules of the membrane to become signals by making inositol phosphate (IP-3) or diacylglycerol (DAG). The IP-3 activates calcium

Figure 1-6 Brief example of 5 types of transmembrane receptor activating the phosphorylation cascade to activate nuclear function. K, kinase; KK, kinase that phosphorylates a kinase. See text for discussion.


release in the cell that is a signal. The DAG activates protein kinase C, which is another major kinase system also signaling to the nucleus. One of the most important cell signal pathways in prostate cancer is the PI-3 kinase that activates AKT and cascades to block the proapoptotic factor Bax and thus increases cell survival. The phosphorylation of AKT is countered by the phosphatase PTEN that is inactivated in many prostate cancers, thus increasing Bax phosphorylation and increasing cell survival. This has been only a brief simplified glimpse at some cell signaling pathways that are involved in cancer. STROMAL EPITHELIAL INTERACTIONS All of the aforementioned signaling mechanisms and many more come together and are synchronized in the cell organization forming the tissue that involves the interaction of many stromal and epithelial signals. The stroma talks to the epithelium and the epithelial cells talk to the stroma, both types are nurtured by blood vessels and nerves. The interface between the stromal and epithelial cells is conducted through the formation of the ECM, which

is formed by secretion and products made from both the stromal and epithelial cells, such as fibronectin, collagen, laminin, and proteoglycans. This structural support system organizes the structure of the cell and polarizes it to receive growth factors and signals that come from the stroma, epithelium, and endocrine hormones diffusing from the blood vessels. This action of growth factors steroids, and the ECM making the stromal–epithelial organization and crosstalk is shown in Figure 1-7, which is a diagram of the prostate, where the epithelium is composed of neuroendocrine, secretory epithelial, and basal cells. It is believed that the basal cells are the stem cells that differentiate to form both secretory and neuroendocrine cells. The stroma is made up of smooth muscle, fibroblast, and nerve cells. Threading their way through the stroma are the capillaries, lined by endothelial cells, and the immune cells, which can move in and out of the prostate. The capillaries bring the steroids, androgens, estrogens, and nutrients to the prostate. Testosterone is converted to the more active dihydrotestosterone (DHT) by 5-α-reductase in the stroma. In the stroma, the DHT stimulates fibroblast growth factor-7 (KGF), which then diffuses up and activates the receptors on the epithelial cells in a

Figure 1-7 Stromal-epithelial interactions in the prostate mediated by DHT regulated growth factors; +, stimulation; −, inhibition; NO, nitric oxide. (Adapted from Partin AW, Coffey DS: In Walsh PC, Retik AB, Stamey TA, Vaughan ED Jr (eds): Campbell’s Urology, 7th edition. Philadelphia, WB Saunders, 1997, with permission.)

16


paracrine manner. DHT also stimulates fibroblast growth factor 2 (BFGF), which both feeds back in an autocrine effect on the stroma and has a paracrine effect on the epithelial cells. A similar stimulation is induced by DHT on the production of insulin-like growth factor II (IGF-II), which also has an autocrine and paracrine effect. Insulin-like growth factors are bound to a family of insulin-like growth factor binding proteins (IGFBP), which are also made by the stroma. DHT can diffuse from the smooth muscle into the epithelial cells, where it induces the synthesis of epidermal growth factor and TGF-α. In the epithelial cells, the androgen also induces production of IGFBP, which complexes the insulin-like growth factors and keeps it inactive. One of the main secretory proteins made by the prostate is PSA, which hydrolyzes the IGFBP to release active IGF-I and IGFII, which then can stimulate the growth of the epithelial cells. PSA is a major secretory protein in the ejaculate. This diagram shows some of the cross-talk between the stroma and epithelial cells via the testosterone and DHT induction of growth factors that can function in an autocrine and paracrine way to these cell components. It is also important to note that many neurotransmitters are made in the prostate, such as NO. NO is produced by the endothelial, immune, and nerve cells and can have a strong stimulatory effect on stromal and epithelial components how this entire system is organized in the embryo, grows to adult size and then becomes dysregulated to produce tumors with aging is the basis of much research. AGING AND TELOMERASE Although aging is involved in cancer, we know very little about what really brings about this irreversible and deteriorating effect. Certainly, accumulated damage from free radicals from reactive oxygen, as well as cross-linking and stiffening of collagen, are all key components in how we age. Importantly, there is also a biologic clock that counts each cell division; this brings about senescence. At the end of each chromosome are repetitive pieces of DNA called telomeres. When the cell divides each time, it loses a small amount of these telomeres, which is caused by the inability of the DNA synthesis mechanism to fully replicate the last little bit of terminal DNA. The loss of these repetitive pieces of DNA is therefore accumulative and acts as a mitotic clock, counting the cell cycles. After approximately 50 doublings, the telomeres of the cell have been reduced to a critical length, resulting in the cell’s senescence and death. Every cell is limited by this mitotic clock except cells that have learned how to become immortal. The immortal cells stabilize their telomeres by activating the enzyme called telomerase. Telomerase is an enzyme that carries its own small template made of RNA that is copied into telomere

units that allow the cell to replace the telomeres that are lost when the cell divides. In any cell in culture, telomerase has to be activated or the cells would not be immortal. This is also the case only in the stem cells and the germ cells. The other cells do not have telomerase activity and are subject to cell death as the mitotic clock ticks down counting each cell cycle. In cancer cells, telomerase is activated and the cells have become immortal. We have reported that telomerase is one of the best markers so far in denoting prostate cancer cells from normal and benign prostatic hypertrophy (BPH) cells. This will be a new diagnostic marker when applied in an appropriate manner. Telomerase is one of the most exciting frontiers in understanding senescence, immortality, and how the cancer cell has broken through this aging barrier to become immortal.6 Telomere shortening is one of the earliest molecular lesions in cancer and can initiate genetic instability by altering chromosome structure. OVERCOMING THE TUMOR CELL HETEROGENEITY: APTAMERS AND IN VITRO EVOLUTION One of the major obstacles in the treatment of urologic cancers is their tremendous heterogeneity. Although clinically appearing as a homogeneous tumor, it actually consists of a heterogeneous pool of cancer cell clones. When we apply any treatment, such as chemotherapy or radiotherapy, we select for subclones in the tumor that are resistant to our treatment. This is not related to the response of the tumor cells to our treatment but to their ability to use evolutionary techniques to escape any given therapy. There are now new technologies that will allow us to turn therapeutic evolution on the evolution of the tumor and thus beat the cancer at its own game. Aptamers can be small peptide, DNA, or RNA molecules that will bind in an antibody like fashion to any given target. Large pools of randomized molecules can be easily made and will provide the molecular diversity to let the tumor cells select the best binding molecules to all the different tumor cell clones. For example, by randomizing the four bases of a 15-nucleotide RNA sequence it is possible to create pools with more than 415 to 109 different molecules. A selection screen is set up in a way allowing us to select the best RNA molecules out of the random pool, that will bind with a high affinity and specificity to our tumor cells. Bound RNA species are then recovered and amplified. This enriched RNA fraction is then subjected to a new round of selection. After 10 to 20 rounds of selection, recovery, and amplification, the pool will contain RNA molecules with high binding specificity. Figure 1-8 gives an overview of a typical selection and amplification cycle that we have involved in in vitro evolution to prostate cancer cells. Those aptamers can then be analyzed and produced in large quantities. They


REFERENCES

Figure 1-8 Selection cycle for enriching the binding of a random (109) RNA (aptamers) pool to tumor cells. PCR, polymerase chain reaction for amplifying DNA; enriched RNA. The final selected aptamer binds specifically to the tumor cells.8

can be used as highly specific cancer probes, to improve diagnosis or, when linked to a cytotoxic “warhead,” as a new therapeutic approach to treat cancer.8 ACKNOWLEDGMENTS We wish to acknowledge the outstanding effort of Vivian Bailey in preparing this chapter and Don Vindivich in constructing the figures.

1. Levins M, Tjian R: Transcription regulation and animal diversity. Nature 2003; 424:147. 2. Bray D: Molecular networks: the top-down view. Science 2003; 301:1864. 3. Stuart GR, Holcroft J, De Boer JG, Glickman BW: Prostate mutations in rats induced by the suspected human carcinogen 2-amino-1-methyl-6-phenylimidazol [4,5-6] pyridine. Cancer; 60:266. 4. Nelson WG, De Marzo AM, Isaacs WB: Mechanisms of disease prostate cancer. N Engl J Med 2003; 349:366. 5. Coffey DS: Similarities of prostate and breast cancer; evolution, diet, and estrogens. Urology 2001; 57(Suppl 4A):31. 6. De Marzo AM, Nelson WG, Isaacs WB, Epstein JI: Pathological and molecular aspects of prostate cancer. The Lancet 2003; 361:955. 7. Easton DF, Schaid DJ, Whittemore AS, Isaacs WB: Where are the prostate cancer Genes?—A summary of eight genome wide searches. The Prostate 2003; 57:261. 8. Lupold SE, Hicks BJ, Lin Y, Coffey DS: Identification and characterization of nuclease stabilized RNA molecules that bind human prostate cancer cells via the prostate-specific membrane antigen. Cancer Res 2002; 62:4029.

C H A P T E R

2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations Martin G. Sanda, MD, and Ronald Rodriguez, MD, PhD

Over 50 years of scientific research following the discovery of DNA1 have led to recent insights that have set the stage for preclinical development of gene therapy strategies and their assessment in clinical trials. The enormous volume of scientific research that comprises the foundation for therapeutic use of molecular biology reflects the complexity of linking the most fundamental unit of life, the human genome, to direct clinical intervention. These profound complexities were manifest as several unforeseen adverse events in clinical gene therapy clinical trials observed concurrently with observed effective treatment by gene therapy.2,3 Consequently, the initial exuberant enthusiasm for clinical gene therapy has been tempered by an emerging respect for how the profound complexity of in vivo gene transfer faces obstacles to therapeutic efficacy and carries the potential for significant clinical toxicity. Preclinical studies have identified several therapeutic strategies based on gene replacement or gene transfer that, in some cases, have moved to evaluation in clinical trials. Gene therapy strategies under development include correcting tumor-specific genetic abnormalities by either inhibiting the function of oncogenes (abnormal tumor genes that promote tumor cell longevity or proliferation) or restoring functional tumor suppressor genes (such as genes that can regulate DNA repair), which are commonly functionally mutated or absent in cancer. Alternatively, the immune response of patients with cancers harboring any of these abnormalities can be stimulated by gene therapies based on use of recombinant tumor vaccines. Pivotal to all avenues of gene therapy is the gene transfer vector. GENE TRANSFER VECTORS As the vehicles for therapeutic gene delivery, gene transfer vectors delegate clinical prospects and limita18

tions. Gene transfer vectors can be generally classified as being of either viral or nonviral origin. Vector design is guided by their desired functions: efficiency of gene transfer, stability of gene expression, and safety of clinical use. Gene transfer efficiency indicates how well a vector delivers a recombinant gene to a target cell and how effectively the protein encoded by that gene is subsequently expressed. Highly efficient gene transfer is desirable in almost all clinical strategies using gene transfer. Two critical components determine gene transfer efficiency: gene delivery by the vector and activity of a vector’s expression cassette. The first determinant of efficiency, gene delivery, refers to a vector’s capacity for cellular attachment, entry, and delivery of the therapeutic gene (within an expression cassette) to a site such as the target cell nucleus at which gene expression can occur. Delivery mechanisms of each vector system are distinct.4–6 Cell surface density of specific receptors required for vector attachment, as well as stability of the vector itself in the micro-environment surrounding the target cell, affects a vector’s capacity for therapeutic gene delivery.7–9 The second principal determinant of vector efficiency is the vector expression cassette, which contains, in addition to the therapeutic gene, a promoter sequence controlling therapeutic gene transcription. Some vectors (such as poxviruses) encode their own machinery for gene transcription,6 while others rely entirely on preexisting polymerases in the target cell10; however, all vectors carry a promoter region flanking the therapeutic gene. The promoter profoundly affects therapeutic gene expression and vector efficiency.11 The stability of gene expression by a specific vector system depends on the intracellular localization of the

Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 19

therapeutic gene by the vector. Typically, episomal localization (when the therapeutic gene is not integrated in the target cell chromosome) leads to transient expression of the gene because most mammalian cells have efficient mechanisms for extruding episomal foreign DNA. In contrast, vectors that allow integration of the transferred gene into the host cell chromosomal DNA, such as retroviral vectors, provide longer duration of stable expression. Although stable, durable expression may be desirable in treating hereditary disorders and chronic disorders, it should be noted that transient gene expression might be sufficient for the purposes of using gene transfer for cancer treatment.10 RETROVIRUS VECTORS Retroviral vectors were used in the first clinical trials of gene therapy.12,13 Although retroviral vectors provide distinctly stable long-term expression of therapeutic genes, use of these vectors is limited by complexity of retroviral genetic engineering and vector purification as well as by safety obstacles.3,8,9 These vectors are currently being used predominantly in ex vivo gene transfer protocols, although in vivo gene transfer applications are emerging. Vector genome with therapeutic gene expression casette

Vector Production Production of replication-deficient retroviral vectors is accomplished with vector packaging cell lines (Figure 2-1). Vector particles secreted into packaging cell supernatant are purified and concentrated in preparation for use for gene transfer. Gene Delivery Cells targeted for gene transfer using the purified retroviral vector incorporate the vector by endocytosis via a specific receptor (Figure 2-2). Reverse transcriptase then converts vector RNA into DNA, which is then integrated into the target cell chromosomal DNA during target cell proliferation. This requirement for target cell proliferation as a prerequisite to transferred gene expression is unique to retroviral vectors; retroviral vectors thus do not readily transfer genes to quiescent cells.8,9 Gene Expression After integration of the retroviral vector expression cassette (the therapeutic gene flanked by sequences that Virus envelope or protein coat

Viral genome containing therapeutic gene expression cassette Factors for initiation of expression in targety cell

Transfection Viral vector packaging cell line

Assembled recombinant viral vector particles

Transfection

Vector complementary viral gene(s) Figure 2-1 Production of recombinant viral vectors for gene therapy. A schematic representation of retroviral vector production is shown; analogous systems are in use for the production of adenoviral and poxvirus vectors. For retroviral vector production, packaging cell lines in which the therapeutic gene has replaced retroviral gag, pol, and env genes (these genes are normally required for retrovirus particle production and packaging by infected cells). The packaging cell line has been co-transfected with these viral genes in trans to complement the replication defective vector genome, allowing the packaging cell line to produce and package replication-deficient viral vector particles. (Based on Danos O, Mulligan RC: Proc Natl Acad Sci USA 1988; 85:6460; Ghosh-Choudhury G, Haj-Ahmad Y, Brinkley P, et al: Gene 1986; 50:161; Mulligan RC: Science 1993; 260:926.)

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Figure 2-2 Gene transfer by retrovirus vectors. Retroviral gene transfer is mediated by integration of the therapeutic gene into the target cell chromosomal DNA, and therefore requires target cell DNA replication. (Based on Danos O, Mulligan RC: Proc Natl Acad Sci USA 1988; 85:6460; Mulligan RC: Science 1993; 260:926; Crystal RG: Science 1995; 270:404; Miller N, Vile R: FASEB J 1995; 9:190.)

promote gene expression) into the chromosome of the target cell, the therapeutic gene is expressed by the target cell’s own polymerases and other mediators of gene expression. Because the therapeutic gene is integrated into the target cell genome, it is stably expressed by the cell long-term and is passed onto progeny should the cell continue to proliferate. Further contributing to long-term stability of retroviral transferred gene expression is the immunologically inert phenotype of these vector constructs: immune responses targeting the vector itself have not been an obstacle to retroviral vector use. Although stable genomic integration, as can be achieved with retroviral vectors, may be desirable for some therapeutic strategies (such as tumor suppressor gene replacement), stable and permanent alteration of the target cell genome in vivo also poses potential safety pitfalls such as potentially irreversible untoward genetic effects in vivo. Reflecting the profound in vivo effects of retrovirus vector integration into chromosomal integration, such vectors proved effective in treating severe combined immunodeficiency disease in children; however, cancers developed in some of these children that are believed to have been consequent to integration of the retroviral vector.3

Attributes and Applications Due to limitations in the functional concentration (or titer) of retroviral preparations, and rapid inactivation of unbound retrovirus in vivo, direct in vivo gene transfer using retroviral vectors has generally been inefficient, with only a small fraction of target cells expressing the transferred gene. Retrovirus vectors can, however, mediate highly efficient gene transfer ex vivo (Table 2-1).4 Cancer therapy applications of retroviral vectors have therefore predominantly involved ex vivo gene transfer, for example, to augment the immunogenicity of patientderived tumor cells (by introducing into such tumor cells an immunostimulatory gene) prior to use of such cells in vivo as a gene-modified tumor cell vaccine or for marker studies.12,14,15 Because retroviral gene transfer itself neither damages the host cell nor induces undesirable vector-specific immunity, these vectors are ideally suited for gene-modified cancer cell vaccine therapies seeking to elicit tumor-specific immunity. Despite early encouraging results of clinical trials that used retroviral vectors to create gene-modified tumor vaccine studies for renal cancer and prostate cancer, the recent observation of vector-induced leukemias in children undergoing retroviral gene replacement therapy3 will likely reduce enthusiasm


Table 2-1 Attributes of Vectors for Therapeutic Gene Delivery Vector

Duration of Therapeutic Gene Expression

Efficiency of Gene Transfer

Other

Retrovirus

Stable long-term

Variable

Labile in vivo

Adenovirus

Transient

Highly efficient

Immunogenic

Poxvirus

Transient

Highly efficient

Immunogenic

Nonviral plasmid or naked DNA

Transient

Inefficient

Fewer safety concerns

for clinical applications to only those wherein stable chromosomal integration is required for the desired therapeutic effect. ADENOVIRUS VECTORS Interest in adenoviral vectors was prompted by their capacity for highly efficient gene transfer in vivo. The propensity of adenovirus vectors to induce nonspecific inflammation and a vector-specific immune response, however, has limited efficacy of this vector system in clinical trials evaluating adenovirus vectors for gene replacement therapy for noncancerous diseases.9,16 Moreover, an inflammatory response against the adenovirus vector has been suspected as possibly contributing to the first incidence of a fatal complication of gene therapy.2 Whether the efficacy of antitumor therapies using this vector system will be attenuated or augmented by inherent immunogenicity of adenoviral vectors remains to be elucidated. Vector Production Recombinant adenoviral vectors are rendered infectious but replication defective (while retaining their capacity to infect cells) by deletions in an early region DNA (E1) required for viral replication.5 The deleted E1 region and other regions of the adenovirus genome serve as sites for therapeutic genes by using shuttle plasmids and homologous recombination with complementary deletion mutants (see Figure 2-1). A packaging cell line (293 cells, a transformed human embryonic kidney cell line containing the adenovirus E1 DNA) transfected with the E1 deleted adenoviral vector containing a gene of interest is used to produce the replication-deficient adenoviral vectors.5 High concentrations of adenoviral vector (titer >1011 pfu/ml) can be readily purified. Gene Delivery Adenoviruses are taken up by the target cells via a twostep process, involving binding and internalization.

Binding occurs through the interaction of the knob of the protruding viral capsid fiber protein to its cellular receptor, referred to as Coxsackie and adenovirus receptor (CAR). Internalization occurs as a result of the interaction of the RGD motif of the viral penton base capsid protein with the cellular integrins (αVβ5 or αVβ3, Figure 2-3).9,17,18 After internalization, the vector is transported from the endosome to the cytoplasm, where the adenoviral protein coat is lost as the adenoviral DNA migrates to the nucleus. In the target cell nucleus, the vector remains epichromosomal and is not integrated into the target cell chromosome. Replication of the target cell is not required for therapeutic gene delivery. Gene Expression Nuclear localization of the adenoviral vector allows the target cell’s own polymerases and other mediators of gene expression to participate in expression of the therapeutic gene. However, because they remain epichromosomal, expression of adenoviral vector genes is transient, lasting only weeks.9 Attributes and Applications Adenovirus vectors are characterized by transient duration of gene expression in target cells, significant induction (by the vector) of inflammation and immunity, and capacity for highly efficient gene transfer in vivo (see Table 2-1). The transient gene expression associated with adenoviral vectors is less likely to constrain the utility of these vectors for cancer therapy than for other applications: gene-targeted immunotherapy, as well as apoptosis-inducing therapies, does not require permanent expression of therapeutic genes, and adenovirus vectors have been effectively applied for such therapeutic strategies in preclinical models.19,20 Indeed, the transient nature of adenovirus-mediated gene transfer circumvents the safety issue of irreversible undesirable genetic effects such as could be encountered with retroviral gene transfer.

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Figure 2-3 Gene transfer by adenovirus vectors. Adenoviral vectors do not require target cell DNA replication for efficient gene transfer. However, nuclear localization of the vector DNA is required since target cell nuclear factors are used for gene expression. Because these vectors are epichromosomal, therapeutic gene expression is typically less durable than with retroviral vectors. (Based on Ghosh-Choudhury G, Haj-Ahmad Y, Brinkley P, et al: Gene 1986; 50:161; Crystal RG: Science 1995; 270:404; Miller N, Vile R: FASEB J 1995; 9:190.)

Adenovirus vectors are potent immunogens.16 Although potentially desirable for gene-targeted immunotherapies, the inherent immunogenicity of adenoviruses may also limit repeated administration of these vectors due to sensitization-induced inflammatory toxicity.9 Moreover, adenovirus-specific immunity may constrain in vivo gene transfer with adenoviral vectors by inducing humoral and cellular responses capable of eliminating the vector and further reducing duration of target gene expression.16 Despite these limitations, the receptivity of many human cells to adenoviral transfection, coupled with the relative stability and ease of production of adenoviral vectors, led to significant tumor reduction in several preclinical models of direct in vivo gene transfer and broad clinical applications.19–22 The immunogenicity of adenoviral vectors was found to carry potentially dire consequences; however, a systemic inflammatory response, possibly manifested by unrestricted complement activation, was implicated in the widely publicized death of Jesse Gelsinger, a patient who received a dose of 38 trillion adenovirus particles on a phase I trial of adenoviral gene therapy for an inherited hepatic enzyme deficiency.2 Nevertheless, early phase clinical studies using adenoviral vectors continue, and

utilizing adenoviral vectors for prostate cancer have resulted in encouraging biologic activity and is an area of active translational research.23–25 POXVIRUS VECTORS Vaccinia and other poxvirus vectors are derived from one of the greatest triumphs of post-classical medicine: the smallpox vaccine.6 Jenner’s discovery in 1798 that a bovine poxvirus was an effective human vaccine against smallpox eventually led to implementation of a concerted worldwide vaccination program by WHO, which was implemented in 1967, and Jenner’s prediction of “the annihilation of the smallpox” was finally realized in 1995, nearly 200 years after the introduction of poxvirus vaccines for human use. Current use of poxvirus vectors for experimental cancer therapy relate to the ability of these vectors to induce potent immune responses in vivo. Vector Production Because recombinant poxviruses are used as live, replication-competent viruses (albeit in attenuated or otherwise


nonpathogenic forms when administered in vivo), production can be achieved by simply infecting specific host cells that allow productive infection.6 Genetically engineered packaging cell lines, such as those used for retrovirus or adenovirus vector production, are not required. Immunostimulatory cytokine, accessory molecule, or tumor antigen genes can be inserted into vaccinia or other poxvirus vectors by flanking these genes with poxvirus sequences in a “shuttle” plasmid and then introducing this plasmid into a cell that has been infected with whole vaccinia virus. Homologous recombination (as with adenoviral vector systems) in the vaccinia and shuttle plasmid co-transfected cells then leads to insertion of the gene of interest in a small proportion of the viral progeny (see Figure 2-1). Linking the therapeutic gene with an adjacent selectable marker gene allows subsequent purification and production of exclusively recombinant poxvirus containing the gene of interest.6 Up to 25,000 base pairs of foreign DNA can be accommodated by vaccinia vectors, representing the greatest size capacity of currently available recombinant viral vectors for transferred genes.6

cytoplasm and intracytoplasmic release of the virion complex core (Figure 2-4).6 The virion complex core contains the vector genome, as well as RNA polymerases and other enzymes required for expression of the vector genes; the vector remains in the cytoplasm, where gene expression controlled by elements contained in the virion complex core occurs.

Gene Delivery

Attributes and Applications

Infectious poxvirus virions enter the target cell via fusion of the virion lipoprotein envelope with the target cell

Poxvirus transfection is transient and eventually toxic to the target cell (see Table 2-1). The successful history of

Gene Expression Poxvirus vectors are unique in their ability to express therapeutic genes without requiring transport of the vector to the target cell nucleus. In contrast to other vector systems, which require host cell nuclear factors and enzymes for gene expression, poxviruses carry the apparatus for synthesis of translatable RNA (including virusencoded RNA polymerases, transcription factors, capping enzymes, and poly(A)polymerases) either prepackaged within the complex virus core or encoded within the viral genome itself.4 Expression cassettes in poxvirus vectors thus require unique poxvirus-specific promoter regions that can be recognized by viral transcription factors.

Figure 2-4 Gene transfer by poxvirus vectors. Poxvirus vector particles contain viral RNA polymerases, obviating any need for nuclear localization or chromosomal integration. Therapeutic gene expression occurs entirely in the target cell cytoplasm. (Based on Moss B: Science 1991; 2252:1662.)

24


vaccinia use for smallpox eradication and the relative ease of cloning genes into vaccinia vectors have uniquely poised vaccinia and other poxvirus vectors for use as recombinant tumor vaccines. As with adenovirus vectors, use of poxviruses for immunogene therapy is tempered by potentially competitive, antivector, immune response induction.26 NONVIRAL VECTORS: LIPOSOMAL GENE TRANSFER Nonviral approaches to gene therapy avoid disadvantages of viral vectors such as safety issues related to potential replication-competent virus formation and limited target cell diversity related to receptor requirements for viral envelope adsorption.7,9,10,17,18 The most extensively developed nonviral gene delivery systems are liposomemediated gene transfer and high-velocity particle-mediated gene transfer, also known as the “gene gun.” Vector Production Plasmid–liposome complexes for gene delivery are comprised of DNA formulated with cationic lipids. Most of the cationic lipid–DNA complexes commonly used for gene delivery in clinical trials are not true lipo-

somes containing plasmid DNA within a lipid envelope but are rather particulate complexes in which plasmid DNA is dispersed among the bound lipids.7,9,27 Gene Delivery These complexes promote cellular gene delivery by hydrophobic interaction and fusion of the lipid–DNA complex with the target cell membrane. Unlike viral vectors, however, no signal exists to facilitate transport of the plasmid DNA containing the therapeutic gene to the nucleus (Figure 2-5).7 Transfection efficiency is therefore typically relatively inefficient (see Table 2-1). DNA complexes with copolymers, in contrast, offer the added advantage of incorporation of targeting ligands, such as folate or transferrin. Early work in this regard has demonstrated enhanced gene transfer with systemic delivery of these targeted complexes.28,29 In contrast, high velocity particle-mediated gene transfer, or gene gun, technology allows the delivery of thousands of copies of DNA into targeted cells. This is achieved by coating 1–3 μm gold particles with plasmid DNA or mammalian chromosomal genomic DNA up to 44 kb in size; a gene gun is then used to deliver the particles in vivo by generating a high-pressure gas burst that accelerates the particles to a velocity sufficiently high for

Figure 2-5 Nonviral gene transfer by liposomal vectors. Liposomal vectors in current use are complexes of cationic lipids and plasmid DNA. Although relatively safe and immunologically inert, liposomal vectors require nuclear localization for access to target cell transcription factors. (Based on Ledley FD: Hum Gene Ther 1995; 6:1129; Crystal RG: Science 1995; 270:404.)


EMERGING VECTORS AND OTHER GENE DELIVERY SYSTEMS

Figure 2-6 Nonviral gene transfer via particle bombardment (gene gun). In the helium pulse gene gun, motive force is generated by release of a high-pressure burst of helium gas from a reservoir (A) at a preset pressure (150-700 psi). A release valve (B) discharges helium through a cartridge (C) containing DNA-coated gold particles. After being dispersed by an exit nozzle (D), the DNA-coated gold particles (E) penetrate target cells or tissue with sufficient force to penetrate multiple cell layers and deliver plasmid DNA intracellularly. (Reprinted from Yang NS, Sun WH: Nat Med 1995; 1:481, with permission.)

penetration of multiple cell layers (Figure 2-6).8 As with lipid–DNA complex gene transfer, translocation of plasmid DNA to the nucleus after gene gun delivery is not a specifically targeted event. Gene Expression Plasmid DNA that does manage to translocate to the nucleus usually is not integrated into the target cell genome and remains epichromosomal (see Figure 2-5).5 Similar to adenoviral vectors, expression relies on target cell transcription factors and is typically relatively transient. Attributes and Applications The principal advantage of nonviral gene delivery systems, including cationic lipid–DNA complexes, the gene gun, and other nonviral delivery systems, is that these systems circumvent three potentially problematic characteristics of viral vectors: immune reactivity, reliance on viral receptor expression by target cells, and safety issues related to potential pathogenic recombinant contaminants in viral preparations. Enthusiasm and applicability of nonviral vectors are tempered by relatively inefficient gene delivery and transient therapeutic gene expression (see Table 2-1). As transient expression systems, nonviral and gene gun delivery systems have been useful for induction of antitumor immunity. Induction of cytokine secretion using the gene gun has been associated with reduction of renal cell carcinoma progression in a mouse model.30 Clinical studies using lipid–DNA complexes have shown induction of antitumor immune mediators in melanoma patients, and trials using these vectors for renal cell cancer are underway.27,31

The preceding discussion has focused on gene transfer vectors currently being used in clinical trials as investigative agents for urologic cancers. A variety of other novel viral, as well as nonviral, vectors are currently under development. Among emerging viral vectors are gene delivery constructs derived from herpesvirus, parvovirus, and adeno-associated viruses.32–34 Nonviral vectors under development include eukaryote-derived vectors such as Listeria monocytogenes and recombinant BCG, synthetic constructs such as dendrimers, and others.35 The ideal vector for most gene therapy applications will likely evolve as a hybrid vector merging the desirable properties of viral vectors with advantageous attributes of nonviral delivery systems.11 MOLECULAR TARGETS OF GENE THERAPY Gene therapy for urologic malignancy can be categorized into four distinct strategies based on the molecular target of gene transfer: immunogene therapy, direct tumor cell death induction, antioncogene therapy, and tumor suppressor gene restoration (Table 2-2). Immunogene therapy affects tumor growth indirectly by inducing a tumor-specific immune response either via immunostimulatory gene transfer ex vivo (followed by in vivo administration of genetically altered cells to induce a tumor-specific immune response) or via direct in vivo transfer of immunostimulatory or tumor antigen genes. Direct tumor cell death induction relies on delivery of genes encoding cellular toxins or apoptosisinducing proteins. Antioncogene therapy specifically inhibits or eliminates oncogene activity. Tumor suppressor gene restoration therapy inhibits tumor growth by restoring genes that prevent transformation of the normal cell but have been functionally disabled during carcinogenesis. The preclinical rationale for these gene therapy strategies, and consequent gene therapy clinical trials treating urologic cancers are discussed (Table 2-3). Immunogene Therapy Via Ex Vivo Gene Transfer Gene therapy via transfer of immunostimulatory genes to induce a tumor-specific immune response is perhaps the most extensively evaluated strategy of gene therapy to date. This is partly because early gene transfer systems limited gene therapy to strategies using ex vivo (rather than in vivo) gene transfer, and this approach is widely applicable as immunogene therapy using, for example, patient-derived cultured tumor cells for a gene-modified tumor cell vaccine.15,36–43 Generally, clinical applications of these studies used retroviral vectors as the vehicles for gene transfer.15,44 Strategies of immunogene therapy

26


Table 2-2 Characteristics of Gene Therapy Strategies in Current Clinical Trials Therapeutic Gene

Extent of Potential Efficacy In Vivo*

Relative Obstacles

Immunogene: ex vivo transfer

Systemic

Tissue procurement and cell culture required

Immunogene: in vivo transfer

Systemic

Vector-specific immunity may interfere with induction of tumor-specific immunity

Cyto-toxicity/apoptosis

Local-regional

Requirement for highly efficient gene delivery in vivo; possibility of cytotoxic injury to normal cells

Antioncogene/antisense

Local-regional

Requirement for highly efficient gene delivery in vivo and durable expression of therapeutic gene

Tumor suppressor

Local-regional

Requirement for highly efficient gene delivery in vivo and durable expression of therapeutic gene

*Based on current vector limitations.

Table 2-3 NIH-Approved Clinical Trials of Gene Therapy for Urologic Cancer Principal Investigator

Vector: Therapeutic Gene

Cancer Histology

Status

Immunotherapy: gene transfer ex vivo

Gansbacher Simons Simons Paulson

Retrovirus: IL-2 Retrovirus: GM-CSF Retrovirus: GM-CSF Liposome: IL-2

Renal cell Renal cell Prostate Prostate

Open Completed Open Pending

Immunotherapy: gene transfer in vivo

Vogelzang

Liposome: class I MHC Liposome: class I MHC Poxvirus-vaccinia: GM-CSF Poxvirus-vaccinia: PSA

Renal cell

Completed

Renal cell

Open

Transitional cell

Open

Prostate

Open

Strategy

Figlin Lattime Chen Cytotoxic

Scardino

Adenovirus: HSV-tk

Prostate

Open

Anti-oncogene

Steiner

Retrovirus: myc antisense

Prostate

Pending

Tumor suppressor gene restoration

Small

Adenovirus: Rb gene

Transitional cell

Pending

have also been formulated that rely on gene transfer in vivo.45–49 It is therefore useful to evaluate immunogene therapy strategies in the context of whether the particular strategy requires ex vivo gene transfer or in vivo gene transfer (see Table 2-2). Therapies using genetically modified, patient-derived cells for a genetically engineered tumor vaccine have comprised the principal use of ex vivo immunogene ther-

apy for urologic malignancies in preclinical studies and clinical trials as well. For these therapies, tumor cells isolated from fresh surgical specimens are genetically transduced during tissue culture with an immunostimulatory gene. The resected genitourinary cancer cells serve principally as vehicles for autologous tumor antigens and are transduced for immunostimulatory gene expression. The gene-modified tumor vaccine is typically irradiated ex


vivo prior to being reinjected into the patient as a genetically engineered tumor cell vaccine (Figure 2-7). Initial preclinical studies evaluating this strategy of gene therapy showed that a tumor-specific, T-cell mediated immune response could be augmented by vac-

cination using tumor cells derived from the same tumor but transduced to secrete IL-2; such vaccination protected animals from subsequent tumor challenge.36,37 Gamma-interferon gene transfer was shown to promote a similar protective effect.38 Subsequently, transfer of

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Treatment GROUP A Hanks BSS (control) GROUP B XRT-MLL GROUP C XRT-MLL + SOLUBLE huGM-CSF 8500 ng GROUP D XRT-MLL-MFG-huGM-CSF 140 ng/10/24

Percentage cancer free

80

CELL DOSE 5 X 106

60

40 (Wilcoxon P=0.001)

20

0 0

15

30

Vaccine Rx (Day 3,13,23)

45

60

75

90

105

120

135

150

Days after prostate cancer implantation

A

Primary culture

Immunostimulatory gene transfer

Surgery

Irradiation of human gene modified prostate cancer vaccine

Vaccination

B Figure 2-7 Immunogene therapy via ex vivo gene transfer. A, Preclinical models have shown that vaccination of tumor bearing animals with tumor cells that have been retrovirally transfected ex vivo to produce immunogene products (in this case GM-CSF) can induce complete or partial tumor regression at a distant metastatic site (as shown in the illustrated experiment using hormone-refractory Dunning rat prostate cancer). (Reprinted from Sanda MG, Ayyagari SR, Jaffee EM, et al: J Urol 1994; 151:622, with permission.) B, Schema of an analogous human gene therapy protocol being evaluated in an ongoing clinical trial based on experiments such as that in part-figure A. (Reprinted from Sanda MG, Simons JW: Urology 1994; 44:617, with permission.)

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granulocyte-macrophage colony-stimulating factor (GM-CSF) and other immunostimulatory genes into tumor cells used for vaccination led to elimination of preestablished microscopic tumor cell deposits in animal models. Antitumor immune mediators (such as helper T cells, cytolytic T cells, NK cells, and dendritic cells) are activated by the expression of therapeutic immunostimulatory genes in close proximity to tumor-specific antigens present in the genetically engineered tumor vaccine cells. The immune mediators then circulate and, ideally, eradicate distant micrometastases. Preclinical in vivo efficacy of such gene-modified tumor cell vaccines has also been shown in several models of urologic malignancy, including renal cancer, bladder cancer, and prostate cancer (see Figure 2-7).14,40–43 Several clinical trials using immunogene therapy with ex vivo gene transfer specifically for urologic cancers are underway or forthcoming (see Table 2-3).15,44,50,51 Therapeutic genes encoding IL-2 and GM-CSF targeted prostate cancer or renal cell carcinoma in these studies. In one completed study, no dose limiting toxicities were encountered, and a dose-dependent lymphocyte infiltrate was noted at the vaccine site.15 The single patient who exhibited a partial response in this phase I study also showed the greatest DTH response in the study group, suggesting that GM-CSF secreting vaccine cells can induce tumor-specific immune responses with minimal toxicity. Evaluation of potential clinical efficacy with this strategy awaits a larger phase II study. A significant limitation of these ex vivo gene transfer therapies, however, is the need for cell culture of cancer cells that serve as targets for gene transfer (see Table 2-2). Problems associated with the need for cell culture include: requisite surgery to procure adequate tumor volumes for vaccine cell production; unreliable tumor cell yield with regard to both tumor cell number and tumorigenic genotype; and a requirement for cumbersome, expensive cell culture for each treated subject, limiting the widespread applicability of this therapy.15,41,52 To circumvent these limitations of ex vivo tumor cell culture for gene transfer, the development of nonretroviral gene transfer vectors has led to alternative immunogene therapies using in vivo gene transfer techniques. Immunogene Therapy Via In Vivo Gene Transfer The advent of vectors capable of efficient and safe direct gene transfer in vivo, such as poxvirus, adenovirus, and liposome vectors, has provided an avenue for overcoming problems unique to ex vivo gene transfer therapies such as the need for tumor cell procurement and culture (see Tables 2-1 and 2-2). Two general approaches using in vivo gene transfer for immunogene therapy have been developed through preclinical studies to the arena of clinical trials; one entails in vivo transfer of immunostimulatory

genes, and the other entails in vivo delivery of tumor antigen genes by recombinant viral vectors vaccines. In vivo gene transfer of immunostimulatory genes has been evaluated using poxvirus and liposomal vectors encoding GM-CSF, IL-2, IL-12, and other genes for therapy of renal, bladder, and prostate cancer.30,31,48,53 Rather than removing tumor cells to achieve genetic modification in vitro and then using the gene-modified cells as a vaccine, the gene transfer vector is administered directly into tumor in vivo, such as by intravesical instillation or intratumoral injection. The transfected tumor cells essentially function as an in situ vaccine to induce activity both against the transfected primary tumor site and distant metastases, without having undergone ex vivo processing and culture. A potential advantage of this approach is that genuine tumor antigen expression by the in vivo-transfected tumor cells is conserved, while interference by in vitro artifact antigens is avoided (see Table 2-2). This approach has also been extensively evaluated with other vector systems in nonurologic tumor models, and clinical trials in urologic and other tumors based on these studies have been undertaken.54–58 Some distinct advantages of bladder cancer and prostate cancer, specifically, support a focus on these malignancies with in vivo immunostimulatory gene transfer. First, regional targeting of localized bladder and prostate cancer is potentially readily achieved in these sites by either intravesical administration or transrectal prostatic injection. Second, prostate cancer immunogene therapy poses the possibility of using not only tumor antigens, but also potentially of normal prostate antigens (such as prostate-specific antigen [PSA], expressed in normal and malignant prostate cells alike) as targets of immune effector cells. Use of recombinant vectors encoding specific tumor antigens as agents for recombinant vaccination differs from other immunogene therapy strategies in that the viral vector itself provides the antigen to stimulate a tumor-specific immune response. In this setting, the patient’s tumor cells are not relied on as an effective antigen-presenting cell nor are they a required target of direct immunogene transfer. Instead of targeting tumor cells as the recipients of the therapeutic gene (as shown in Figure 2-4), systemically administered recombinant vector vaccines target professional antigen-presenting cells as recipients for the therapeutic gene (which in this strategy encodes a tumor antigen). By using antigenpresenting cells, such as dendritic cells, to induce immune mediators that then recognize and eliminate tumor cells, this strategy avoids potential tumor cell mechanisms for actively suppressing immune induction, such as secretion of TGF-β.59–61 Initial studies using recombinant vectors as tumor-specific vaccines focused on relatively simple vector constructs encoding a specific tumor antigen alone as the basis for induction of immunity. Along these lines,


clinical trials have been conducted using a vaccinia vaccine encoding PSA for prostate cancer therapy.49,62 The goal of vaccinia-PSA immune gene therapy is to induce an immune response against any cells expressing PSA under the hypothesis that activated PSA-specific T cells will kill cancer cells that express PSA (as in the setting of recurrence after radical prostatectomy). Innate immune tolerance to PSA as a normal self-antigen, however, will need to be overcome to achieve the desired therapeutic effect. The efficacy of preclinical immunogene therapy studies should be viewed in context. When evaluated in highly lethal, nonimmunogenic tumor models, which most closely mimic human malignancy, the antitumor effect has been modest—in the range of 4-log kill. This would indicate that clinical efficacy of a gene-modified tumor cell vaccine approach may potentially be limited to an adjuvant setting. In addition, characteristics common among urologic cancers, including deficient class I MHC expression, overproduction of immunosuppressive TGF-β, and heterogeneous target tumor antigen expression, all represent potential immune evasion mechanisms that may impede efficacy of immunogene therapies. The immunogene therapy patient conversely may harbor generalized limitations to potential immune stimulation.63 In addition, immune responses against the vector backbone may interfere with tumor-specific immune effectors. A new generation of recombinant vector vaccines seek to address these and other obstacles by combining the advantages of immunostimulatory gene transfer and vector-encoded tumor antigen gene transfer in vectors designed to deliver two therapeutic genes in one vector: an immunostimulatory gene in tandem with a tumor antigen gene.46 Despite potential obstacles, therapeutic efficacy in the setting of transient gene transfer and durability of tumor-specific immunity comprise advantages of immunogene therapy that fuel continued clinical development. Gene Transfer for Direct Induction of Target Cell Death Hypothetical barriers to tumor therapy by transfer of cell death genes traditionally included the potential need for nearly 100% efficient gene transfer in vivo to achieve remission and lack of effective strategies for targeting tumor cells specifically without concurrent death induction in normal tissues. The availability of vectors that transfer genes efficiently in vivo, the discovery of bystander effects which allow transmission of cell death signals to nontransduced cells, the characterization of organized cell death (apoptosis) pathway abnormalities in cancer cells, and the development of dominant cell deathinducing genes, however, have all prompted a reevaluation of these hypothetical barriers (see Table 2-2).64–69

Three general approaches to targeting cell death (independent of tumor-specific immunity) are in development. First, gene transfer of a drug susceptibility gene (such as herpesvirus thymidine kinase, HSV-tk) renders target cells sensitive to subsequent gancyclovir-mediated cytotoxicity.70 Second, transfection of cellular toxin genes can induce cell injury, disruption, and necrosis. Third, gene transfer of dominant apoptosis-inducing genes can trigger organized cellular death, or apoptosis.71,72 Gene transfer of HSV-tk, as a means of rendering tumor cells susceptible to subsequent gancyclovirmediated cytotoxicity, was among the first approaches in efforts to induce tumor cell death via gene transfer.70,73,74 In this system, gancyclovir acts as a prodrug that becomes cytotoxic only after it is phosphorylated by HSV-tk. Mammalian cells normally lack HSV-tk; hence the requirement for gene transfer. Phosphorylation of gancyclovir by HSV-tk leads to the formation of gancyclovir triphosphate, a potent nucleotide competitor that interferes with DNA synthesis. A bystander effect, whereby nontransduced adjacent malignant cells are killed in part to the transfer of the toxic analog via gap junctions or apoptotic vesicles, was initially described in HSV-tk gene transfer studies.64 HSV-tk gene transfer can be accomplished by retroviral or adenoviral vectors in vivo. Due to ease and efficiency of use, adenoviral vectors have been used for HSV-tk gene transfer in animal models of prostate cancer in which in vivo delivery was accomplished by intratumoral injection.75 Subsequent systemic administration of gancyclovir led to significant reduction of tumor growth. This effect was synergistic with androgen withdrawal in a mouse model of androgen responsive prostate cancer.68 Clinical trials based on these findings and using intratumoral injection for delivery have been completed with modest PSA responses.24,76 A limitation of HSV-tk gene transfer is the need to coordinate and optimize administration of two agents: the sensitizing gene transfer vector and the prodrug gancyclovir. An alternative strategy for direct cytotoxicity is gene transfer of cellular toxin genes, such as ricin and diphtheria toxin, which disrupt protein synthesis resulting in lethal cellular injury.72 Although ricin gene transfer itself has not been applied to urologic tumors, direct administration of ricin gene products is cytotoxic to human prostate cancer cells, providing rationale for further development of this strategy.77 Adenoviruses encoding diphtheria toxin have demonstrated remarkable potency at eliminating established tumors;71,78 however, the extreme potency of the toxin makes it capable of killing nontarget cells, even when used with a tissuespecific promoter. Hence, unless better transcriptional control can be achieved, this approach will probably not be readily translated into clinical utility. Third and perhaps most promising of the gene therapy strategies, which aim to directly induce cell death, is

30


gene transfer of apoptosis-inducing genes. Organized cell death in the form of apoptosis differs from toxic or necrotic cellular disruption (such as ricin-mediated toxicity) in that apoptosis occurs as a normal entity of the eukaryotic life cycle in vivo, without concomitant inflammation or other local toxicity. Prostate biology revealed some of the earliest evidence for apoptosis as a normal component of cellular homeostasis, and prostate cancer was the first among several solid tumors whose growth and progression has been shown to result from defective apoptosis rather than augmented proliferation.79 Gene products involved in a cascade of intracellular events mediating apoptosis have been successfully targeted for induction of apoptosis in tumor cells. An ideal apoptosisinducing gene would induce apoptosis in tumor cells without altering homeostasis in normal cells. Candidate genes that may exhibit such selective effects to some degree include caspases and p53; the ability of adenoviral vectors encoding these genes to induce apoptosis in tumor cells in vitro and in vivo has been shown, and effects on normal cells and stem cells are under intensive study.20,22 Early findings indicate that gene transfer of Bclx-s with adenovirus vectors, for example, has little effect on normal cells while tumor growth was profoundly affected in vivo.20 Oncolytic Virotherapy During the late 1950s, a variety of viruses were evaluated as cancer therapeutics; however, with the advent of chemotherapy, improved radiotherapy, and the lack of specificity of virotherapy, these strategies were largely abandoned.80 In the early 1990s, however, a resurgence in this concept occurred, when a herpesvirus was specifically engineered to replicate selectively in central nervous system tumors.81 Subsequently, it was found that naturally occurring mutants of certain viruses were capable of selective replication in cancer cells defective in certain pathways. In the case of the E1B deleted Onyx-015 virus, replication occurred selectively in those cells that were defective in some way in the p53 axis of apoptosis regulation.82 Similarly, others discovered that the reovirus was capable of enhanced replication in those cells with activated ras.83 However, not all malignancies share the same path to oncogenesis. Hence, efforts were made to develop a conditionally replication-competent oncolytic adenovirus (CRAd), which would only replicate and passively lyse cells when it was in a particular cell type. The first of these CRAds was CV706, which preferentially replicated and lysed prostatic epithelial cells by virtue of the PSA promoter and enhancer that were used to activate the replicative genes, E1A and E1B.84 These CRAds demonstrated excellent activity and specificity in vitro and in vivo and hence were rapidly translated into clinical trials.23–25 The results of these initial trials have

also been encouraging in that they have demonstrated a clear dose response, with marked reductions of PSA occurring in most of the men treated at the higher dose levels. However, the response is limited, because the viral infection lasts less than 2 weeks and not all of the cancer cells are transduced by the replicating virus. Given enough time, all the patients with clinical response relapsed with a PSA progression. Of note, however, is the fact that when these viruses are given directly into the prostate, the presence of neutralizing antibodies had no significant clinical impact on the efficacy of the vector. Hence it appears that while such neutralizing antibodies may present a serious obstacle to systemic oncolytic viral therapy, it is of a lesser concern with local therapy. Recent advances in the understanding of adenoviral replication have discovered that the molecular pathways necessary for promoting viral replication are also pivotal in terms of sensitizing the cells to chemotherapy and radiation therapy. The combination of radiation therapy and CV706 results in a 6.7-fold enhancement of tumor reduction over the predicted response from the addition of the two treatments alone.85 This synergy of effect has led to a robust enthusiasm for further clinical translation. If oncolytic virotherapy can potentiate radiation therapy significantly, then the acceptance of this combination is likely to meet with less resistance. As urologists, this combination would be particularly attractive if the combined therapy could be administered contemporaneously through a brachytherapy platform. Like other molecular therapies, oncolytic adenoviral gene therapy is still highly experimental and in its early developmental stages. However, it is becoming increasingly clear that the earliest clinical utility of these methods will be in combination with conventional therapy and at least initially will be limited to local-regional delivery. Antioncogene Therapy: Approaches Using Antisense and Ribozyme Constructs Targeting oncogenes with gene transfer is theoretically advantageous because this strategy can potentially selectively affect tumor cell growth without affecting normal cells, which may lack functionally expression of the target oncogene. By exploiting the ability of complementary RNA strands to bind to each other, delivery of genes containing such complementary or “antisense” sequences to specific oncogenes can revert the tumorigenic phenotype by inhibiting expression of specific oncogenes in target tumor cells. Interference with translational machinery due to pairing of antisense RNA constructs with their oncogeneencoding RNA targets is one mechanism of antioncogene activity postulated as active in this strategy. By interfering with translation of oncogene RNA, oncogenic proteins are produced at much lower levels, if at all. In addition to interfering with translation, moreover, antisense constructs


may activate endogenous ribonucleases, which in turn degrade the bound RNA. Regardless of the mechanism, the net effect of antisense therapy is the reduction of oncogenic protein expression due to binding of oncogene RNA by the antisense gene product (see Table 2-2). Although early antisense strategies focused on direct administration of short antisense oligonucleotides (sometimes modified for improved solubility), more recently the delivery of longer antisense constructs, as well as dominant negative mutation constructs, via recombinant vector systems has emerged.86–88 Retroviral transfer of a myc antisense gene (delivered by direct injection of retroviral vector into small prostate cancer nodules in rodents), for example, was found to impede in vivo prostate cancer growth in a rodent model.89 Based on these findings, a clinical trial of antioncogene therapy using intraprostatic injection of retroviral vector encoding antisense myc has been proposed.89 The discovery of ribozymes, or RNA sequences, that catalyze RNA cleavage and splicing, opened a promising extension of gene therapy strategies based on oncogene targeting via antisense recognition of oncogene RNA (Figure 2-8).90 Ribozymes can be designed to degrade RNA containing a short segment of complementary nucleotides. In theory, almost any RNA containing a unique 15-base pair or longer sequence can be specifically degraded by designing a ribozyme containing a complementary binding motif. Adenoviral vectors have been used to deliver oncogene specific ribozymes (for

example, targeting H-ras in a bladder cancer cell line) with consequent repression of in vivo tumorigenesis.91,92 The efficacy of this strategy in the setting of in vivo gene delivery remains as yet untested. However, the direct target specificity of ribozyme-targeted antioncogene therapy, in the setting of a well-characterized effector mechanism, suggests that ribozyme-based strategies may be the most promising antisense-based therapeutic strategy under current development. Tumor Suppressor Gene Restoration The observation that renal cell cancer tumorigenicity can be reversed by in vitro transfer of the von Hippel-Lindau (VHL) gene prior to full biochemical and functional characterization of the VHL gene product attests to the potential utility of gene therapy targeting tumor suppressor gene restoration.93,94 This observation indicates that restoring tumor suppressor genes may reverse tumorigenic potential of individual, in vitro transduced cells. Tumor suppressor gene transfer in vivo, however, has had less impressive effects than in vitro transfection.95 At least two factors may contribute to the discrepancy between in vitro and in vivo effects of tumor suppressor gene restoration: first, intratumoral injection of vectors into solid tumors is not a highly efficient approach for gene delivery—most of the vector is likely cleared before it accesses tumor cells, and the initial vector distribution in injected tissue is unlikely to be uniform. Second, stable

Figure 2-8 Antioncogene ribozyme consensus sequence. The hammerhead ribozyme contains three nonconserved helical regions (stems I, II, and III) along with the conserved sequence of the central core. Stems I and III, which determine the specificity of the ribozyme for its target, hybridize to target oncogene RNA. The target RNA is then cleaved at the site indicated by the arrow, disabling oncogene expression. Nucleotides designated as N can be any nucleotide. (Reprinted from Thompson JD, Macejak D, Couture L, Stinchcomb DT: Nat Med 1995; 1:277, with permission.)

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long-term integration (as with a retrovirus vector) of the therapeutic suppressor gene, in the setting of 100% efficient in vivo transduction, would be required to arrest tumor growth (see Table 2-2). This strategy could be optimized by using vectors capable of stably integrating the transgene into the target cell genome, such as retroviral vectors, and also capable of highly efficient in vivo transduction, such as adenoviral vectors. In that no vector currently has both of these characteristics (see Table 2-1), using any vector system will have limited efficacy at present. For example, one potential tumor suppressor target, c-cam, is a cellular attachment molecule, which is absent in some prostate cancers, and thereby potentially contributes to the uninhibited and metastatic growth potential of these cells. Intratumoral injection of an adenoviral vector encoding c-cam, used to restore expression of this molecule in preestablished prostate cancer xenografts, slowed but did not reverse tumor progression (Figure 2-9).95 Similar effects have been seen with adenovirus vector-based therapy targeting restoration of other tumor suppressor genes. Despite these limitations, survival of tumor-bearing animals can be extended with in vivo suppressor gene restoration therapy, and a clinical trial that evaluates the efficacy of Rb gene delivery via intravesical instillation of

adenovirus vector has been proposed (see Table 2-3). The association of Rb gene abnormalities in bladder cancer and poor prognosis supports the rationale for intravesical adenovirus-Rb gene therapy.96 For many tumor suppressor genes, restoration of suppressor gene function alone may not suffice for cytoreduction of established tumors even in the theoretical setting of totally effective and durable in vivo tumor suppressor gene transfer. Most tumor suppressor genes do not encode signals for direct induction of cell death but rather affect tumor growth more indirectly, such as by regulating DNA repair, cellular attachment, or cell cycle control.97 In this setting, restoration of normal suppressor gene via gene transfer may require accompanying cytoreductive systemic or regional therapies (chemotherapy, radiation) to treat established tumors. The need for accompanying cytoreductive therapy is further evidenced by the transient expression associated with the most efficient vector systems—once transgene expression fades, the tumorigenic phenotype associated with absence of the suppressor gene will reappear (efficient in vivo vectors are required for this strategy as most, if not all, target cells must directly express, or confer expression via bystander effect, of the transferred gene for effective tumor reduction)

Figure 2-9 Tumor suppressor gene therapy inhibits tumor growth in animal models. Injection of adenovirus encoding c-cam1 (filled circles) into human prostate cancer nodules grown in nude mice reduced tumor growth compared to saline (filled triangle) and vector (open circle) controls. Delay of tumor growth without complete tumor remission is typical of strategies relying on local-regional injection of recombinant vectors encoding therapeutic tumor suppressor, antioncogene, or cytotoxicity genes. (Reprinted from Kleinerman DI, Zhang WW, Lin SH, et al: Cancer Res 1995; 55:2831, with permission.)


Some tumor suppressor genes may also serve as gatekeepers for intracellular apoptosis-inducing signals. In addition to suppressing the tumorigenic growth potential of individual cells, restoration of these tumor suppressor genes should also be able to reduce established tumors via apoptosis induction. The inability of an adenoviral vector encoding p53 to eliminate preestablished malignancy, however, indicates that near-complete transduction of all tumor cells may be required for optimal therapeutic effect. This level of efficiency is clearly not achieved by direct solid tumor injection with currently available vectors. Improvements in vector and delivery systems will be needed to optimize this, and other, gene therapy strategies that rely on direct effects of gene transfer in the tumor cell target. FUTURE DIRECTIONS: TARGETING VECTOR SPECIFICITY Most vectors, which, at present, have shown functional efficacy in vivo, lack significant specificity in target cell attachment or restriction in transgene expression. The vector envelopes or coats of retroviruses, adenoviruses, and liposomal vectors enter cells via families of receptors that, as a group, are virtually ubiquitous. The promoters controlling transgene expression in these vectors are typically potent promoters susceptible to little or no regulation by the host cell. Targeting of gene therapy to specific

cells or tissues has therefore been achieved principally via the route of vector administration. The feasibility of conferring specificity via the administration route, in the case of urologic targets, has been demonstrated for renal cancer after renal tubule vector infusion and for bladder epithelium after intravesical instillation of viral vectors.98,99 This approach may be applicable to local-regional therapy of early stage, organ-confined malignancy (see Table 2-2). Systemic applications of cytotoxic, antioncogene, or tumor suppressor therapeutic gene transfer, however, will require specific targeting based not only on vector administration route but also on molecular rather than mechanical targeting. Molecular vector targeting can be achieved either by modifying tropism (altering the affinity of the vector coat for attachment and entry to a limited range of human target cells) or by restricting transcription (constructing expression cassettes containing promoters with selective activity in different tissues) (Figure 2-10). Modified Vector Tropism Two approaches have been used for modifying vector tropism. First, vectors can be derived from viruses with inherent tropism for a specific tissue target. Due to the relative paucity of molecular characterization of viruses with natural and specific tropism for the genitourinary tract, this approach has limited utility. Nevertheless, at

Figure 2-10 Restricting target cell specificity of recombinant viral vectors. The ability to specifically target gene delivery can facilitate systemic gene therapy with cytotoxic vectors. Approaches to confer specificity include: (A) engineering vector coat specificity; (B) restricting promoter-regulated transcription; (C) chemically modifying vector-target affinity. (Based on Miller N, Vile R: FASEB J 1995; 9:190.)

34


least one virus (BK virus, which has specific tropism for transitional epithelium) has shown potentially useful tropism specificity for transitional epithelium.100 Recombinant BK episomal vectors were constructed that led to reporter gene expression specifically in human transitional cell (TCC) lines that are relative to absent expression in other tumor cells. Limited characterization of the elements regulating BK specificity and lack of replication defective BK vectors, however, has limited further development of this vector system thus far. Second, molecular engineering and conjugate formation to alter the native vector coats has been used to confer specific tropism. In regards to retroviral vectors, engineering of envelope or vector coat sequences (pseudotyping) has been limited, principally due to the potential of functionally disrupting the ability of engineered envelopes to mediate target cell attachment and entry. Pseudotyping has thus succeeded in producing vectors with extended or altered target cell tropism, without more restricted target specificity per se.11 In contrast, a detailed analysis of the fiber gene has allowed the alteration of adenoviral tropism by either changing the knob domains for different adenoviral serotypes, or by specifically introducing targeting ligands into portions of the knob that are unimportant for fiber folding and viral assembly.101,102 Molecular conjugate formation has successfully conferred altered and refined specificity to adenoviral, liposomal, and retroviral vectors, alike. This has been achieved via covalent linkage of vectors with ligands such as growth factor receptors or antibody haptens, which confer the desired tropism for cells expressing the specific receptor and via noncovalent association of hybrid vector components.103–106 Restricted Transgene Expression: Transcriptional Targeting An alternative to vector targeting at the target cell binding level is to limit expression of therapeutic genes by regulating transcription with a promoter region having either tissue restricted activity, or preferential activity in malignant cells. Such promoter-regulated specificity has been used to target retroviral and adenoviral vectors alike.11,107 Tissue-specific promoters are potentially useful for regulating expression of cytotoxic genes in vectors targeting nonvital tissues, such as prostate, to widen potential therapeutic windows.108 To this end, vectors have been constructed with the promoter region that normally regulates PSA expression used to control expression of a reporter gene.109,110 Cloning of therapeutic cytotoxic genes, such as HSV-tk, into analogous vectors using tyrosinase promoter has been shown to inhibit tumor growth in melanoma animal models111; analogous vectors to target prostate cancer are under development.

In contrast to tissue-specific transcriptional targeting, oncogene-associated regulatory sequences may promote selective expression of therapeutic genes in tumor cells that harbor transcriptional overexpression of the oncogene. This has been demonstrated with a vector using ERBB2 promoter sequences to the cytotoxic gene cytosine deaminase; this vector conferred selective sensitivity on ERBB2-overproducing cells.112 SUMMARY Based on a growing volume of preclinical data, clinical trials of gene therapy for urologic cancer are underway. Therapeutic genes that are under current or forthcoming clinical study include immunogenes, cell death-inducing genes, antioncogenes, and tumor suppressor genes. Although systemic therapy with immunogenes is feasible, other gene therapy strategies, which do not rely on an intervening antitumor immune response, are at present limited to local-regional targeting. This constraint is largely due to limitations of gene transfer vectors, as well as in vivo gene delivery systems. Refinement of gene transfer vectors, such as hybrid vectors construction, is actively being pursued to broaden the utility and applicability of direct gene therapy strategies. The early phase of cancer gene therapy clinical trials should be viewed in context. Preclinical models predict modest, if any, therapeutic effects with current forms of human cancer gene therapy. Equally as important as clinical outcome in gene therapy clinical trials, however, are biologic surrogate endpoints to guide continued improvement of gene therapy strategies. The earliest clinical trials have indeed shown the ability of clinical gene therapy to alter biology of human urologic cancer.15,23–25 However, groundbreaking clinical trials of gene therapy have also been associated with significant toxicity, including a fatality and induction of vectorinduced leukemia.2,3 To attain its full potential, gene therapy must be approached with realistic expectations, respect for its potential toxicity, and a recognition of the need for its continued refinement.

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C H A P T E R

3 Principles and Applications of Radiation Oncology Steven J. Chmura, MD, PhD, Wendla Silverberg, MD, and Ralph R. Weichselbaum, MD

The treatment of both benign and malignant diseases with ionizing radiation (IR) began shortly after the discovery of x-rays by Wilhelm Roentgen in 1895.1 The therapeutic applications of IR were quickly realized when the first patient was treated by Emil Grubbe in 1896.2 Despite the initial enthusiasm in the clinical applications of IR, subsequent experimental and clinical experience demonstrated the adverse effects on normal tissues when attempting to treat tumors located deep below the skin. The development of implantable radioactive sources (brachytherapy) permitted high doses of radiation to be delivered directly to the tumor tissue while decreasing the normal tissue toxicity with the first prostate patient treated in 1909. The introduction of high-energy (megavoltage) external beam radiation therapy (EBRT) in the 1950s allowed treatment to a higher dose of tumors deep within the body, while decreasing the surface dose to the skin. Despite the advances in both the imaging of tumors and the hardware and software employed to deliver radiation therapy, normal tissue toxicity remains the limiting factor in most human malignancies. The following section reviews both the physical and biologic bases of radiation therapy. Advances in both biologic modifiers and new technologies to deliver radiation therapy that may increase tumor cell killing while limiting normal tissue complications are also discussed. Specific examples of particular interest for urologic oncology are highlighted. THE PHYSICS OF RADIATION THERAPY AND DELIVERY External Beam Radiation Therapy EBRT is used to treat many tumor types, including head and neck, gynecologic, thoracic, and genitourinary

malignancies. While earlier technologies utilized gamma rays from radioactive sources, such as cobalt (Co60) to deliver photon therapy, modern linear accelerators (Figure 3-1) generate and deliver either high-energy photons (x-rays) or charged particles (electrons). The x-rays are produced through the deceleration of highkinetic energy electrons (bremsstrahlung) within the head of the linear accelerator as they strike a tungsten target.3 After striking the target, the electrons emit x-rays with a spectrum ranging from zero energy to their maximum kinetic energy. The photons are emitted from a point source, much like a flashlight, that diverges in a cone shape. The energy of the photons decreases as the inverse square of the distance (1/d2) from the source (the inverse square law).3 Through advancements in technology, the energy of radiation therapy has been greatly increased since its clinical introduction, thus permitting treatment of tumors deep within the body. The beam quality or energy employed in a particular patient refers to the highest energy photons generated. Modern linear accelerator energies span from the kilovolt (kVp) to megavolt (MV) range. Outside of superficial treatment of such lesions, EBRT is almost exclusively delivered in the 4 to 18 MV range. For example, most prostate cancer patients are treated with energies ranging from 6 to 18 MV in order to spare superficial tissues and maximize the dose to the prostate. The photons decelerate exponentially as they interact with matter. The distance they travel through tissue is proportional to their initial energy (see above). Thus, higher energy beams are able to penetrate tissues deeper and result in fewer interactions at the skin surface. As the photons interact with matter, either superficially or deep within tissues, charged particles, such as electrons, are

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Figure 3-1 Example of a modern linear accelerator used to deliver photons or electrons in the clinical setting.

set in motion that results in ionization and excitation of other atoms. The energy absorbed in tissue by the secondary charged particles represents the dose delivered. The accepted unit of dose is the gray (Gy), which is defined as the absorption of 1 J/kg. In radiation therapy clinical outcome papers, the terms centigray (cGy) or radians (rad) are commonly used with 1 cGy (or rad) representing 0.01 Gy. Prior to 3D treatment planning techniques, dose was prescribed to a point, for example, in the middle of a patient or in the middle of a tumor. With modern 3D treatment planning techniques, dose can also be prescribed to a volume of interest, for example, the tumor and areas of tumor spread. Current 3D planning terminology of dose refers to the minimum dose absorbed by the volume of the target. The interaction of the charged particles with tissue results in production of free radicals along with direct damage to DNA. The biologic effects of absorbed dose are discussed in detail later. Linear accelerators can also be configured to produce electrons by removing the tungsten target and guiding them through the accelerator toward the patient. Unlike the photons that comprise x-rays, an electron is a charged particle that travels a known range in tissue. By selecting the initial energy of the electrons, one can calculate the depth of tissue that will be irradiated. Tissues beyond that range receive little irradiation. Since electrons are charged particles, they interact directly with matter in tissue by depositing dose and causing damage to the tumor cell.

Other types of particles have been employed as therapeutic modalities, including neutrons4 and protons.5 Neutron beams are similar to photon beams in that their energy decreases exponentially in tissue. While neutron beams have been employed to treat a variety of tumor sites, including prostate and brain, they are seldom used clinically, as multiple randomized studies have failed to demonstrate a clear benefit when compared to photon therapy in terms of tumor control and normal tissue toxicity. Proton beams are generated by a cyclotron. These heavy charged particles are unique; they deposit their dose near the end of their range. This phenomenon, known as a Bragg peak, can be manipulated to deliver a high dose to a small tumor deep within the body while minimizing high doses to more superficial tissues.5 While there has been significant interest in expanding the therapeutic applications of proton therapy, the substantial cost of a cyclotron (proton production machine) along with limited clinical outcome data has resulted in very few of them being constructed around the world. As the technology to build cyclotrons becomes cheaper to implement, more are expected to be constructed. Theoretic and preliminary data suggest that proton therapy may be appropriate for prostate cancer treatment. Brachytherapy In contrast to EBRT, brachytherapy delivers dose through the placement of radioactive sources that remain in place either temporarily (minutes to days) or permanently. Initially, naturally occurring isotopes, such as radium, were used in brachytherapy. Newer artificially produced isotopes have replaced radium due to their wider availability and improved safety profiles. The prescribed dose in brachytherapy is normally defined based on a limited number of 2D tissue points. Increasingly, 3D dose prescriptions are becoming more common for brachytherapy. Intracavitary brachytherapy involves placement of the sources within a body cavity. For example, most intermediate- to advanced-stage cervical cancers are treated, in part, with a Fletcher-Suit applicator. A hollow tube (tandem) is inserted into the uterus, and two other hollow tubes (colpostats) are placed within the vagina against the lateral fornices. Dose is delivered through insertion of radioactive sources into the hollow tubes that are secured in place. The sources (cesium 137) remain in place for 3 to 4 days (low-dose rate [LDR] brachytherapy) depending on the clinical scenario and choice of the physician. Intracavitary brachytherapy has also been used to treat tumors of the head and neck, biliary tree, and bronchi. By placing the hollow cylinders or catheters before loading the radioactive sources (after loading), radiation exposure to the staff is minimized.

Chapter 3 Principles and Applications of Radiation Oncology 41

conform the dose to the target depends on many factors, including target location, external contour of the patient, tissue density, beam energies availability, and the EBRT hardware availability.10–12 Current 3D treatment planning and 3D treatment (3D-CRT) rely almost exclusively on computed tomography (CT)-based imaging to generate a customized plan for each patient. The following sections outline treatment planning and plan generation using a prostate patient as a model assuming that 3D treatment planning is available. Simulation and Patient Immobilization

Figure 3-2 Initial pelvic film immediately following implantation of permanent iodine125 prostate brachytherapy seeds. Due to subsequent swelling of the prostate, the seeds will move and rotate during the next 60 days when they are most radioactive.

Interstitial brachytherapy delivers dose directly within a tumor or surgical bed. Hollow flexible catheters are initially surgically inserted into the tumor or site of tumor resection. After 5 to 7 days of healing, radioactive needles are inserted into the catheters to deliver dose. Prostate brachytherapy involves the placement of permanent radioactive seeds (iodine 125) within the prostate (Figure 3-2). These seeds deliver a dose over the course of many months to the prostate and surrounding tissue. As discussed above, traditional LDR intracavitary brachytherapy is delivered over 3 to 4 days as an inpatient procedure or sources with a short half-life left in permanently as is the case with prostate brachytherapy. Recently, high-dose rate (HDR) techniques are increasing in popularity. High-activity iridium sources deliver dose rapidly, permitting patients to be treated as an outpatient requiring only minimal anesthesia. Clinical studies employing HDR have demonstrated efficacy in head and neck, cervix, and prostate.6–8 TREATMENT PLANNING AND DELIVERY As previously described, the dose to be delivered during EBRT is prescribed to a volume in 3D conformal radiation therapy (3D-CRT). The aim of the prescription is to uniformly irradiate the volume (target) while minimizing the dose to surrounding normal tissues.9 The ability to

Most prostate cancer patients are treated with fractionated (administered in multiple daily treatments) EBRT for 6 to 8 weeks. Patients normally lie supine on the treatment table as shown in Figure 3-1. In order to deliver dose to the prostate each day and minimize dose to the surrounding normal tissue (such as the rectum), the patient’s position on the table must be reproduced during each treatment. In addition, patient motion must be minimized during the treatment that normally lasts 5 to 15 minutes. Prior to initial treatment, a simulation of the actual treatment technique is performed to determine the ideal patient positioning. In order to ensure the reproducibility of the patient’s position, immobilization devices are constructed out of foam cradles that will be used on all subsequent patient treatment days. Through the use of these immobilization devices and newer imagining techniques, such as video-assisted setup, radiation therapists are able to reproduce patients’ positions to within millimeters daily. A CT simulator is a specialized scanner used to directly acquire CT data while the patient is immobilized in the desired treatment position. The CT data acquired from imaging guides radiation therapy planning by providing geometric information on external patient contour and tumor size, shape, and location relative to adjacent critical structures.13 Following the acquisition of the CT data, the physician defines three volumes to be used in the treatment planning process. The gross tumor volume (GTV) represents the tumor visible on the CT simulation data. The clinical target volume (CTV) is defined as the GTV and the draining lymphatic and other tissues that may contain microscopic disease. The planning target volume (PTV) is created based on expansion of the GTV and CTV in order to compensate for patient setup uncertainty, such as patient and organ motion. For a typical prostate patient plan, the PTV expansion typically ranges from 0.6 to 1 cm.14 Normal tissues are also defined in order to design a plan that will minimize the dose to those organs, such as the rectum. The treatment planning is based on the volumes entered by the physician following the simulation.

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Treatment Planning

Treatment Delivery and Verification

Treatment planning software permits physicists and physicians to generate a dose distribution superimposed on the CT images and volumes that have been designed. Although the specifics of the treatment planning software may vary widely based on the technology available at institutions, certain variables are universally required for treatment planning. These variables include beam energy, type of beam (photon or electron), number beam angles, relative beam weights, and beam-modifying devices. Superficial tumors can be treated with either low-energy photon beams (100 to 250 kVp) or electron beams. Tumors deep within the body, such as the prostate, are treated with energies ranging from 6 to 18 MV and from 4 to 9 beam angles. For example, most prostate plans employ 4 to 5 beam angles with 6 MV photons. The beam modifying devices include customized shielding blocks that alter the quality, intensity, and shape of the beam. These are further discussed in the section on intensity modulated radiation therapy (IMRT). Dose volume histograms (DVH) provide a quantitative evaluation of treatment plans. The DVH represents the volume of a particular organ irradiated as a function of dose (Figure 3-3). These data coupled with known toxicity research aid the physician in selecting the proper treatment plan. For example, based on both retrospective and randomized data, most physicians planning a prostate treatment attempt to limit the volume of rectum receiving >70 Gy to 70 Gy was 95%) and has a very large volume of distribution (450 to 5200 l/m2).231–235 It undergoes hepatic metabolism and biliary excretion with only around 7% of drug found unchanged in the urine.231 This suggests that dose reduction in liver disease may be warranted while adjustment for renal impairment may not be of value.236 The terminal half-life is long ranging from 8.9 to 189 hours.235,237,238 Mitoxantrone acts through DNA intercalation, DNA–protein cross-linkage and DNA–DNA linkage, and topoisomerase II inhibition.236 The major acute toxicity of mitoxantrone is myelosuppression, especially neutropenia, while nausea and vomiting tends to be mild. Cardiac toxicity occurs with mitoxantrone but is less common than with the anthracyclines. Alopecia secondary to mitoxantrone administration is normally mild.239 Mitoxantrone has significant activity in PC but not other genitourinary cancers.240,241 It has been licensed by the FDA for use in symptomatic HRPC based on the results of a randomized trial conducted by National Cancer Institute of Canada showing major improvement in quality of life.242–244 The potential role of mitoxantrone in earlier stage disease is under intense investigation245,246 and is the subject of a randomized trial being carried out by the Southwest Oncology Group. Drugs That Act Through Tubulin Modulation Vinca Alkaloids The vinca alkaloids, which occur naturally in the periwinkle (Catharanthus roseus), are formed from two multiplering planar units, an indole nucleus and a dihydroindole nucleus. The two most commonly used drugs, vincristine and vinblastine, are almost identical, differing only in a single substitution on the dihydroindole nucleus.247 They both act by binding to tubulin and inhibit microtubule assembly, which in turn inhibits mitotic spindle formation. This causes an accumulation of cells in

Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 65

metaphase. Although the vinca alkaloids are thought to be cell cycle phase specific for mitosis, the cytotoxic effect probably occurs in S phase and its effect seen in the M phase. After intravenous administration, the vinca alkaloids are extensively bound by serum proteins and blood components and are rapidly cleared from the plasma and concentrated in various tissues. The disposition is triphasic,90,248 with a rapid initial half-life (t1/2α less than 5 minutes), t1/2β of 1 to 2 hours, and t1/2γ of 1 to 3 days. They approximate total body water in their distribution. The major route of excretion is hepatic,249 with appreciable amounts appearing in the stool, and liver disease may necessitate a change in dosage. A small component of excretion is urinary. Although similar in structure, the vinca alkaloids have substantially different profiles of toxicity. Vincristine is predominantly associated with neurologic side effects, including a range of peripheral sensorimotor neuropathic changes, autonomic neuropathy, jaw pain, and central nervous system effects. Less commonly vincristine causes myelosuppression, gastrointestinal effects, alopecia, and the syndrome of inappropriate ADH production. By contrast, vinblastine is associated with predominant myelosuppression (in particular granulocytopenia), more marked gastrointestinal toxicity (especially paralytic ileus), and alopecia; the neurologic toxicities, while quite prominent, occur less frequently and less severely than for vincristine. Both agents are significant vesicants. The vinca alkaloids have had particular application in the treatment of advanced germ cell tumors,250,251 small cell cancer of the prostate, and in bladder cancer (vinblastine, in particular)252 but appear to have less single agent activity in the treatment of prostate adenocarcinoma, adrenal carcinoma, and renal carcinoma. As noted earlier, the vinca alkaloids have substantial clinical activity against the urologic malignancies, in particular germ cell tumors and urothelial malignancy. For this reason, the development of new vinca alkaloids with a higher degree of experimental antitumor activity is of interest. A potentially promising new agent in this class is vinorelbine (Navelbine), which has been under investigation in Europe and has recently been introduced into the United States. The compound is 5′-noranhydrovinblastine. Although it shares the mode of action of the other vinca alkaloids, discussed earlier, in experimental systems it has less affinity for axonal microtubules compared with its affinity for the microtubules of the mitotic spindle. This indicates the possibility that it might produce interruption of mitosis at concentrations that would not give rise to neurotoxicity.253 It has also shown a higher degree of activity than vincristine or vinblastine against some experimental tumors.254,255 In phase I testing, neutropenia was the dose-limiting toxicity, and the maximam tolerated dose (MTD) was 35 mg/m2/week. It did give rise to peripheral neuropathy at higher doses, but this was

relatively mild.256 An initial study of the pharmacokinetics by Bore et al.,257using tritiated vinorelbine and also a radioimmunoassay, showed a low urinary excretion based on elimination. The primary excretion route was the feces, with 34% to 58.4% of the total dose being excreted by this route over a period of 21 days.257More recently, Rowinsky et al.258 published the results of a bioavailability study in which the drug was given intravenously and orally to the same patients. Bioavailability was 27% ± 14%. The volume of distribution was large, 20.02 ± 8.55 l/kg, and the terminal phase half-life was 18 hours. Plasma decay was triphasic.258 Vinorelbine has activity in HRPC259 but has not produced impressive results in limited trials in patients with testicular germ cell tumors, renal cell carcinoma, or urothelial cancer.204,260 The activity of vinorelbine in PC is apparently increased by the concurrent administration of estramustine but with the consequent side effects attributable to the estrogenic effects of that drug.261–263 The potential of this combination relative to other chemotherapeutic approaches in this setting remains to be determined. Taxanes A very important new class of drugs that is being extensively evaluated in a broad spectrum of tumor types is the taxanes. The two FDA-licensed drugs in this class are paclitaxel and docetaxel; the structures are shown in Figure 4-3. Paclitaxel is extracted from the bark of the western yew tree264; and, initially, this severely limited the supply of the drug for investigation. Compounded by the low water solubility of the drug, this slowed the development of the drug. However, these difficulties were overcome because of the interest generated by the high degree of activity of the drug in experimental systems and because the drug was shown to have a unique mode of action.265–270 The drug acts on the microtubules, but unlike the vinca alkaloids, which also interact with microtubules, the taxanes stabilize the microtubule. It has been shown that a microtubule is in dynamic equilibrium with the tubulin heterodimers, which make up its structure. These associate at one end and dissociate at the other. The action of the vinca alkaloids is to prevent the tubulin from binding and thus the microtubules undergo spontaneous disassembly. The action of the taxanes is the opposite. The microtubule is stabilized, so that growth continues by association of tubulin but disassembly does not occur. Thus the cell becomes filled with a tangle of elongated but functionally useless microtubules, leading to cell death. Paclitaxel has undergone very extensive testing and is approved for use in ovarian carcinoma271 and lung cancer. In phase I studies, it was initially given by short infusion.272,273 However, acute allergic reactions and

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O R O

C

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Figure 4-3 Structures of paclitaxel (1), docetaxel (2).

disturbances of cardiac rhythm led to progressive lengthening of the infusion time to 24 hours, which became the standard for administration of the drug. When given by 24-hour infusion, the MTD was 200 to 275 mg/m2 given every 3 weeks. The dose-limiting toxicity was neutropenia, which was often profound but short lived and which relatively uncommonly led to toxic death.274 Other toxicities, as noted above, included acute cardiac effects (mainly arrhythmias), hypersensitivity reactions, peripheral neuropathy, and gastrointestinal toxicity. In a phase I study in leukemia,275 in which grade IV myelosuppression was accepted as routine, mucositis was the dose-limiting toxicity at a dose of 390 mg/m2. Total alopecia was another feature, and it involved the hair on the head, body hair, and eyelashes. It was subsequently recognized that paclitaxel-related cardiac arrhythmias276 (and in particular bradycardia, the most common of the paclitaxelrelated arrhythmias) are clinically less dangerous than initially feared. With suitable premedication with steroids, H1 and H2 histamine antagonists, the drug can be safely given by a 3-hour infusion.277 This markedly reduces the myelosuppression without apparently reducing the antitumor effect.278,279 One-hour infusion of the

drug is currently under evaluation. These developments are important in enabling the drug to be given on an outpatient basis. The pharmacokinetics of paclitaxel were evaluated during the early clinical studies using high performance liquid chromatography (HPLC) assay for the drug. Both a biphasic and a triphasic plasma decay have been described, with the terminal phase half-life being in the range of approximately 4 to 7 hours for the biphasic plasma decay and in the range of approximately 10 to 50 hours where a gamma phase was described.280 The earlier studies reported linear pharmacokinetics, but recent reports have indicated nonlinear pharmacokinetics with shorter infusions. Volumes of distribution have been variable in the reported studies and have been generally in the range of 50 to 100 l/m2; however, very large volumes of distribution have been described in the study reported by Huizing et al.281 Very little of the drug is eliminated unchanged through the kidneys and systemic clearance appears to result from metabolism, biliary excretion, and binding to tissue components. The main route of metabolism is by cytochrome P450-dependent hydroxylation, the principal hydroxylated metabolite in bile being 6-hydroxy paclitaxel.282 Of interest, cisplatin


given first in combination with paclitaxel is more toxic than the reverse sequence. This appears to be related to the fact that cisplatin inhibits the metabolism of paclitaxel, causing an increase in the area under concentration × time curve (AUC) of the latter drug.283 For the same schedule of administration, the degree of myelosuppression is related to the total drug exposure as measured by the AUC. A shorter infusion gives less toxicity for the same AUC than a longer infusion, suggesting that duration of exposure to a minimum cytotoxic concentration may be an important factor in the toxicity of the drug.284 Paclitaxel has shown antitumor activity in early studies of germ cell tumors and transitional cell carcinoma of the urothelium. Patients with germ cell tumors, with prior therapy, showed a 24% response rate to paclitaxel 250 mg/m2 24-hour infusion with 2 CR and 4 PR in 25 patients.285 Previously untreated patients with transitional cell carcinoma of the urothelium received the same dose and schedule of paclitaxel and showed a 42% response rate.286 Studies in renal cell carcinoma have been negative.287 Early studies with paclitaxel in HRPC show modest single agent activity,288 and subsequent trials have examined the potential of adding other agents to the taxanes including estramustine and carboplatin (see later).185,289 Docetaxel (taxotere, Figure 4-2) is a synthetic analog of paclitaxel that is prepared from 10 diacetyl baccatin III, a compound extracted from the needles of the European yew tree, Taxus baccata. It is thus derived from a biologically renewable source. It is more potent in vitro than paclitaxel.290 Although its mode of action is similar, it is reportedly active against cells, which are resistant to paclitaxel.290 It has undergone phase I testing in 1-hour, 2-hour, 6-hour, and 24-hour infusions291–293 and as a 1hour infusion daily for 5 days.294 The MTD ranged from 70 to 115 mg/m2, and neutropenia was dose limiting in all of the studies, although mucositis was also a major toxicity in the study of the 24-hour infusion.293 It has been suggested that anaphylactic reactions are less common with docetaxel than with paclitaxel but that skin toxicity may be more marked. Plasma decay is triphasic with a gamma phase t1/2γ of 11.8 ± 6.7 hours.292 Docetaxel has activity in HRPC,295 where it is currently most commonly combined with estramustine,296–298 urothelial cancer,299 penile cancer, and testis cancer. It has limited activity in renal cell carcinoma.300 At present, it is difficult to be dogmatic regarding the respective merits of paclitaxel and docetaxel with respect to antitumor efficacy, but it is quite clear that they have different spectra of toxicity. Estramustine Estramustine is constituted by the carbamate linkage of estradiol and nor-nitrogen mustard molecules and is

therefore best considered a combination hormonalcytotoxic therapy. However, the mechanism by which estramustine exerts its antineoplastic effect is unclear. Following oral ingestion estramustine phosphate is rapidly dephosphorylated and absorbed with a bioavailability of 37% to 75%.301 Concurrent ingestion of calcium rich foods, such as dairy products, can interfere with estramustine absorption.302 After absorption estramustine is metabolized to estromustine, which is preferentially taken up by and retained in prostate tissue and PC cells by estramustine-binding protein.303 Estramustine is metabolized in the liver and excreted in the bile with very minimal renal excretion.301 The terminal half-life of estromustine is 10 to 20 hours.301 As a single agent, estramustine has not demonstrated benefit over continued or alternate hormonal therapy in PC.304 However, in combination with selected cytotoxic agents, the current clinical wisdom is that estramustine appears to contribute to increased response,259,305–307 although this has not been proven in well-structured trials. While the mechanism for this is unclear, the effect of estramustine may occur through a phase activation of PC cells so that they are more sensitive to subsequent or concurrent cytotoxic effect. Estramustine alters cellular microtubular configuration and may have synergy with other drugs that act on microtubules such as taxanes (paclitaxel, docetaxel) and vinca alkaloids (vincristine, vinblastine, and possibly vinorelbine).305,308–310 Recent reports from phase I and phase II trials suggest that the combination of estramustine and docetaxel is well tolerated and produces a decrease of >50% in serum PSA in around 50% of HRPC cases treated.296,297,311–315 Given significant estrogenic side effects related to estramustine therapy, particularly thromboembolic phenomena, its place in combination therapy with cytotoxic agents for HRPC still requires proof of efficacy over the cytotoxic agents alone, as well as the optimization of dose and scheduling to minimize toxicity. Alkylating Agents The alkylating agents are a group of chemical compounds of diverse structure, which share the common property of labile, electrophilic alkyl groups that can react with most biologic molecules to form adducts. The alkyl groups can be added to oxygen, nitrogen, phosphorus, or sulfur atoms, and thus can function at extremely diverse sites. However their most important reactions are with the nitrogen atoms of DNA, particularly the N7 position of guanine residues, altering the structure or function of the DNA. These drugs are all cell cycle dependent, but not cell cycle specific; that is, they exert their effects on cells throughout the cell cycle (analogous to radiation). They appear most active against rapidly proliferating cells. Agents included in this group include

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cyclophosphamide, ifosfamide, thiotepa, melphalan, nitrogen mustard, busulfan, chlorambucil, and the nitrosoureas. The alkylating agents, through their common mechanism of action, are potentially cytotoxic and carcinogenic. Although sharing common functional traits, differences in their chemical structures account for the variation in their pharmacologic characteristics. This is of particular importance as an explanation for why crossresistance may not occur in all situations. Cyclophosphamide Cyclophosphamide is 2-bis-(2-chloroethyl)aminotetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide monohydrate, a cyclic phosphamide ester of nor-nitrogen mustard. The monohydrate is not ionized and is lipid soluble. This agent is a bifunctional substituted nitrogen mustard, which must be activated in the liver before it is active. Its activation is a multistep process that occurs in the hepatic microsomal P450 enzyme system.83,316 There is thus no rationale to using the drug for intraarterial chemotherapy nor as an intravesically administered agent. It can be usefully administered as an oral agent (90% bioavailability) or intravenously. Hepatic inactivation is the major mechanism of active drug elimination, whereas after intravenous administration about 15% of the drug is excreted unchanged in the urine and the rest as metabolites. The plasma half-life is approximately 5 to 6 hours.316 As cyclophosphamide is bifunctional, it can cross-link the two strands of DNA, yielding an interstrand crosslink, or can produced intrastrand cross-links, or even can bind DNA to protein. The binding of the active metabolite of cyclophosphamide to DNA does not cause cell death per se; rather the cells progress slowly through the S phase and arrest and subsequently die in the G2 phase. Information regarding potential drug interactions with cyclophosphamide is relatively scant. As it must be metabolized by hepatic microsomes to be active, drugs, which induce this system (such as the barbiturates, phenytoin, and carbamazepine) may increase the conversion of cyclophosphamide to its metabolites; similarly cyclophosphamide may have an impact on the activity of the barbiturates. It has also been reported that cimetidine increases the toxicity of cyclophosphamide via a change in the concentration × time relationship of its active metabolites.317,318 Cyclophosphamide produces significant leukopenia and immunosuppression but is not usually associated with thrombocytopenia.83,89 Nausea and vomiting may occur, although usually in association with high dose intravenous usage. Similarly alopecia is more commonly associated with high dose administration. Of particular importance, excretion of acrolein, one of the metabolites,

which is particularly irritating to the bladder mucosa, can cause hemorrhagic cystitis, and this can lead to bladder fibrosis or even transitional cell carcinoma of the bladder. In the context of intravenous administration, this toxic effect can be avoided by the use of sodium-2-mercaptoethane sulfonate (MESNA), which is excreted in the urine, providing reactive thiols that bind to the acrolein, protecting the bladder mucosa. Occasionally, cyclophosphamide may cause interstitial pneumonitis, gonadal atrophy, anaphylaxis, and in higher doses, the syndrome of inappropriate ADH production and cardiotoxicity (including acute cardiac necrosis when given in transplant-intense dosage). The most common application of cyclophosphamide for genitourinary cancer is in the treatment of adenocarcinoma of the prostate,64,65 and it has also been used in the past in the treatment of advanced germ cell tumors.250,319 It is less frequently used for germ cell tumors in current practice because of the risks of carcinogenicity and infertility. The drug is inactive in the treatment of renal and adrenal carcinomas and has only limited activity in the treatment of bladder cancer. Ifosfamide Ifosfamide is a structural analog of cyclophosphamide, differing only in the position of one of the two chloroethyl groups. It is also a metabolically activated alkylating agent and must first undergo hydroxylation by hepatic microsomes.316 However, the change in its structure has resulted in changed pharmacology, and its activation within the liver occurs more slowly than for cyclophosphamide. Ifosfamide is well absorbed orally and can also be administered intravenously. Its pharmacology is similar to that of cyclophosphamide. Its plasma half-life has been reported to be as short as 5 to 6 hours, either after oral or intravenous administration,82,320 although Creaven et al.81 documented a plasma half-life of radioactively labeled ifosfamide of nearly 14 hours. In current clinical practice, it is most commonly administered intravenously, with schedules varying from a single infusion, to multiple-day schedules, with MESNA coverage to prevent hemorrhagic cystitis. Creaven et al.81 have suggested that the alkylating activity ratio of ifosfamide is 1:5, when compared to cyclophosphamide. The pattern of toxicity is similar to that of cyclophosphamide,81 but with less myelosuppression and a greater tendency to cause cystitis. In addition, ifosfamide has a greater prevalence of central nervous system toxicity, including altered mental status, cerebellar dysfunction, seizures, and extrapyramidal effects.81,321,322 It is not really clear whether there is a definite dose-response relationship for ifosfamide, and thus an optimal dose has not been defined.


Ifosfamide is currently used in salvage and high-risk regimens for advanced germ cell tumors323–235 and for metastatic urothelial cancer.326–328 In broad-based phase I and phase II trials, little activity has been reported in PC, although the drug has not been assessed since PSA has been introduced as a surrogate marker of response. Ifosfamide is inactive in renal carcinoma, but single agent activity has been identified in squamous cell carcinoma, including cancer of the penis.

O

O O O O O H O O O

Thiotepa N,N′,N′′-triethylenethiophosphoramide (thiotepa) is an aziridine drug, a polyfunctional alkylating agent, which can produce interstrand cross-links, DNA adducts and strand breaks, and a range of other DNA lesions.329 After IV injection the t1/2α was 7.7 minutes and the t1/2β 25 minutes in the study by Cohen et al.330 Thiotepa is administered by intravenous or intracavitary routes, the latter including intraperitoneal, intrathecal, and intravesical delivery. It is not a vesicant and does not cause local soft tissue reactions. In the standard dose range, thiotepa is associated with myelosuppression, both granulocytopenia and thrombocytopenia, as well as nausea, vomiting, headache, and occasionally alopecia. In transplant-intense doses, thiotepa may cause mucositis, cutaneous changes, and occasional organic brain syndrome.331 When administered intravesically, thiotepa causes little systemic toxicity unless used within a few days of extensive transurethral resection; thiotepa, a relatively small molecule, is absorbed significantly through an extensively denuded bladder surface. The major clinical application for thiotepa has been in the intravesical chemotherapy of superficial bladder cancer,67 although this agent is now used less frequently because of its risk of carcinogenicity and the development of more effective treatment options. Epipodophyllotoxins Podophyllotoxin, a derivative of the mandrake root, has been known to have antimitotic properties for more than half a century, and extracts of the mandrake root have been used for medicinal purposes for centuries.332 Although the early podophyllotoxin derivatives were excessively toxic, two derivatives (etoposide and teniposide) have shown substantial clinical activity with a tolerable profile of side effects.332–334 Although initially believed to act by binding to tubulin and inhibiting microtubule assembly, additional studies have suggested that the epipodophyllotoxins arrest cells in late S phase or early G2 phase,335 rather than at G2M. More recently, these agents have been shown to exert their anticancer effects by impeding the function of the topoisomerase II enzyme.336

O

H

O

O O

Figure 4-4 Structure of etoposide.

Each compound has a complex structure composed of a multiringed structure linked to a glucopyranoside sugar (see etoposide structure in Figure 4-4). Both drugs are routinely administered intravenously, although etoposide is now formulated for oral administration. The optimal schedule of administration has not been defined, although prolonged schedules (multiple daily short infusions or continuous infusion) are most commonly employed because of the phase-specific mode of action. The pharmacokinetics is biphasic, with half-life values of 90 minutes and 3 to 11 hours.334 After administration of radiolabeled etoposide to humans, 40% to 90% of radioactivity is recovered in the urine within 48 hours, fecal recovery is less than 20%, and biliary excretion is only minimal.332. The major toxicity of the epipodophyllotoxins is doserelated myelosuppression, with predominant leukopenia.333 Gastrointestinal complications, such as nausea, vomiting, and anorexia are usually mild. Other side effects include alopecia, headache, fever, and hypotension. Severe hypotension may occur if the drug is infused too rapidly, and this can occasionally be accompanied by bronchospasm or rarely by anaphylaxis. It is believed that these allergic phenomena may be due to the use of the diluent, cremophor. Etoposide phosphate, a watersoluble derivative that is rapidly hydrolyzed to etoposide in the plasma, is currently undergoing clinical trial. Recently there has been emerging information that etoposide is occasionally associated with iatrogenic acute myeloid leukemia, and such cases have now been recorded among patients cured of germ cell tumors.180 The indications for the use of the epipodophyllotoxins for genitourinary cancer are relatively limited, with the most common application being in the management of advanced germ cell tumors.250,251 Most studies have sug-

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gested that there is only very limited activity against bladder cancer and prostatic adenocarcinoma, although there is a clear role for this drug in the treatment of small cell anaplastic PC. Etoposide is inactive in the treatment of renal carcinoma, and only scant data are available with respect to penile and adrenal cancers. Antimetabolites Antifolates The role of the antimetabolites in cancer treatment was first explored 50 years ago with the investigation of aminopterin, an analog of folic acid. This early work gave rise to the development of methotrexate, the 4-amino, 10-methyl analog of the parent compound, which has come to be one of the most widely used agents for the genitourinary cancers. Methotrexate inhibits dihydrofolate reductase (DHFR), an important enzyme in folic acid metabolism, which catalyzes the reduction of dihyrofolate to tetrahydrofolate. DHFR maintains the intracellular reduced folate pool, which in turn is required for the synthesis of thymidine and purines and thus for the production of DNA, RNA, and protein. Methotrexate undergoes polyglutamation intracellularly to varying extents; the polyglutamated forms do not traverse cellular membranes. Polyglutamation occurs to a greater extent in tumor cells than in normal cells, and this may explain the selective action of the drug. The polyglutamated form is retained preferentially within cells, sometimes for very lengthy periods337 and can directly inhibit other folate-dependent enzymes, including thymidylate synthase.338 Methotrexate may also cause single- and doublestranded breaks in DNA.339 It is most active against rapidly proliferating cells and appears to exert its major effect during S phase; and is thus classified as a cell cycle phase-specific antimetabolite. Methotrexate uses the same active transport mechanisms to enter cells as does folic acid. At least two such mechanisms have been identified, including a low-affinity carrier that transports methotrexate and reduced folates and a high-affinity system, which is more avid for reduced folates than for methotrexate. The metabolic block induced by methotrexate can be circumvented by the use of calcium leucovorin, which feeds into the folic acid cycle beyond the block of DHFR. Calcium leucovorin and its metabolite, 5-methyltetrahydrofolate, share the latter common transport mechanism with methotrexate. It appears that normal cells can be selectively rescued by calcium leucovorin, either because of differences in transport or because of differences in the rate of DNA synthesis between normal and cancer cells. The complex biochemistry of methotrexate, its reversal and mechanisms of resistance, is beyond the scope of this chapter but has been detailed elsewhere.340

Methotrexate may be given by oral, intramuscular, intravenous, intraarterial or intrathecal routes. An optimal dosing route and schedule has not been defined. A broad range of parenteral dosing has been reported, with doses as varied as in the range between 50 and 15,000 mg/m2, predicated on the ability to rescue normal tissues with calcium leucovorin. Caution must be exercised as the higher dose range is potentially lethal if sufficient leucovorin is not administered. Alkalinization (as measured by assessment of the urine pH), by increasing the solubility of the drug and of the 7-hydroxy metabolite will also reduce toxicity. Methotrexate levels must be monitored after high dose treatment to determine the length of leucovorin rescue. More than 50% of the drug is bound to plasma proteins. Methotrexate is widely distributed in the body. In standard doses, methotrexate is excreted unchanged in urine, whereas in high doses some metabolism of the drug occurs. Plasma decay of methotrexate is either biphasic or triphasic,341–343 with the terminal phase of excretion having been reported to be in the range of 10 to 26 hours. Methotrexate is highly schedule dependent; its toxicity is more a function of the time during which plasma levels are maintained above a minimum cytotoxic concentration than of the total AUC. Thus any factor that can lead to a prolonged low level of drug will greatly increase its toxicity. Principal among such factors are impaired renal function and localization in “third space” compartments such as pleural effusion or ascites with a slow release into the circulation. In these situations, methotrexate must be used with caution; rescue with leucovorin employed as necessary. The spectrum of toxicity of methotrexate is a function of age, dose, the use of calcium leucovorin, drug metabolism, drug interactions, and renal function.340,344 Patients may experience no toxic effects at all. Hematologic side effects include leukopenia, thrombocytopenia, and anemia. Gastrointestinal toxicity includes nausea, vomiting, diarrhea, and stomatitis. Hepatotoxicity has been reported in patients receiving chronic low dose oral therapy and in high dose parenteral administration. Occasionally, methotrexate can cause self-limited pneumonitis. One of the most dangerous toxic effects is the induction of renal failure, as adequate renal function is necessary to ensure satisfactory excretion of the drug. Methotrexate can cause skin rash, pruritus, urticaria, alopecia, and a range of other cutaneous side effects. Less commonly, central nervous toxicity can occur, especially after intrathecal administration. Fluoropyrimidines 5-Fluorouracil (5-FU) was synthesized to act as a false pyrimidine and thus to inhibit the formation of thymidine.345 There are several proposed mechanisms of action, including inhibition of thymidylate synthase by an


active metabolite (FdUMP), incorporation of the triphosphate 5-FUTP into RNA, and incorporation of the 2′ deoxy triphosphate 5-FdUTP into DNA.346 The presence of reduced folate is critical to the function of 5-FU in inhibiting thymidylate synthase. Gastrointestinal tumors with increased expression of thymidylate synthase, with or without increased levels of the metabolizing enzymes, thymidine phosphorylase, and dihydropyrimidine dehydrogenase, tend to be resistant to fluoropyrimidines.347 Testing for expression levels in individual tumors may identify genitourinary cancers with susceptibility to this group of drugs, but further testing of this hypothesis is required.348 5-FU can be administered by oral, intravenous, intraarterial, or intraperitoneal routes. Bioavailability is poor and erratic when the drug is given by mouth,349 and this route of administration is no longer used (however, see following discussion on modulation and capecitabine). When given intravenously the drug has an extremely short terminal phase half-life measured in minutes.73,350 This is due to its rapid degradation by dihydrouracil dehydrogenase (DHD) to 5,6-dihydro 5-FU that then undergoes ring rupture and is degraded to small molecules.346 A rare deficiency of this enzyme can lead to severe toxicity following administration of 5-FU.346 Because of its mode of action, 5-FU is an S-phase specific drug and this combined with its extremely short halflife would lead one to anticipate that it would be highly schedule dependent. However, paradoxically, rapid infusions of 5-FU are more toxic than the same dose given over a period of several hours. This is probably due to the fact, although that the drug itself has an extremely short plasma half-life, the persistence of the active metabolite FdUMP intracellularly is measured in days.351 The bolus injection of the drug probably temporarily exceeds the capacity of DHD, thus making drug available for conversion to active metabolites. The nucleoside derivative of 5-FU, 5-fluoro2′-deoxyuridine (FUdR, floxuridine) is extremely schedule dependent. The dose that can be given by short-term infusion is approximately three orders of magnitude greater than the dose that can be given when the drug is given by a long-term continuous infusion.352 A number of compounds have been used in conjunction with fluoropyrimidines to enhance their activity through biochemical modulation. These include interferon, PALA (N-phosphonoacetyl-L-aspartate), and leucovorin.353 Of these, leucovorin has been the most extensively investigated and has proven to be the most clinically useful by raising the response rate to 5-FU in colorectal cancer by a factor of about three.354 It acts by leading to stabilization of the ternary complex formed between the active metabolite FdUMP, the active site of the enzyme thymidylate synthase, and a reduced folate cofactor (5, 10 methylene tetrahydrofolate), which is derived from leucovorin.355 An investigational modulator eniluracil has been evaluated in a clinical trial setting.356–358 This compound, which

inhibits DHD, decreases the first-pass effect and enables 5-FU to be given orally. Capecitabine is an orally bioavailable prodrug of 5-FU.359 It is generally administered on a twice-daily basis either continuously or with a week-off therapy every 3 or 4 weeks. After absorption capecitabine is metabolized by hepatic carboxylesterase to 5′-deoxy-5-fluorocytidine and then converted to 5′-deoxy-5-fluorouridine by cytidine deaminase, which is also present in the liver.76 5′-Deoxy-5-fluorouridine then enters cells and is metabolized by thymidine phosphorylase to 5-FU. The result is a cellular 5-FU concentration that exceeds that achieved in the serum and surrounding normal tissue.76 Capecitabine has been evaluated as a potential alternative to 5-FU infusion in a number of cancer types.360.361 It has modest activity in renal cell carcinoma,362,363 but is yet to be fully evaluated in other genitourinary cancers. The primary toxicities of the fluoropyrimidines are gastrointestinal toxicity, stomatitis and diarrhea, and myelosuppression. The pattern of toxicity varies with the schedule of administration and is also influenced by the presence of modulators. Weekly bolus 5-FU produces mainly myelosuppression (primarily leukopenia). Loading dose 5-FU, prolonged infusions, and 5-FU used with leucovorin produce primarily gastrointestinal toxicity; cerebellar toxicity and cardiotoxicity have been described364 but are uncommon at standard doses. Capecitabine may produce tenderness and desquamation of the hands and feet (the so-called hand-foot syndrome), in addition to the side effects seen with other fluoropyrimidines. Gemcitabine A new pyrimidine antimetabolite, 2′deoxy-2′difluorocytidine (gemcitabine), has recently been introduced into clinical practice for urothelial and a range of other tumors. In preclinical systems gemcitabine showed very significant activity against experimental solid tumors365 and human tumor xenografts.75 Its structure is shown in Figure 4-5. Like cytosine arabinoside, an antimetabolite which it resembles structurally, it is activated intracellularly to the triphosphate, 2′deoxy-2′difluoro-cytidine 5′-triphosphate (dFdCTP), and in this form is incorporated into DNA.366–368 Gemcitabine entry to cells requires the presence of the nucleoside transporter system, with cells deficient in this transporter being gemcitabine resistant.366 The presence of dFdCTP within the cells inhibits its own degradation via deamination by deoxycytidine deaminase and promotes 2′deoxy-2′difluoro-cytidine phosphorylation by deoxycytidine kinase (dCK), at least in part by ribonucleotide reductase (RR) inhibition. Forced overexpression of cytidine deaminase,369 increased expression of RR370 and decreased expression of dCK371,372 are associated with decreased sensitivity to gemcitabine in cell line systems. The antineoplastic effect of gemcitabine derives, in part, from

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NH2 N N HOCH2 O F

OH

F

Figure 4-5 Structure of gemcitabine.

dFdCTP incorporation into DNA instead of dCTP by polymerases involved in repair.373 However, RR is an S-phase specific, potentially rate-limiting enzyme for DNA synthesis. The activity of gemcitabine is cell cycle specific with blockade at the G1/S phase transition, perhaps suggesting that RR inhibition is an important contributor to gemcitabine antineoplastic effect. In the initial phase I clinical trial, the drug was given over a 30-minute infusion weekly for 3 weeks every 4 weeks. The maximum tolerated dose was 790 mg/m2 with myelosuppression, predominantly thrombocytopenia and anemia, being the dose-limiting toxicity.374,375 Other toxicities have been relatively mild. However, subsequent studies have shown that considerably higher doses can be given safely, particularly to patients with little or no prior therapy. In patients with nonsmall cell lung cancer and no prior therapy, O’Rourke et al.376 found that 2500 mg/m2 given over 4 hours every 2 weeks was below the MTD. Initial pharmacokinetic studies showed a rapid elimination of the drug with a median half-life of 8 minutes. The drug was rapidly converted to the corresponding uracil metabolite 2′,2′-difluorodeoxyuridine, which had a longer half-life, with a median of 14 hours. The active metabolite 2′,2′-difluorodeoxycytidine triphosphate was analyzed in circulating mononuclear cells. A peak was observed within 30 minutes of the end of the infusion and increased with dose up to a dose of 350 mg/m2. Beyond this dose, there was no increase in the active metabolite indicating saturation of the activation to the triphosphate.366 Subsequent study suggests that infusion of gemcitabine at a fixed dose rate of 10 mg/m2/minute produces an optimal cellular level of active metabolite.377,378 Infusion rates faster than this may result in a lower cellular exposure (area under the concentration curve concentration) of 2′,2′-difluorodeoxycytidine triphosphate by exceeding the rate at which the nucleoside transporter system and/or which the enzymes involved in producing this active metabolite

can act.378–381 The net result of faster infusions is that the maximal 2′,2′-difluorodeoxycytidine triphosphate concentration is achieved for a shorter time with the additional amount of drug wasted therapeutically but potentially contributory to side effects. On this basis and given that fixed dose rate infusion at 10 mg/m2/minute does not produce more toxicity than more rapid infusion, administration of gemcitabine in this manner is standard practice. Antitumor activity for gemcitabine against bladder cancer was noted in the phase I study by Pollera et al.382 in 14 patients receiving gemcitabine at doses greater than 875 mg/m2, they observed 1 CR and 2 PR. A response rate of 28% was observed in a phase II trial in previously untreated patients with bladder cancer.383 Subsequently, the combination of gemcitabine and cisplatin was assessed in a phase II trial with a response rate of 41%.384 This combination was then compared to MVAC in a randomized phase III trial and found to produce equivalent response and survival with better quality of life.375 De Mulder et al.385 noted response rate of 8.1% or 3 of 39 patients who could be evaluated in a phase II study of gemcitabine in renal cell carcinoma, with durable responses exceeding 12 months in 2 patients. Subsequently, researchers at the University of Chicago have reported on combination of gemcitabine with 5-FU in RCC with possible improved survival over historical controls and response rate of 17%.386 This study is currently being replicated with dose-scheduling variation and the incorporation of capecitabine instead of 5-FU. Phase II studies in PC are ongoing, but highly preliminary data suggest that gemcitabine may have some palliative benefit in the absence of major falls in serum PSA concentration,387 Gemcitabine has some activity in chemo-refractory testicular cancer388,389 and this is being pursued in further clinical trials. CAMPTOTHECINS An important group of drugs under active clinical development are analogs of camptothecin. Camptothecin was isolated from extracts of the Japanese tree Camptotheca acuminata by Wall et al.390 and shown to be active in experimental leukemia and some solid tumors. The structure of the camptothecins incorporates five rings (Figure 4-6). The fifth, or E, ring can exist in a closed ring lactone or an open ring hydroxy acid form. The closed ring form of camptothecin is highly water insoluble; however, the sodium salt of the open ring hydroxy acid form is water soluble. It was in this form that the compound was introduced into early clinical trials in the late 1960s. Phase I trials showed that the compound gave rise to substantial gastrointestinal toxicity and myelosuppression and also had a tendency to produce hemorrhagic cystitis.391,392 It showed antitumor activity


R3

R2

O

R1

N N

CH3CH2 OH

R1

O

R2

R3

O Irinotecan

Topotecan

N

N

C

O

OH

H

CH3CH2

(CH3)2NCH2

H

Figure 4-6 Structures of irinotecan (CPT-11), topotecan.

in the phase I studies, but a subsequent phase II study in gastrointestinal malignancies proved to be negative,393 and development of the compound was halted. Work continued in the laboratory on the mode of action of this compound, which proved to be unique.394–398 The compound combines with a cleavable complex formed between DNA and the enzyme topoisomerase I, an enzyme important in relieving the torsion that develops as the strands of DNA unwind for replication and transcription. The role of topoisomerase I is to cleave one of the strands of the DNA, thus allowing the supercoiled DNA to unwind. The combination of camptothecin with the cleavable complex prevents the resealing of the DNA and thus causes single-strand DNA breaks.397,399 Mutations in topoisomerase I mutations alter both DNA cleavage and unwinding, as well as the interaction with camptothecin.400 The identification of this unique mode of antitumor action stimulated the development of analogs of camptothecin that would be more soluble and more active. It was shown that the closed ring form of the E ring is essential for activity, being several orders of magnitude more active than the hydroxy acid form.401 This may account for the variable activity of camptothecin, which as noted above, was given as a sodium salt of the open ring hydroxy acid form. Several compounds were developed as analogs of camptothecin; to date, the two most important are irinotecan (CPT-11) and topotecan. The structures of these are shown in Figure 4-6.

Irinotecan Irinotecan is 7 ethyl 10[4-(1 pyridino)-1-pyridino] carbonoxy camptothecin. It is the most extensively evaluated of the newer camptothecins. In phase I studies, the drug showed major toxicities of leukopenia, nausea, and vomiting and diarrhea.402 On a weekly schedule the recommended dose for phase II studies was 100 mg/m2/week,403 and when intermittent doses were administered every 3 weeks,404 the recommended dose was 240 mg/m2. With intensive treatment of diarrhea with loperamide, dosing up to 750 mg/m2 every 3 weeks has been reported.405,406 A variety of other schedules have been reported, including a single dose every 4 weeks, 5-day continuous infusion every 3 to 4 weeks, and daily 3× every 3 weeks.402 CPT-11 is virtually inactive in vitro. To be activated, it must be hydrolyzed to 7-ethyl-10-hydroxy camptothecin (SN38), which is 3 orders of magnitude more active than the parent drug.407 Consequently, pharmacokinetic studies of the drug require the measurement of the total and the lactone forms of both CPT-11 and SN38. No relationship between nonmyeloid toxicity and any pharmacokinetic parameter was found in the study of Rowinsky et al.404 A relationship between AUC of total SN38 and percent decrease in absolute neutrophil count (ANC) was found using a sigmoidal Emax model. Irinotecan is still undergoing early phase trials in the genitourinary malignancies. The Southwest Oncology Group is conducting a phase II trial for patients with

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advanced bladder cancer, and other studies in PC are ongoing. We are not aware of published data with respect to the utility of this agent in renal and other genitourinary cancers. Topotecan Topotecan is a semisynthetic water soluble camptothecin analog, which in preclinical systems is active against experimental tumors and against human xenografts. In early phase I trials, the drug was given daily for 5 days every 3 or 4 weeks.408,409 On this schedule, the doselimiting toxicity was neutropenia, and the recommended dose for phase II studies was 1.25 to 1.5 mg/m2. Subsequent studies have evaluated infusions of from 24 hours up to 21 days.410–412 With the 24-hour infusion, a dose of 1.5 mg/m2/week was recommended for phase II evaluation. Thrombocytopenia was more marked than neutropenia in the 21-day infusion study (MTD of 0.53–0.6 mg/m2/day in patients previously treated with cytotoxic therapy and 0.8 mg/m2/day in chemotherapy naïve patients). Of interest, granulocyte-colony stimulating factor (G-CSF) did not permit dose intensification in one study because dosing was limited by fatigue and thrombocytopenia.409 In pharmacodynamic studies, dose but not the AUC of the topotecan lactone could be related to mean percentage change in ANC by a sigmoidal Emax model. The dose required to produce a 50% decrease in ANC was 0.86 mg/m2/day, given daily for 5 days.408 Data on the activity of topotecan against genitourinary tumors is scant, but evaluation is ongoing. SUMMARY There is no current consensus on the optimal strategy for the clinical use of chemotherapy against cancers of the genitourinary tract. The most common approach has been to use combination regimens in preference to single agents, predicated largely on the success of combination chemotherapy for a variety of other solid tumors. There is no doubt that the introduction of the combination of cisplatin, etoposide, and bleomycin revolutionized the management of advanced germ cell tumors, providing a cure rate of up to 90%, compared to a cure rate of less than 40% with single agent treatment. Similarly, after several years of clinical development of combination regimens for bladder cancer, a seminal randomized trial revealed a survival benefit from the combination of MVAC compared to cisplatin alone in this context. A further landmark trial demonstrated that the combination of gemcitabine and cisplatin was equivalent in efficacy to MVAC but less toxic. Mitoxantrone has an established role in improving symptoms and quality of life in HRPC, while taxane-based combinations may provide a further

advance or at worst a further option in patients with this stage of disease. By contrast, randomized trials have not proved a role for combination chemotherapy in renal carcinoma and clinical practice in this areas is still in an early stage of evolution. At present, one of the major investigational emphases is the combination of conventional and novel cytotoxic agents with biochemical and biologic modulators that target the effectors of multidrug resistance, cellular regulation, and immunologic function. However, these studies are beyond the scope of this chapter on principles and applications of conventional chemotherapy. Further clinical trials to evaluate new approaches are required in the genitourinary cancers, and in particular those tumors that fail to respond to conventional firstline therapy. In addition to the need for new treatment strategies, careful definition of endpoints and appropriate design of clinical trials is essential if outcomes are to improve.

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371. Dumontet C, Fabianowska-Majewska K, Mantincic D, et al: Common resistance mechanisms to deoxynucleoside analogues in variants of the human erythroleukaemic line K562. Br J Haematol 1999; 106:78–85. 372. Ruiz van Haperen VW, Peters GJ: New targets for pyrimidine antimetabolites for the treatment of solid tumours. 2: Deoxycytidine kinase. Pharm World Sci 1994; 16:104–112. 373. Gandhi V, Legha J, Chen F, Hertel LW, Plunkett W: Excision of 2′,2′ -difluorodeoxycytidine (gemcitabine) monophosphate residues from DNA. Cancer Res 1996; 56:4453–4459. 374. Abbruzzese JL, Grunewald R, Weeks EA, et al: A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 1991; 9:491–498. 375. von der Maase H, Hansen SW, Roberts JT, et al: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study,. J Clin Oncol 2000; 18:3068–3077. 376. O’Rourke TJ, Brown TD, Havlin K, et al: Phase I clinical trial of gemcitabine given as an intravenous bolus on 5 consecutive days. Eur J Cancer 1994; 30A:417–418. 377. Touroutoglou N, Gravel D, Raber MN, Plunkett W, Abbruzzese JL: Clinical results of a pharmacodynamically-based strategy for higher dosing of gemcitabine in patients with solid tumors. Ann Oncol 1998; 9:1003–1008. 378. Gandhi V, Plunkett W, Du M, Ayres M, Estey EH: Prolonged infusion of gemcitabine: clinical and pharmacodynamic studies during a phase I trial in relapsed acute myelogenous leukemia. J Clin Oncol 2002; 20:665–673. 379. Grunewald R, Abbruzzese JL, Tarassoff P, Plunkett W: Saturation of 2′ ,2′-difluorodeoxycytidine 5′-triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine. Cancer Chemother Pharmacol 1991; 27:258–262. 380. Grunewald R, Kantarjian H, Du M, et al: Gemcitabine in leukemia: a phase I clinical, plasma, and cellular pharmacology study. J Clin Oncol 1992; 10:406–413. 381. Patel SR, Gandhi V, Jenkins J, et al: Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol 2001; 19:3483–3489. 382. Pollera CF, Ceribelli A, Crecco M, Calabresi F: Weekly gemcitabine in advanced bladder cancer: a preliminary report from a phase I study. Ann Oncol 1994; 5:182–184. 383. Stadler WM, Kuzel T, Roth B, Raghavan D, Dorr FA: Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol 1997; 15:3394–3398. 384. Kaufman D, Raghavan D, Carducci M, et al: Phase II trial of gemcitabine plus cisplatin in patients with metastatic urothelial cancer. J Clin Oncol 2000; 18:1921–1927. 385. De Mulder PH, Weissbach L, Jakse G, Osieka R, Blatter J: Gemcitabine: a phase II study in patients with

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Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 87 401. Hertzberg RP, Caranfa MJ, Holden KG, et al: Modification of the hydroxy lactone ring of camptothecin: inhibition of mammalian topoisomerase I and biological activity. J Med Chem 1989; 32: 715–720. 402. Slichenmyer WJ, Rowinsky EK, Donehower RC, Kaufmann SH: The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst 1993; 85:271–291. 403. Negoro S, Fukuoka M, Masuda N, et al: Phase I study of weekly intravenous infusions of CPT-11, a new derivative of camptothecin, in the treatment of advanced non-small-cell lung cancer. J Natl Cancer Inst 1991; 83:1164–1168. 404. Rowinsky EK, Grochow LB, Ettinger DS, et al: Phase I and pharmacological study of the novel topoisomerase I inhibitor 7-ethyl-10-[4-(1-piperidino)-1piperidino]carbonyloxycamptothecin (CPT-11) administered as a ninety-minute infusion every 3 weeks. Cancer Res 1994; 54:427–436. 405. Abigerges D, Armand JP, Chabot GG, et al: Irinotecan (CPT-11) high-dose escalation using intensive high-dose loperamide to control diarrhea. J Natl Cancer Inst 1994; 86:446–449. 406. Abigerges D, Chabot GG, Armand JP, et al: Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients. J Clin Oncol 1995; 13:210–221.

407. Kaneda N, Nagata H, Furuta T, Yokokura T: Metabolism and pharmacokinetics of the camptothecin analogue CPT-11 in the mouse. Cancer Res 1990; 50:1715–1720. 408. Rowinsky EK, Grochow LB, Hendricks CB, et al: Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor. J Clin Oncol 1992; 10:647–656. 409. Saltz L, Sirott M, Young C, et al: Phase I clinical and pharmacology study of topotecan given daily for 5 consecutive days to patients with advanced solid tumors, with attempt at dose intensification using recombinant granulocyte colony-stimulating factor. J Natl Cancer Inst 1993; 85:1499–1507. 410. Haas NB, LaCreta FP, Walczak J, et al: Phase I/pharmacokinetic study of topotecan by 24-hour continuous infusion weekly. Cancer Res 1994; 54:1220–1226. 411. Hochster H, Liebes L, Speyer J, et al: Phase I trial of low-dose continuous topotecan infusion in patients with cancer: an active and well-tolerated regimen. J Clin Oncol 1994; 12:553–559. 412. Hochster H, Liebes L, Speyer J, et al: Effect of prolonged topotecan infusion on topoisomerase 1 levels: a phase I and pharmacodynamic study. Clin Cancer Res 1997; 3: 1245–1252.

C H A P T E R

5 Immunotherapy: Basic Guidelines Jason B. Wynberg, MD, FRCSC, W. Marston Linehan, MD, and Richard Childs, MD

Harnessing the power of the immune system against malignant cells is often thought of as a relatively modern treatment modality for patients with advanced cancer. However, more than 100 years have passed since the first report was published by Dr. W. Coley documenting immune-mediated disease regression against cancer following injections of bacterial toxins directly into tumor lesions.1 Since then, investigators have gained tremendous insight into the mechanisms by which tumors are able to evade the innate immune system2–4 (Table 5-1) and remain resistant to “conventional” cancer immunotherapies. The steady expansion in our knowledge of tumor biology over the past few decades is gradually being translated into improvements in the efficacy and safety of cancer immunotherapeutics. CYTOKINE THERAPY Cytokines are protein molecules produced and secreted by immune and inflammatory cells that bind to complementary cytokine receptors resulting in either the stimulation or inhibition of immune cells. Cytokines usually act in an autocrine or paracrine fashion, in contrast to hormones, which typically act at a distance from their cells of origin. Following the binding of the cytokine to its receptor target, cell signaling is initiated through intracellular pathways, such as the Jak-STAT tyrosine kinase, Src, Zap70 and related proteins, phosphatidylinositol 3-kinase, IRS-1, IRIS-2, and phosphatases.5 Cytokines that typically up-regulate immune responses include interleukin-2 (IL-2) and interferon (IFN), whereas cytokines that typically down-regulate immune responses include transforming growth factor β, interleukin-6, and interleukin-10. Through their secretion of immunosuppressive cytokines (e.g., transforming growth factor β), certain tumors are able to directly impair the hosts’ immune defenses. Interestingly, some tumors can stimulate their own proliferation by secreting IL-2, which

88

binds to IL-2 receptors expressed on their cell surfaces. Administration of IL-2 at pharmacologic doses, as is done in the treatment of metastatic renal cell carcinoma (RCC), appears to directly interrupt this autocrine pathway.6,7 The field of cytokine therapeutics has grown dramatically since the development of recombinant DNA technology in the 1980s, which enabled cytokines to be produced in large quantities.8–10 A discussion of the cytokines commonly administered in the setting of advanced urologic malignancy is presented below. Interleukin-2 and Interferon-a Background In 1992, the Food and Drug Administration (FDA) approved high-dose IL-2 for the treatment of metastatic RCC.11 Although the precise mechanism accounting for tumor regression in RCC patients treated with IL-2 is not known,12 many in vitro effects of IL-2 on immune effector populations have been characterized (Table 5-2).13,14 Whereas IL-2 and resting lymphocytes separately fail to kill RCC tumor cells, prior incubation of the same lymphocytes with IL-2 significantly augments their in vitro tumor cytotoxicity. These observations provided some of the first preclinical evidence that the immune system could mediate antitumor effects, providing theoretical grounds for the pursuit of immune-based cancer therapy in humans. Unlike the interleukins, IFNs are a family of proteins secreted by leukocytes in response to viral infection and other antigenic stimuli. IFNs have powerful antiproliferative and immunoregulatory activity (Table 5-3),13 such as up-regulation of class I and class II major histocompatibility complex (MHC) molecules.15 When administered in a therapeutic setting, IFN-α is typically given as a subcutaneous injection. Due to its relatively short half-life, IFN-α is most commonly administered at least three times per week. Recently,

Chapter 5 Immunotherapy: Basic Guidelines 89

Table 5-1 Mechanisms of Tumor Escape from Immune System Tumor-related

Host-related

Decreased tumor Ag expression Decreased MHC class I expression Failure to express immune costimulatory molecules (e.g., B7.1) Production of immune inhibitors (e.g., TGFβ, IL-6, IL-10, free tumor Ag) Tumor antigens weakly immunogenic Induction of T cell apoptosis by tumor expression of Fas ligand (FasL)

Antigen-specific suppressor T cells Deficient presentation of tumor antigens by host antigen-presenting cells Failure of host effectors to reach the tumor (e.g., stromal barrier) Immune dysfunction due to carcinogen, infections, age

Development of T cell anergy or tolerance to tumor antigens

MHC, major histocompatibility complex; TGFβ, transforming growth factor β; Ag, antigen.

Table 5-2 Effects of Interleukin-2 Proliferation of T cells, B cells, NK cells, and monocytes Potentiation of Fas-mediated apoptosis of T cells to prevent clonal persistence Induction of antibody synthesis by B cells No direct anti-tumor activity

Table 5-3 Effects of Interferon-alfa Direct antiproliferative effects on tumor and other tissues Antiviral activity Occasionally promotes partial reversal of the malignant phenotype Increases expression of MHC molecules and tumorassociated Ags Activates T cells, augments NK cell function Upregulates macrophage antigen presentation Increases macrophage production of angiogenesis-inhibitor MHC, major histocompatibility complex; NK, natural killer; Ag, antigen.

investigators have shown that the serum half-life of IFNα-2b can be extended dramatically by covalently linking polyethylene glycol (PEG) to its histidine-34 moiety, thus making dosing schedules more convenient16. IFNs may have direct antitumor effects against a variety of malignancies, including hairy cell leukemia, cervical intraepithelial neoplasia, basal cell cancer, Kaposi’s sarcoma, melanoma, renal cell carcinoma, multiple myeloma, and chronic myelogenous leukemia.13

Cytokine Therapy as Treatment of Metastatic Renal Cell Carcinoma Despite early enthusiasm based on favorable outcome of pilot clinical trials, neither IL-2 nor IFN-α has proven to be a panacea for the treatment of metastatic RCC (Table 5-4).17–30 Unfortunately, the great majority of patients treated with either cytokine fail to respond, with median survival typically being 2 years or less. Despite their overall low response rate, however, some patients clearly benefit from treatment with IL-2 and IFN-α. Partial responses, defined as a ≥50% reduction in the sum of the products of maximal perpendicular diameters of all measurable metastatic lesions, occur in approximately 15% of patients treated with either IL-2 or IFN-α (see Table 5-4). Although partial responses can be associated with significant disease palliation, longterm survival in partial responders is a rare event. Among patients who achieve a complete response (defined as the complete disappearance of all evidence of metastatic disease for at least 1 month) to high-dose IL2 therapy, 60% to 90% remain alive and free of disease for 8–10 years after treatment. In contrast, virtually no evidence exists of long-term survival following IFNbased therapy (see Table 5-4). It is, therefore, not surprising that many urologists and oncologists consider high-dose IL-2 to be superior to IFN-α in the treatment of metastatic RCC. Nonetheless, many oncologists continue to treat metastatic RCC patients with IFN-α, largely due to concerns regarding the substantial toxicities associated with high-dose IL-2. Toxicities associated with high-dose IL-2 therapy are primarily the consequence of a cascade of cytokines being released from circulating leukocytes following drug exposure. This cytokine shower can significantly increase capillary permeability, leading to dramatic fluid shifts, reduced peripheral vascular resistance, and sometimes profound hypotension, renal failure, and pulmonary edema. The severity of these symptoms is dose dependent. Toxicities related to IFN therapy are also dose and schedule dependent, and include primarily

85 93 86 93 75 87 82 79 100 100 92 52 86

References Fisher et al.17 Yang et al.18 Dutcher et al.19 Yang et al.18 McDermott et al.21 Dutcher et al.22 Rogers et al.23 Negrier et al.24 Mickisch et al.25 Flanigan et al.26 Negrier et al.27 Motzer et al.29 Gleave et al.30*

Subcutaneous IL-2

Subcutaneous IL-2/IFN-α

91

145

147

92

42

70

33

47

94

150

71

156

255

N

12

15

13

11.1

17

13

10

20

NA

18

15.5

18

16.3

Median Survival (Months)

1

6

5

3

7

2

9

13

10

9

11

14

8

PR (%)

3

1

1

0

12

0

0

4

2

4

7

7

7

CR (%)

No long-term data available

No long term data available

One CR alive, NED at 10 years28

Not applicable—no CRs


Not applicable—no CRs


One CR alive at 49 (+) months


50% of CRs alive, NED at median 10.1 years

90% of CRs alive, NED at >8 years20

73% of CRs alive, NED at median 9.3 years

>60% of CRs alive, NED at 10 years

Long-Term Survival of CRs

IL-2, interleukin-2; IFN-α, interferon-alpha; RCC, renal cell carcinoma; N, number of patients; CR, complete response; PR, partial response; IV, intravenous; mos., months; NED, no evidence of disease; NA, not available. Note: No treatment-related mortalities were experienced in any of the above studies, except for Fisher et al.17, in which 4% of patients receiving high-dose IL-2 died of treatment-related complications. *IFN-γ rather than IFN-α was used in this study.

Subcutaneous IFN

High-dose IV IL-2

Prior Nephrectomy (%)

Table 5-4 Treatment with Il-2 or IFN-α in Metastatic Clear Cell RCC

90 Part I Principles of Urologic Oncology


hematologic effects (i.e., bone marrow suppression and cytopenias) and flu-like symptoms.13,15,25 A large preliminary series of patients given high-dose IL-2 at the National Cancer Institute reported a 4% treatmentrelated mortality rate.17 Because this mortality rate approached the complete response rate with high-dose IL-2, many oncologists still consider it unacceptable to have one regimen-related death for every patient cured with this therapy. Since its initial use, the mortality rate related to highdose IL-2 therapy has dropped dramatically at the National Cancer Institute, with no deaths among the last 800+ patients treated. This improvement in outcome is likely multi-factorial, owing to alterations in eligibility criteria, the treatment regimen, and improvements in supportive care.31 Other groups similarly contend that high-dose IL-2 can be given safely when patients are carefully selected and treatment is given in a wellmonitored setting.32,33 Despite improvements in morbidity related to highdose IL-2 therapy, there has been considerable interest in the development of low-dose IL-2 regimens in the hope of reducing drug-related complications. A randomized study comparing high-dose versus low-dose IL-2 in the setting of metastatic RCC has recently been completed.18 The vast majority of patients enrolled on this trial (93%) had previously undergone cytoreductive nephrectomy. Although no regimen-related mortalities occurred in this study, toxicities were greater in the high-dose IL-2 arm compared to the low-dose IL-2 arm, especially in terms of clinically significant hypotensive episodes (36.4% versus 2.9%, respectively). The overall response rate (CR + PR) was higher in the high-dose versus the low-dose arm (21% versus 13%, p = 0.048). Importantly, the durability of responses among complete responders was superior in the high-dose arm (73% disease-free + an additional 18%

disease-free following a resection of limited recurrent disease = total 91% alive and disease-free at a median of 9.3 years) compared to the low-dose arm (50% alive and disease-free at a median of 10.1 years) (Figure 5-1A). However, no difference in overall survival was observed between the high-dose and low-dose cohorts (Figure 5-1B), again reflecting the unfortunate fact that complete responders to any form of IL-2 therapy are in the significant minority. Another prospective randomized study compared lowdose intravenous IL-2 (group 1) versus subcutaneous IFN-α-2a (group 2) versus both drugs combined (group 3) in patients with metastatic RCC.27 A total of 425 patients were randomized between 1992 and 1995 into one of three treatment groups. As with the previous trial, the majority of patients (>90%) enrolled in the study had undergone a prior nephrectomy. Toxicities were most evident among those receiving IL-2 (groups 1 and 3), including 67% who became hypotensive and 50% who experienced high fevers. Importantly, all patients ultimately recovered from these adverse events and returned to their pretreatment status. Response rates were 6.5%, 7.5%, and 18.6% (p < 0.01) for patients receiving IL-2, IFN-α-2a, and IL-2 plus IFN-α-2a, respectively. Although the response rate was higher among those receiving both IL-2 and IFN-α, no longterm survival benefit was observed in this group (Figure 5-2). Biochemotherapy is another field of research wherein chemotherapeutic drugs are administered concomitant with biologic agents, such as IL-2, in hopes of improving therapeutic indices. 5-Flurouracil (5-FU) has been the most widely used chemotherapeutic agent that has been combined with cytokines in the setting of advanced RCC, with response rates up to 30% in several small studies. However, the vast majority of responses are par-

1.0

1.0

0.7 0.6 0.5 Low dose

0.4 0.3

p2 = 0.04

0.2

0.8 0.7 0.5 0.4 0.3 0.1 0.0

24

36

48

60

72

84

Survival time in months

96 108 120 132

High dose (fail/total = 117/155)

0.2

0.0 12

High-dose versus low-dose (p = 0.41)

0.6

0.1 0

A

0.9

High dose

0.8

Proportion surviving

Proportion surviving

0.9

Low dose (fail/total = 121/150) 0

B

12

24

36

48

60

72

84

Survival time in months

Figure 5-1 A, Disease-free survival in patients achieving a complete response with high-dose or low-dose IL-2. B, Survival by treatment received—high-dose or low-dose IL-2. (From Yang JC, Sherry RM, Steinberg SM, et al: J Clin Oncol 2003; 21(16): 3127-3132, with permission.)

96 108 120 132

92


Overall survival (%)

100

Interferon alfa-2a

90

Interleukin-2 + interferon alfa-2a

80

Interleukin-2

70 60 50 40 30 20 10 0 0

6

12

18

24

30

36

Months after randomization Kaplan-Meier curves for overall survival among patients in the three treatment groups. Tick marks represent censored data on patiients who were alive or lost to follow-up. The results shown are from an intention-to-treat analysis. p = 0.55 for the comparison among the groups.

Figure 5-2 Overall survival in patients treated with IFN-α-2a with or without IL-2. (Based on Negrier S, Escudier B, Lasset C, et al: N Engl J Med 1998; 338(18):1272–1278, with permission.)

tial only, with no data supporting long-term disease-free survival using this approach.34 Reactive oxygen species (ROS) are released by tumor infiltrating monocytes and macrophages and inhibit cytokine-stimulated lymphocytes. Histamine dihydrochloride is a biogenic amine that inhibits the formation of ROS and has been used in clinical trials as an adjuvant to IL-2 and IFN-α with a view to reducing oxidative inhibition of lymphocytes.35 Although clinical efficacy has been observed in melanoma patients,36 no benefit has yet been observed in the setting of advanced RCC.37 Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a trans-membrane protein expressed on immune cells that plays a primary role in natural killer cell-mediated tumor surveillance. Based on its high specificity and cytotoxicity against tumor cells in vitro, TRAIL remains as an active area of research.38–40 Intravesical Interferon Therapy for the Treatment of Superficial Bladder Cancer Intravesical IFN-α is currently being evaluated as an immunotherapeutic agent in patients with superficial bladder cancer. Interim results from a national multicenter phase II trial of combination Bacille Calmette-Guerin (BCG) plus IFN-α-2b suggest that this agent has biologic activity in this setting.41 A total of 337 patients who could be evaluated with moderate to high-risk superficial tumors (BCG naïve = 206 patients, BCG failures = 131 patients) received induction, followed by maintenance courses of BCG + IFN-α. At a median follow-up of 24 months, the simple tumor recurrence rates were 35% for

BCG-naïve patients and 53% for BCG-failure patients. Kaplan– Meier estimates for freedom-from-disease were 71% and 61% for BCG-naïve patients and 53% and 40% for BCG-failure patients at 1 and 2 years, respectively. The toxicity-related premature dropout rate among BCG-naïve patients was 3.7% and among BCG-failure patients was 7.3%. This multicenter trial substantiates the earlier encouraging reports of the efficacy of combination BCG + IFN as upfront and salvage therapy for patients with moderate to high-risk superficial bladder cancer.41–43 Longer follow-up will be needed to define the ultimate role this cytokine will play in the treatment of superficial bladder cancer. Colony-Stimulating Factors Both granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) are recombinant cytokines that stimulate the bone marrow to increase production of neutrophils, monocytes, eosinophils, and dendritic cells. Both cytokines are used clinically to speed recovery from chemotherapy-induced neutropenia. Because GM-CSF also has immunomodulatory effects (Table 5-5),13,44 investigators have explored whether this agent has immunotherapeutic activity in RCC patients. Unfortunately, to date no significant clinical benefits have been attributable to this cytokine.45–48 BACILLE CALMETTE-GUERIN Intravesical BCG for bladder cancer represents one of the most clinically successful applications of nonspecific


Table 5-5 Effects of GM-CSF Activates macrophages, monocytes, and dendritic cells Enhances tumoricidal activity of macrophages and monocytes against tumor Upregulates macrophage antigen presentation Increases macrophage production of angiogenesis-inhibitor Enhances antibody-dependent cellular toxicity Chemotactic for monocytes and polymorphonuclear cells GM-CSF, granulocyte-macrophage colony-stimulating factor.

immunotherapy. The immunologic events associated with the BCG-induced antitumor responses are not well understood, however, it is clear that stimulation of T lymphocytes with subsequent T-cell cytokine secretion are downstream effects of BCG that are critical to its antitumor activity.49–51 The clinical results of intravesical BCG as treatment for patients with superficial bladder cancer are discussed in detail in Chapter 18. ADOPTIVE CELLULAR THERAPY Lymphokine-Activated Killer Cells Lymphokine-activated killer (LAK) cells are generated ex vivo by collecting circulating lymphocytes by large volume of lymphocytapheresis and incubating them in IL-2rich media for several days (Figure 5-3A). Although LAK cells have shown dramatic MHC class I nonrestricted cytotoxicity against RCC and other tumor cells in vitro, their clinical value in humans is questionable, as two phase III randomized trials failed to demonstrate a survival advantage in metastatic RCC patients treated with LAK cells + high-dose IL-2 compared to those who received high-dose IL-2 alone.52,53 Tumor-Infiltrating Lymphocytes Tumor-infiltrating lymphocytes (TILs) are lymphocytes (T cells + NK cells) that are extracted from fresh tumor specimens (e.g., nephrectomies) and expanded in vitro in IL-2-rich media (see Figure 5-3B). By virtue of their having infiltrated into tumor tissue and their previously demonstrated antitumor activity in vitro (class I MHC restricted), TILs are thought to contain a population of T cells that recognize antigens specific to the tumor. Following in vitro expansion, TILs are reinfused into the patient along with other immunomodulators, such as IL-2. A trial evaluating TIL + IL-2 in patients who failed in previous IL-2-based therapy for metastatic melanoma or RCC demonstrated a 14% response rate.54 Given the historical data showing the ineffectiveness of IL-2

retreatment in patients who had previously failed IL-2, these data provided indirect evidence suggesting in vivo activity of TIL in humans. However, in a follow-up multicenter, randomized phase III trial of TILs with IL-2 in the setting of metastatic RCC, patients who received TILs + IL-2 failed to have a survival advantage or improved response rate compared to those receiving IL-2 alone (see Figure 5-3B).55 Although unselected TILs appear to be of limited benefit in patients with metastatic RCC, a recent study demonstrated significant clinical benefits when TILs, prescreened in vitro for cytotoxicity against melanoma cells, were expanded and then given back to melanoma patients following nonmyeloablative immunosuppression (see Figure 5-3C).56 It has been hypothesized that immunodepleting chemotherapy given with this regimen may have created “immunologic space” or perhaps obliterated T-suppressor cell populations, allowing for an increased in vivo expansion of melanoma-toxic TIL. HEMATOPOIETIC CELL TRANSPLANTATION Approximately 35 years ago, allogeneic hematopoietic stem cell transplantation (HCT) was devised as a method to maximize the dose of chemotherapy that could be given to patients with advanced malignancies. It was hypothesized that patients with chemotherapy-resistant tumors might benefit from “dose-intensification,” largely based on evidence showing a dose–response relationship of some neoplasms to chemotherapy. The transplantation of HLA-matched hematopoietic stem cells (the allograft) is used as a means of regenerating hematopoiesis rendered defunct as a consequence of intensive chemotherapy (the conditioning regimen). The traditional method of harvesting hematopoietic stem cells is via multiple bone marrow aspirations from the posterior iliac crest under general anesthetic. Alternatively, G-CSF, GM-CSF, or even low-dose chemotherapy, can be used to mobilize bone marrow stem cells, which are then collected from the peripheral circulation by leukapheresis. The actual bone marrow transplant involves simply infusing the allograft into one of the patient’s peripheral or central veins. The infusion of the donor allograft (referred to as “day 0”) is usually performed 1–2 days following the completion of the conditioning regimen.57 The allograft consists of not only donor hematopoietic stem cells but also immune cells (including NK, B, and T-cells) that were eradicated in the patient by the conditioning regimen. Patients typically receive immunosuppressive drugs, such as cyclosporine (CSA), or tacrolimus, for the first 3–6 months following the procedure to prevent the donor immune cells from attacking normal host tissues, such as the liver, GI tract, or skin, a complication known as graft-versus-host disease (GVHD).

Tumor infiltrating lymphocytes (TILs) extracted from renal cell carcinoma

Lymphocytes isolated from circulating blood on days 8–10 ( ) (following IL-2)

In vitro screening of TILs against melanoma cells

1 4 7 10 13 16 19 22 25 28 31

1 4 7 10 13 16 19 22 25 28 31

1 4 7 10 13 16 19 22 25 28 31

Single treatment cycle (days)

Figure 5-3 Newer methods of adoptive immunotherapy. A, LAK cells. (Based on Law TM, Motzer RJ, Mazumdar M, et al: Cancer 1995; 76(5):824–832, with permission.) B, TIL cell. (Based on Figlin RA, Thompson JA, Bukowski RM, et al: J Clin Oncol 1999; 17(8):2521–2529, with permission.) C, Tumoricidal TILs. (Based on Dudley ME, Wunderlich JR, Robbins PF, et al: Science 2002; 298(5594):850–854, with permission.)

RCC, Renal cell carcinoma.

Immunodepleting chemotherapy.

Tumor with infiltrating lymphocytes (TILs).

Lymphocyte infusion.

Tumoricidal TILs + IL-2 14 days

Unselected TILs + IL-2 ⫻ 5 days

Lymphocytes + IL-2 ⫻ 5 days

Preparation of lymphocytes

Leukapheresis (collection of lymphocytes from peripheral blood).

Intravenous IL-2.

Immunodepleting C chemotherapy + Tumor infiltrating lymphocytes (TILs) Tumoricidal extracted from melanoma tumor TILs

Tumor infiltrating B lymphocytes (TILs)

Lymphokine A activated killer cells (LAK cells)

Collection of lymphocytes

Partial response in 6/13 melanoma patients; no complete responses56

No improvement in objective response rate over IL-2-alone regimen in metastatic RCC patients52,53,55

Results

94 Part I Principles of Urologic Oncology


In conventional myeloablative HCT, the primary antitumor effect comes from the high-dose chemotherapy and/or total body irradiation (conditioning regimen) (Table 5-6). The term “myeloablative” indicates that the patient’s bone marrow is totally obliterated as a result of these highly cytotoxic interventions. It is now known that powerful antitumor effects against those malignant cells surviving high-dose conditioning are generated by donor lymphocytes transplanted with the allograft. This allogeneic immune-mediated antineoplastic effect, called graft-versus-leukemia (GVL) or graft-versus-tumor (GVT), is capable of curing patients with a variety of treatment-refractory hematologic malignancies. Knowledge of RCCs susceptibility to immune effectors has recently led investigators to test allogeneic transplantation as a form of immunotherapy in patients with metastatic RCC. Pilot trials were based on the hypothesis that GVT effects, analogous to the GVL effect seen in leukemias and lymphomas, might be generated following the transplantation of allogeneic donor T cells.58 Nonmyeloablative Hematopoietic Cell Transplantation “Mega-dose” conditioning is largely responsible for the 25% to 35% regimen-related mortality associated with traditional myeloablative HCT. The powerful and curative capacity of the GVT effect has recently brought into question the need for toxic myeloablative conditioning regimens. Reduced intensity conditioning regimens or nonmyeloablative transplants were proposed as a potentially less toxic alternative to conventional HCT. In contrast to a myeloablative HCT, the primary antitumor effect in a nonmyeloablative HCT results from the immune cells that are transferred to the patient from the immunocompetent HLA-matched donor. In this setting, the conditioning regimen serves primarily to suppress the patient’s immune system just enough to prevent host rejection of the donor allograft (see Table 5-6). Accordingly, the dose of chemotherapy and toxicities related to the conditioning regimen are less following nonmyeloablative compared to myeloablative HCT. After donor cell engraftment, the patient’s hematopoietic

cells typically contain cells from both the patient and the donor, a condition referred to as mixed chimerism (in Greek mythology, a Chimaira was a fire-spouting monster with a lion’s head, goat’s body, and serpent’s tail).59 Mixed chimerism results in a “tolerogenic state,” meaning that the immune cells that develop from the donor’s engrafted cells are unable to kill the patient’s tumor. In order for these cells to acquire antitumor activity, the hematopoietic environment needs to transition to “full donor chimerism,” in which patient’s immune system is completely replaced by donor cells. This transformation is facilitated by the withdrawal of posttransplant immunosuppression (e.g., tacrolimus or cyclosporine) and the administration of donor lymphocyte infusions.60 Nonmyeloablative HCT is capable of inducing curative GVT effects against a number of hematologic malignancies. Equally important, preliminary data show the approach is associated with a lower risk of regimen-related mortality (7.5% to 18%) compared to conventional myeloablative procedures (25% to 35%). The improved toxicity profile observed with nonmyeloablative HCT has provided the basis for exploring allogeneic immunotherapy’s potential to induce GVT effects in patients with treatment-refractory solid tumors. Recently, a few groups have published the results of pilot trials investigating nonmyeloablative HCT for the treatment of cytokinerefractory metastatic RCC. The strategy used at the National Institutes of Health involves nonmyeloablative conditioning with a cyclophosphamide and fludarabinebased regimen, intended to induce host immunosuppression, followed by infusion of a G-CSF mobilized peripheral blood stem cell graft from an HLA-identical sibling donor (Figure 5-4). Ten of the first nineteen61 and subsequently 22 of the first 55 patients undergoing this approach had evidence for a GVT effect, including 6 patients who had a complete response and 15 with a partial response. Many of the responses were durable, including the first patient treated who remains in complete remission 512 years after transplantation. GVHD was the most common complication, with approximately two-thirds of the patients experiencing acute grade II–IV GVHD. However, patients developing this complication were more likely to have a disease response than those who never developed

Table 5-6 Allogeneic Hematopoietic Cell Transplantation (HCT) Conditioning Regimen

Source of Transplanted Cells

Mechanism of Tumor Regression

Myeloablative allogeneic HCT (Conventional HCT)

High-dose chemotherapy +/− Total Body XRT

HLA-compatible donor

Conditioning regimen and graft-versus-tumor effects

Non-myeloablative HCT (“Mini-transplant”)

Low-dose chemotherapy +/− Low-dose total body XRT

HLA-compatible donor

Immune mediated via graft-versus-tumor effects

HCT, Hematopoietic cell transplantation; HLA, Human leukocyte antigen; XRT, External beam radiation therapy.

96


Transfuse donor T-cells (DLI)

Nonmyeloablative chemotherapy Transplant day –7 –6 –5 –4 –3 –2 –1

30

45

60

100

GVT effect

Transfuse the allograft

Taper dose of cyclosporine Cyclosporine DLI, Donor lymphocyte infusion; GVT, Graft-versus-tumor.

Figure 5-4 Nonmyeloablative hematopoietic cell transplantation.

GVHD.61 Disease regression was typically delayed by 4–6 months following the procedure, and occurred after cyclosporine had been tapered and after T-cell chimerism had converted to predominantly donor in origin. Despite the advanced disease status of patients enrolled on this pilot trial, transplant-related mortality was relatively low, with 6 patients succumbing to nonrelapse-related mortality. Figure 5-5 shows a clinical response following nonmyeloablative HCT in a patient with metastatic RCC that

was refractory to high-dose IL-2. Preliminary experience would suggest that certain patient and tumor characteristics herald a better outcome, such as small tumor burden, lung-only disease, slow rate of tumor growth, and good patient performance status. Several other groups have recently reported graft-versus-RCC effects following nonmyeloablative HCT. Using cyclophosphamide and fludarabine for pretransplant conditioning, investigators at the University of Chicago achieved complete donor

Prior to graft-versus-tumor effect Day 100 Posttransplant

A-1

Day 100 Posttransplant

B-1 Following graft-versus-tumor effect Day 189 Posttransplant

A-2

Day 189 Posttransplant

B-2

Figure 5-5 Clinical response following nonmyeloablative hematopoietic cell transplantation in a patient with metastatic refractory RCC.


success of antiCD20 (Rituximab) for low-grade lymphomas and antiHER-2 (Herceptin) for breast carcinoma, monoclonal antibodies (mAbs) for treating cancer remain a very active area of research. Therapeutic monoclonal antibodies were originally derived from rodents. One of the major problems with murine antibodies is their immunogenicity; the patient’s immune system recognizes them as being foreign (Figure 5-6A), leading to an antibody attack against the mouse antibody (human antimouse antibody, HAMA). This host immune response not only neutralized the therapeutic potential of foreign antibody but also occasionally caused life-threatening anaphylactoid reactions.64 Two antibody design strategies were subsequently developed to overcome this problem.64,65 Chimeric antibodies are rodent–human antibody constructs, wherein the variable (antigen binding) region is of rodent origin and the constant (effector) region is of human origin (Figure 5-6B). Humanized antibodies are antibody constructs in which rodent gene segments coding for the antigen binding loops are grafted onto human antibodies (Figure 5-6C). More recently, phage display technology and transgenic approaches have enabled the production of entirely human recombinant antibodies.64,65

engraftment in 12 of 15 metastatic RCC patients undergoing an HLA-matched sibling transplant, four of whom had a partial response. None of the patients who rejected the allograft demonstrated a disease response.62 Investigators from Milan, Italy, reported 4 of 7 patients having a disease response following a nonmyeloablative transplant that used Thiotepa and fludarabine-based conditioning regimen.63 Although these pilot results are encouraging, this approach remains experimental and should be reserved for patients with metastatic RCC who have previously failed cytokine therapy, especially considering the risk of fatal complications (mostly severe GVHD) associated with the procedure. The primary outcome of these trials has been to establish evidence of GVT effects against this malignancy. Larger trials and refinements in the transplant technique to decrease the risk of GVHD are needed to define the role transplantation will ultimately play in their management of these patients. MONOCLONAL ANTIBODIES The potential of antibodies to function as “magic bullets” for the treatment of cancer has great appeal due to their tremendous target specificity. Based on the preliminary “Naked” antibody

Chimeric antibody

Rodent constant regions (heavy, light chains)

Human constant regions (heavy, light chains)

Rodent variable region (heavy, light-chain)

Rodent variable region (heavy, light-chain)

Rodent CDR (complementarity-determining region)

Rodent CDR (complementarity-determining region)

B

A

Humanized antibody

Human constant regions (heavy, light chains) Rodent variable region (heavy, light-chain) Rodent CDR (complementarity-determining region)

C Figure 5-6 Therapeutic rodent monoclonal antibodies (mAbs). A, Naked rodent mAb. B, Chimeric rodent-human mAb. C, Humanized mAb.

98


The first two antibodies to be approved by the FDA were Rituximab, a chimeric antiCD20 monoclonal antibody for treatment of low-grade non-Hodgkin’s lymphoma, as well as Herceptin, a humanized monoclonal antibody against HER-2 for the treatment of metastatic breast cancer. Both drugs have shown individual activity in cancer patients with chemotherapy refractory tumors. Research efforts are underway to develop effective antibodies against prostate-specific membrane antigen (PSMA) in prostate cancer and G250, a cell surface antigen in RCC (clear cell type). However, besides HAMA, a number of other factors limit the efficacy of antibody therapy including their ability to mediate cell death once they have bound to their tumor target (Table 5-7).64,65 Strategies are currently being developed to overcome these barriers in hopes of enhancing antibody efficacy. One such approach

Table 5-7 Barriers to Effective Antibody Cancer Therapy Mouse antibodies are immunogenic, provoking human anti-mouse antibody (HAMA) response Difficulty in identifying antigens that are expressed on tumor cells and not on normal cells Antigen-loss on tumor cell surface Adequate delivery of antibody to tumor depends on good vascularity of tumor Short half-life of some antibodies requires repeated administrations Antibodies are usually species-specific, limiting preclinical animal toxicology studies

involves the conjugation of effector moieties to the antibody to improve tumor killing (Table 5-8).64,65 Vascular endothelial growth factor (VEGF) promotes endothelial cell proliferation and is often secreted by tumors in order to establish and/or increase their blood supply. Clear-cell RCCs often produce and secrete high levels of VEGF due to mutations in the von HippelLindau tumor suppressor gene.66–68 A recent randomized, phase II trial was conducted to assess the efficacy of Bevacizumab, an anti-VEGF humanized monoclonal antibody, in the setting of advanced clear-cell RCC.69 One-hundred and sixteen patients were randomized to receive either placebo, low-dose Bevacizumab (3 mg/kg every 2 weeks), or high-dose Bevacizumab (10 mg/kg every 2 weeks). The vast majority (>89%) had previously undergone nephrectomy and received (and failed) IL-2 therapy. At a second interim evaluation (at a median follow-up time of 27 months from study entry), the National Cancer Institute data safety and monitoring board recommended closure of accrual on the basis of the difference between the placebo and high-dose Bevacizumab in the time to progression of disease (2.5 months and 4.8 months, respectively, p < 0.001 by log-rank test). Only 4 of 116 patients had objective responses (all of which were partial responses), and all of these had received high-dose Bevacizumab. In the high-dose cohort, the response rate was 10% (4 of 39 patients). At the last analysis, there were no significant differences in overall survival between groups ( p > 0.20 for all comparisons). Bevacizumab has further demonstrated antitumor activity in preclinical studies against hormone-refractory prostate cancer70 and in a phase II randomized trial (Bevacizumab + Fluorouracil/Leucovorin versus Fluorouracil/Leucovorin) in the setting of metastatic colorectal carcinoma.71

Table 5-8 Antibody Strategies in Cancer Therapy Ab-Conjugate

Mechanism of Tumor Cell Killing

“Naked” Ab (unconjugated)

CDC, ADCC, direct antiproliferative effects, idiotype/anti-idiotype network

Ab-radioisotope

Direct radiation-induced cytotoxicity

Ab-immunotoxin

Once inside the cell, toxin irreversibly blocks an essential metabolic process

Ab-drug

Tumoricidal drug internalized by tumor cell

Ab-photosensitizer

Photosensitizer-moiety produces oxygen free radical when exposed to light

Ab-Ab (bispecific Ab’s)

Unlike direct conjugations of effector agents to a single antibody, the effector and antigen-binding domains are bound to separate, covalently-linked antibodies

Ab-enzyme, then prodrug (ADEPT)

Enzyme-Ab conjugate administered first, followed by prodrug. Enzyme converts prodrug into active cytotoxic agent at tumor site only

Ab, antibody; CDC, complement-dependent cytotoxicity; ADCC, antibody-dependent cell-mediated cytotoxicity; ADEPT, antibody-dependent enzyme-mediated cytotoxicity


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67. Mukhopadhyay D, Knebelmann B, Cohen HT, Ananth S, Sukhatme VP: The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity. Mol Cell Biol 1997; 17(9):5629–5639. 68. Folkman J, Shing Y. Angiogenesis. J Biol Chem 1992; 267(16):10931–10934. 69. Yang JC, Haworth L, Sherry RM, et al: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003; 349(5):427–434. 70. Fox WD, Higgins B, Maiese KM, et al: Antibody to vascular endothelial growth factor slows growth of an androgen-independent xenograft model of prostate cancer. Clin Cancer Res 2002; 8(10):3226–3231. 71. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003; 21(1):60–65.

C H A P T E R

6 Health-Related Quality of Life Issues in Urologic Oncology David F. Penson, M.D., M.P.H., and Mark S. Litwin, M.D., M.P.H.

The primary goal of health care providers when treating patients with urologic malignancies has traditionally been to prolong patient survival. However, as the past decade has brought new screening modalities and improvements in treatment, clinicians and researchers have begun to focus on other outcomes as well. In particular, as we have recognized that cancer and its treatment affects both quantity and quality of life in our patients, it has become clear that various components of well-being must also be addressed when treating individual patients with cancer or when conducting cancer clinical trials.1 While clinicians must still focus on “traditional” outcomes, such as 5- or 10-year survival rates, complete and partial responses, or serum tumor marker levels, the increased attention to patients’ overall well-being has generated interest in more “refined” endpoints in urologic oncology. One such endpoint is health-related quality of life (HRQOL). HRQOL encompasses a wide range of human experience, including the daily necessities of life, intrapersonal and interpersonal responses to illness, and activities associated with professional fulfillment and personal happiness.2 Importantly, HRQOL involves patients’ perceptions of their own health and ability to function in life. HRQOL is often confused with functional status. While functional status is an important dimension of HRQOL, there are numerous other aspects of HRQOL, including role function, vitality, mental health, pain, and psychosocial interactions, which are equally important. Despite the commonly held belief that this type of data cannot be easily collected, patients’ compliance with HRQOL questionnaires is usually high.3 The impact of HRQOL in clinical oncology is now considered so important that a cancer trial is considered incomplete without the inclusion of HRQOL outcomes.1,4 In this chapter, we review quality of life issues in urologic oncology. We initially review the methodology of

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HRQOL research and discuss various instruments available to assess HRQOL in genitourinary cancers. We then briefly examine the current literature regarding the effect of urologic malignancies on quality of life. Necessarily, we focus primarily on prostate cancer, as this has the largest body of literature. However, we touch on quality of life issues in bladder, kidney, and testicular cancers as well. THE METHODOLOGY OF HEALTH-RELATED QUALITY OF LIFE RESEARCH HRQOL Instruments It is difficult for the novice to understand the task of objectively quantifying quality of life, which is an inherently qualitative phenomenon.5 However, the principles of psychometric test theory 6 may be applied to produce accurate assessments of HRQOL. HRQOL data are collected using patient-centered surveys, called instruments. Instruments can be self-administered by the patient or can be administered with the assistance of a neutral thirdparty interviewer in a standardized fashion. Instruments typically contain multiple questions, or items, that are organized into scales. Each scale measures a different aspect, or domain, of HRQOL. Domains can be general or disease-specific. General HRQOL domains address the components of overall well-being, while diseasespecific domains focus on the impact of particular organic dysfunctions that affect HRQOL.7 General HRQOL domains typically address general health perceptions, sense of overall well-being, and function in the physical, emotional, and social domains. Cancer-specific HRQOL domains focus on more directly relevant domains, such as anxiety about cancer recurrence, nausea from chemotherapy, or urinary incontinence from sphincter damage.

Chapter 6 Health-Related Quality of Life Issues in Urologic Oncology 103

Creation and Testing of New Instruments

Reliability

It is ill-advised to use casually constructed instruments in HRQOL research, as this can result in inaccurate data and flawed conclusions. Therefore, before an instrument is used in a clinical setting, statistical and psychometric testing must be performed to measure the survey’s reliability and validity. Because psychometric testing is so rigorous and time-intensive, it is always preferable to use an established, validated instrument when available. Another advantage of using published instruments in the collection of HRQOL data is that they allow researchers to compare new results to previously studied populations. If an appropriate, established HRQOL instrument is not available for the disease process one is interested in studying, it may be reasonable to design a new instrument. The first step in this difficult process is to pilot test the questionnaire to ensure that the patient population can easily understand and complete the survey. Pilot testing often reveals problems that the researchers may not notice, such as the inadvertent use of medical jargon that patients do not understand (leading to unanswered questions or inaccurate responses), use of diminutive print size (causing difficulty reading the question), or unclear wording (leading patients to misunderstand the question). After pilot testing, new instruments are evaluated for the two fundamental psychometric statistical properties of reliability and validity.

Reliability refers to how reproducible the scale is. In other words, what proportion of a patient’s test score is true and what proportion is due to random variation. Several types of reliability are typically assessed. Test–retest reliability is a measure of response stability over time. It is assessed by administering scales to patients at two distinct time points, typically 1 month apart. The correlation coefficients between the two scores reflect the stability of responses. Test–retest reliability is most easily assessed when the domain of interest is unlikely to change over short periods of time. When assessing test–retest reliability, one needs to ensure that the interval between administrations is not too long, as real change can occur in the variable, artificially deflating test–retest reliability coefficients. Internal consistency reliability is a measure of the similarity of an individual’s responses across several items, indicating the homogeneity of a scale.6 The statistic used to quantify the internal consistency of a scale is called Cronbach’s coefficient alpha.8 Generally accepted standards dictate that reliability statistics measured by these two methods should exceed 0.70.9 These and various other forms of reliability are reviewed in Table 6-1. Validity Validity refers to how well the scale or instrument measures the attribute it is intended to measure. Content validity,

Table 6-1 Types of Reliability Type of Reliability

Characteristics

Comments

Test–Retest

Measures the stability of responses over time, typically in the same group of respondents

Requires the administration of survey to a sample at two different and appropriate points in time. Time points that are too far apart may produce diminished reliability estimates that reflect actual change over time in the variable of interest

Intraobserver

Measures the stability of responses over time in the same individual respondent

Requires completion of a survey by an individual at two different and appropriate points in time. Time points that are too far apart may produce diminished reliability estimates that reflect actual change over time in the variable of interest

Alternate-form

Uses differently worded stems or response sets to obtain the same information about a specific topic

Requires two items in which the wording is different but aimed at the same specific variable and at the same vocabulary level

Internal consistency

Measures how well several items in a scale vary together in a sample

Usually requires a computer to carry out calculations

Interobserver

Measures how well two or more respondents rate the same phenomenon

May be used to demonstrate reliability of a survey or may itself be the variable of interest in a study

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sometimes incorrectly referred to as face validity, is the nonquantitative assessment by experts of the scope and completeness of a proposed items and scales. It is more superficial than other types of validity, and considered by some not to be a true measure of validity at all.10 Nevertheless, it is almost always included in the early stages of instrument development, even if only as a general review of items by physicians or patients. Criterion validity requires the correlation of scale scores with other measurable health outcomes (predictive validity) and with results from other established tests (concurrent validity). For example, the predictive validity of a new HRQOL scale for bony pain in prostate cancer might be correlated with narcotic usage. Likewise, the concurrent validity of a new urinary incontinence scale in prostate or bladder cancer could be correlated with objective results on urodynamic testing. Construct validity is a measure of how meaningful the scale or survey instrument is when in practical use. It is often requires years of experience with a survey instrument to assess correctly. Often it is not calculated as a quantifiable statistic but as a gestalt of how well a survey instrument performs in a multitude of settings and populations over time. An overview of the various types of validity is presented in Table 6-2.

Many clinicians and researchers find the process and patient-centered data collection daunting and mistakenly believe that they can accurately estimate a patient’s quality of life. Numerous studies have documented that physicians tend to underestimate both the degree of symptoms and their negative effect on HRQOL.12–14 Therefore, it is usually preferable to obtain HRQOL data directly from patients; the treating physician should not attempt to estimate the patient’s HRQOL.

Collection of HRQOL Data

Established General HRQOL Instruments

In addition to using validated and reliable HRQOL instruments, clinicians and researchers must collect data in a manner that minimizes bias. For example, data regarding sexual dysfunction following radical prostatectomy should not be collected directly by the operating surgeon, as patients have an unconscious desire to produce responses that they think their physicians want to hear.11 This introduces measurement error. Therefore, it is always preferable that data be gathered by disinterested third parties or that instruments be self-administered by patients to avoid bias.

General HRQOL instruments focus on general domains of HRQOL and have been extensively researched and validated in many types of patients, including sick and well. Examples include the RAND Medical Outcomes Study 36-Item Health Survey (also known as the SF-36),16–20 the quality of well-being scale (QWB),21–25 the sickness impact profile (SIP),21,26,27 and the Nottingham health profile (NHP).21,28–31 All of these instruments assess the various general components of HRQOL, including physical and emotional functioning,

ESTABLISHED HRQOL INSTRUMENTS FOR USE WITH UROLOGIC MALIGNANCIES HRQOL instruments tend to be general or diseasespecific, depending on the domains addressed with the survey. When studying urologic cancers, it is preferable to use both general and disease-specific instruments, as disease-specific symptoms can have profound effects on both disease-specific HRQOL and patients’ general wellbeing and overall functional status. The broad effect of certain symptoms associated with urologic cancer may be overlooked if researchers do not use both general and disease-specific measures.15

Table 6-2 Types of Validity Type of Validity

Characteristics

Comments

Face

Casual review of how good an item or group of items appear

Assessed by individuals with no formal training in the subject under study

Content

Formal expert review of how good an item or series of items appear

Usually assessed by individuals with expertise in some aspect of the subject under study

Criteron: Concurrent

Measures how well the item or scale correlates with “gold standard” measures of the same variable

Requires the identification of an established, generally accepted gold standard

Criterion: Predictive

Measures how well the item or scale predicts expected future observations

Used to predict outcomes or events of significance that the item or scale might subsequently be used to predict

Construct

Theoretical measure or how meaningful a survey instrument is

Determined usually after years of experience by numerous investigators


social functioning, and symptoms and have been thoroughly validated and tested. Cancer-Specific HRQOL Instruments for Use in Urology A number of cancer-specific instruments have long been available. However, recently, many have had modules developed that are specific for urologic disease. For example, the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30)32 is a 30-item questionnaire that includes five scales (physical, role, emotional, cognitive, and social functioning), a global health scale, three symptom scales (fatigue, nausea/vomiting, and pain), and six single items concerning dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties due to disease. The EORTC QLQ-C30 can be used in patients with any type of cancer. However, a 20-item prostate cancer module has recently been developed that specifically includes a bowel symptom scale, urinary symptom scale and sexuality scale. This module has been validated and shown to be reliable in men with both localized33,34 and metastatic35 prostate cancer. Unfortunately, this instrument does not distinguish between function and bother in these domains. Another example of a cancer-specific HRQOL instrument that now has modules for various urologic malignancies is the Functional Assessment of Cancer Therapy (FACT).36–39 The main FACT instrument includes a set of 28 general items that pertain to all cancer patients (FACT-G). Each item contains a statement that a patient may agree or disagree with across a five-point Likert range. The FACT-G domains include well-being in four areas: physical, social-family, emotional, and functional. The FACT-P, a new module to measure HRQOL in men with prostate cancer, was recently validated and may prove useful in the future.40 There is also a FACT module for bladder cancer, although this has not been widely used or validated. The FACT may be accessed at http://www.facit.org/facit_questionnair.htm. HRQOL Instruments Designed Specifically for Use in Urologic Malignancies A number of instruments developed for use specifically in urologic cancers. In the past, most of the research focus has been in prostate cancer, and, therefore, there are more established instruments available for use in this malignancy. Recently, new HRQOL instruments have been developed for use in bladder and kidney cancer as well. In prostate cancer, the University of California, Los Angeles Prostate Cancer Index (UCLA PCI) was the first validated instrument specifically designed for use in this condition and has been the gold standard for measuring

prostate cancer-specific HRQOL.41,42 It is a 20-item, self-administered tool that takes about 10 minutes to complete. It is typically administered alongside the SF-36, a general HRQOL instrument.19 The 20 items of the UCLA PCI are specific for prostate cancer and comprise six scales (urinary function and bother, sexual function and bother, and bowel function and bother) from 0 to 100, with higher scores representing better outcomes. The UCLA PCI has now been used in several national and international studies and has recently been validated in Spanish.43 The UCLA PCI makes the important distinction between function and bother in the prostatespecific domains. This feature is significant because the bother experienced by patients does not necessarily correlate with the level of dysfunction.44 Although the UCLA PCI has been validated and is widely used, its focus on urinary incontinence does not attend to irritative voiding complaints. Hence, researchers at the University of Michigan developed the Expanded Prostate Cancer Index-Composite (EPIC). Building on the UCLA PCI, Wei et al.45 added 30 items to the existing disease-specific domains, for a total of 50 items. The EPIC added additional items to the three existing bother domains (urinary, sexual, and bowel), developed hormonal function and bother domains, and most importantly, expanded the urinary domain by adding items that capture irritative voiding symptoms. Therefore, the EPIC contains eight disease-specific domains: sexual function and bother, urinary function and bother, bowel function and bother, and hormonal function and bother. The urinary function domain contains two distinct subscales, urinary incontinence and urinary irritation/obstruction, each with a separate summary score. Because the disease-specific domains of the EPIC instrument include significantly more items than the original UCLA PCI, general HRQOL is typically measured using the 12-item RAND SF-1246 rather than the SF-36. HEALTH-RELATED QUALITY OF LIFE IN SPECIFIC UROLOGIC MALIGNANCIES Prostate Cancer Of all genitourinary tumors, prostate cancer is the malignancy with the largest body of HRQOL research. There are considerable data in both metastatic and localized disease because both prostate cancer and its treatment affect quality of life. In the case of metastatic prostate cancer, patients experience decrements in quality of life due to both painful bony lesions and hormone ablation therapy. Investigators have shown that as metastatic prostate cancer progresses from hormone-sensitive to hormone resistant disease, general HRQOL worsens accordingly.47 Kim et al.48 also noted that among patients

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treated for metastases, those with progressive disease appeared to have worse quality of life than those with stable disease, particularly for pain, fatigue, sleep, and physical and role functioning. Studies have shown that treatment of advanced prostate cancer improves HRQOL. Albertsen et al.35 studied metastatic prostate cancer patients in remission on LHRH agonists and flutamide and found that their general HRQOL was indistinguishable from an age-matched control population of men without prostate cancer. While treatment of advanced prostate cancer appears to improve HRQOL, at least initially, the therapy itself can negatively affect HRQOL. This is of particular concern in men who present with advanced but asymptomatic prostate cancer, as, in these patients, the tumor itself probably has little impact on HRQOL. For example, Herr and O’Sullivan49 compared patients receiving hormonal therapy to those being observed for asymptomatic advanced disease. Patients who elected to observation until the development of symptoms had better HRQOL than those who opted for early intervention. In particular, men who received early therapy experienced significantly more fatigue and hot flashes that impacted quality of life than those who delayed treatment. Other studies note similar findings. For example, Green et al.50 demonstrated that early hormone ablation therapy was associated with worse sexual function and decreased role and social functioning. However, the patients who received early hormonal therapy did report better physical function than those who received deferred management. Although not a study of metastatic prostate cancer, researchers from the Prostate Cancer Outcomes Study (PCOS)51 compared men with localized disease who received hormone ablation therapy to men with localized disease who were observed. Those who elected hormone ablation therapy reported worse sexual function and more physical discomfort. Although all of these studies were observational in nature and therefore may have been influenced by selection bias, they all underscore the potential deleterious effects of hormone therapy on HRQOL. Once patients elect to receive treatment for metastatic prostate cancer, studies demonstrate that there is little difference in HRQOL outcomes between men undergoing medical versus surgical castration. Litwin et al.52 identified no differences in any of the general or diseasespecific domains of the RAND 36 Item Health Survey (SF-36) or the UCLA Prostate Cancer Index when comparing men who underwent orchiectomy to those receiving combined androgen blockade. Although the method of castration does not appear to have a significant impact on HRQOL, the presence or absence of additional androgen blocker therapy does influence HRQOL. In a clinical trial of 739 men with stage M1 prostate cancer, patients randomized to orchiectomy plus flutamide reported significantly more diarrhea than those who were

randomized to orchiectomy plus placebo.53 However, the negative impact of androgen receptor blockade on HRQOL due to gastrointestinal side effects may be less in patients receiving bicalutamide.54 Quality of life is of particular importance to men with hormone resistant disease where the goal of therapy is often palliative in nature. A number of studies have documented that various chemotherapeutic agents improve HRQOL in men with hormone-resistant disease. For example, Osoba et al.55 assessed HRQOL in 161 men randomized to receive prednisone alone versus prednisone and mitoxantrone over a 26-week follow-up period. At 6 weeks, patients taking prednisone alone showed no improvement in HRQOL scores, whereas those taking mitoxantrone plus prednisone showed significant improvements in global quality of life ( p = 0.009) and four functional domains ( p < 0.01). In the cross-over arm of the study, the addition of mitoxantrone to prednisone after failure of prednisone alone was associated with improvements in pain, pain impact, pain relief, insomnia, and global quality of life ( p < 0.003). After 18 weeks of therapy, those receiving mitoxantrone plus prednisone continued to improve in 11 of the 14 function and symptom scales of the HRQOL measures used. This study and others56,57 demonstrate that palliative chemotherapy can lessen the physical burden of prostate cancer in men with advanced hormone-resistant disease. Although these treatments may not prolong life expectancy, a documented quality of life advantage for a given treatment will result in benefit to the patient and should be strongly considered when choosing therapies. In the case of localized prostate cancer, most of the research examining HRQOL has focused on the effect of treatment on quality of life. However, even in the case of localized disease, prostate cancer itself appears to have an effect on HRQOL. Bacon et al.58 compared general HRQOL in 783 men from the Health Professionals Follow-up Study cohort with incidental prostate cancer to 1928 age-matched controls. They found that the men with localized prostate cancer had worse general health, vitality, social function, and role limitations due to physical and emotional problems (all p values IB(82)>RP(78)

EBRT(89)*>IB(87)*>RP(76)

IB(88)*>EBRT(87)*>RP(68)

Urinary bother

RP(8%)>EBRT(10%)>IB(28%)

EBRT(83)>RP(82)>IB(75)*

EBRT(83)*>IB(77)>RP(74)

Bowel function

RP(93)>EBRT(85)*>IB(76)*,†

RP(86)>EBRT(81)*>IB(80)*

RP(86)>IB(83)†>EBRT(77)*

Bowel bother

RP(3%)>EBRT(7%)>IB(17%)

RP(86)>EBRT(78)*>IB(72)*

RP(83)>IB(79)>EBRT(72)*

Sexual function

EBRT(39)>RP(34)>IB(27)†

IB(36)*>EBRT(34)*>RP(26)

IB(32)*>EBRT(26)*>RP(18)

Sexual bother

EBRT(46%)>RP(50%)>IB(60%)

IB(54)*>EBRT(51)*>RP(43)

IB(40)*=EBRT(40)*>RP(25)

Number of subjects

Domains

Note: Treatments are ranked by mean scores from best to worst, which are presented in the parenthesis. All HRQOL scores are 0 to 100 with higher scores being better quality of life. The one exception to this is the results from the bother domains in the Wei et al. study. As these results were not presented as summary scores, the numbers in parenthesis represent the percentage of patients who reported that symptoms in the particular domain were a moderate or big problem. No statistical testing was performed on the bother domains from the Wei et al. study. External beam radiotherapy and interstitial brachytherapy were not compared statistically in the Bacon et al. study. IB, interstitial brachytherapy; EBRT, external beam radiotherapy; RP, radical prostatectomy. *Statistically significantly different from radical prostatectomy at a p-value less than 0.05. †Statistically significantly different from EBRT at a p-value less than 0.05.


In contrast, others have noted better HRQOL following continent urinary diversions, such as orthotopic neobladders. For example, Boyd et al.82 noted that selfimage was worse among patients with ileal conduits than in those with continent cutaneous Kock reservoirs, although no differences were seen in mental or emotional health indices. Dutta et al.83 compared patients undergoing orthotopic neobladder to those undergoing ileal loop following cystectomy for bladder cancer. Although the study was confounded by age and co-morbidity, the patients undergoing neobladder were found to have marginally better general HRQOL outcomes. Hardt et al.84 reported results from a prospective study of 44 patients undergoing radical cystectomy and either ileal loop (incontinent) diversion or continent diversion for bladder cancer. At 1 year after surgery, general HRQOL had returned to baseline in both groups, but general life satisfaction and social functioning were better in the continent diversion group while they were decreased following incontinent diversion. Finally, McGuire et al.85 compared HRQOL outcomes following incontinent or continent diversion and demonstrated that patients undergoing incontinent diversion had significantly decreased mental health. While these studies must all be considered preliminary, they do provide some support for the commonly held belief that continent diversions, such as orthotopic neobladders, result in better quality of life. More prospective data are needed to confirm this hypothesis. Kidney Cancer There are surprisingly few reports on HRQOL in kidney cancer patients. While a few of the reports of focused on HRQOL in patients with metastatic disease,86–89 recently a number of reports have focused on HRQOL following various surgical techniques for removal of the primary tumor. For example, Shinohara et al.90 compared HRQOL outcomes following either radical or partial nephrectomy for renal cell carcinoma. They noted that, while there were no differences in long-term survival or HRQOL, patients undergoing partial nephrectomy had better physical function in the immediate postoperative period than those undergoing radical nephrectomy. Clark et al.91 performed a similar study. While they noted no difference in overall HRQOL between partial and radical nephrectomy patients, they did find that patients with more intact renal parenchyma reported better physical health. Finally, Pace et al.92 compared HRQOL following laparoscopic or open radical nephrectomy. Again, while there were no differences in long-term general HRQOL outcomes, patients undergoing laparoscopic nephrectomy reported better HRQOL immediately postoperatively and returned to their baseline HRQOL state quicker. These studies indicate that the type of operation and the

surgical technique used appear to influence short-term HRQOL outcomes in kidney cancer. Testicular Cancer There has been minimal HRQOL research in patients treated for testis cancer. Joly et al.93 compared long-term HRQOL outcomes in testicular cancer survivors to agematched controls and found no differences. In another study, Fossa et al.94 studied HRQOL outcomes in men with good prognosis metastatic germ cell tumors. They noted that two years after treatment, 36% of patients had improved general HRQOL, while general HRQOL had deteriorated in 13% of patients. The remaining patients were effectively unchanged. Arai et al.95 used a Japanese translation of a questionnaire that had been validated in English to assess HRQOL in men treated for testicular cancer. Patients treated with chemotherapy (with or without retroperitoneal lymph node dissection), radiotherapy, and surveillance were compared. Working ability was better in the radiotherapy and chemotherapy groups. These patients also reported a greater overall satisfaction with life than those in the surveillance group. Weissbach et al.96 compared HRQOL outcomes in men undergoing retroperitoneal lymph node dissection (RPLND) or upfront chemotherapy for stage II nonseminomatous germ cell tumors as part of a prospective, multicenter clinical trial. HRQOL outcomes were similar between the two groups, leading the authors to recommend surgery for these patients, as chemotherapy could then be avoided in a considerable number of patients with little effect on quality of life. SUMMARY HRQOL is an essential outcome for patients with genitourinary malignancies. While patients are concerned with maximizing their life expectancy following a diagnosis of cancer, they are often just as concerned, if not more so, with maintaining their quality of life after treatment. Clinicians and researchers must be sensitive to this and focus more attention of the effects of therapy on cancer survivors’ quality of life. REFERENCES 1. Fayers PM, Jones DR: Measuring and analyzing quality of life in cancer clinical trials: a review. Stat Med 1983; 2:429. 2. Patrick DL, Erickson P: Assessing health-related quality of life for clinical decision-making. In Walker SR, Rosser RM (eds): Quality of Life Assessment: Key Issues in the 1990s, Chap. 19. Dordrecht, Kluwer Academic Publishers, 1993. 3. Sadura A, Pater J, Osoba D, et al: Quality of life assessment: patient compliance with questionnaire completion. J Natl Cancer Inst 1992; 84:1023.

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4. Altwein J, Ekman P, Barry M, et al: How is quality of life in prostate cancer patients influenced by modern treatment? The Wallenberg Symposium. Urology 1997; 49:66. 5. Litwin MS: Measuring health related quality of life in men with prostate cancer. J Urol 1994; 152:1882. 6. Tulsky DA: An introduction to test theory. Oncology 1990; 4:43. 7. Patrick DL, Deyo RA: Generic and disease-specific measures in assessing health care status and quality of life. Med Care 1989; 27(Suppl):S217. 8. Cronbach LJ: Coefficient alpha and the internal structure of tests. Psychometrika 1951; 16:297. 9. Nunnally JC: Psychometric Theory, 2nd edition New York, McGraw-Hill, 1978. 10. Messick S: The once and future issues of validity: assessing the meaning and consequences of measurement. In Wainer H, Braun HI (eds):Test Validity, Hillside, NJ, Lawrence Erlbaum Associates, 1988. 11. Tannock IF: Management of breast and prostate cancer: how does quality of life enter the equation? Oncology 1990; 4:149. 12. Litwin MS, Lubeck DP, Henning JM, et al: Differences in urologist and patient assessments of health related quality of life in men with prostate cancer: results of the CaPSURE database. J Urol 1998; 159:1988. 13. Bennett CL, Chapman G, Elstein AS, et al: A comparison of perspectives on prostate cancer: analysis of utility assessments of patients and physicians. Eur Urol 1997; 32:86. 14. Crawford ED, Bennett CL, Stone NN, et al: Comparison of perspectives on prostate cancer: analyses of survey data. Urology 1997; 50:366. 15. Parkerson GR Jr, Connis RT, Broadhead WE, et al: Disease-specific versus generic measurement of healthrelated quality of life in insulin-dependent diabetic patients. Med Care 1993; 31:629. 16. Tarlov AR, Ware JE Jr, Greenfield S, et al: The Medical Outcomes Study. an application of methods for monitoring the results of medical care. JAMA 1989; 262:925. 17. Ware JE, Sherbourne CD, Davies AR: Developing and testing the MOS 20-item short-form health survey: a general population application. In Stewart AL, Ware JE (eds): Measuring Functioning and Well-Being: The Medical Outcomes Study Approach, Durham, NC, Duke University Press, 1992 18. Stewart AL, Hays RD, Ware JE: The MOS short-form general health survey: reliability and validity in a patient population. Med Care 1988; 26:724. 19. Ware JE Jr, Sherbourne CD: The MOS 36-item shortform health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992; 30:473. 20. McHorney CA, Ware JE Jr, Rogers W, et al: The validity and relative precision of MOS short- and long-form health status scales and Dartmouth COOP charts. Results from the Medical Outcomes Study. Med Care 1992; 30:MS253. 21. McDowell I, Ewell C: Measuring Health: A Guide to Rating Scales and Questionnaires. New York, Oxford University Press, 1987.

22. Kaplan RM, Bush JW, Berry CC: Health status: types of validity and the index of well-being. Health Ser Res 1976; 11:478. 23. Kaplan RM, Bush JW: Health-related quality of life measurement for evaluation research and policy analysis. Health Psychol 1982; 1:61. 24. Kaplan RM, Anderson JP: A general health policy model: update and applications. Health Ser Res 1988; 23. 25. Hays RM, Shapiro MF: An overview of generic healthrelated quality of life measures for HIV research. Quality Life Res 1992; 1: 91-97. 26. Deyo RA, Inui TS, Leininger JD, et al: Measuring functional outcomes in chronic disease: a comparison of traditional scales and a self-administered health status questionnaire in patients with rheumatoid arthritis. Med Care 1983; 21:180. 27. Bergner M, Bobbitt RA, Carter WB, et al: The sickness impact profile: development and final revision of a health status measure. Med Care 1981; 19:787. 28. Moinpour CM, Feigl P, Metch B, et al: Quality of life end points in cancer clinical trials: review and recommendations. J Natl Cancer Inst 1989; 81:485. 29. Hunt SM, McEwen J, McKenna SP: Measuring health status: a new tool for clinicians and epidemiologists. J Royal College General Practitioners 1985; 35:185. 30. McDowell IW, Martini CJM, Waugh W: A method for self-assessment of disability before and after hip replacement operations. Br Med 1978; J2:57. 31. Martini CJ, McDowell I: Health status: patient and physician judgements. Health Ser Res 1976; 11:508. 32. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and the treatment of Cancer QLQ-C30: a quality of life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; 85:356. 33. Borghede G, Sullivan M: Measurement of quality of life in localized prostatic cancer patients treated with radiotherapy. Development of a prostate cancer-specific module supplementing the EORTC QLQ-C30. Quality Life Res 1996; 5:212. 34. Borghede G, Karlsson J, Sullivan M: Quality of life in patients with prostatic cancer: results from a Swedish population study. J Urol 1997; 158:1477. 35. Albertsen PC, Aaronson NK, Muller MJ, et al: Healthrelated quality of life among patients with metastatic prostate cancer. Urology 1997; 49:207. 36. Cella DF, Tulsky DS: Measuring quality of life today. Oncology 1990; 4:29. 37. Tulsky DS, Cella DF, Bonomi A, et al: Development and validation of new quality of life measures for patients with cancer. Proc Soc Behav Med 0990; 11:45. 38. Cella DF, Cherin EA: Quality of life during and after cancer treatment. Compreh Therapy 1988; 14:68. 39. Cella DF, Orofiamma B, Holland JC, et al: Relationship of psychological distress, extent of disease, and performance status in patients with lung cancer. Cancer 1987; 60:239. 40. Esper P, Mo F, Chodak G, et al: Measuring quality of life in men with prostate cancer using the functional assessment of cancer therapy-prostate instrument. Urology 1997; 50:920.

Chapter 6 Health-Related Quality of Life Issues in Urologic Oncology 111 41. Litwin MS, Hays RD, Fink A, et al: Quality-of-life outcomes in men treated for localized prostate cancer. JAMA 1995; 273:129. 42. Litwin MS, Hays RD, Fink A, et al: The UCLA Prostate Cancer Index: development, reliability, and validity of a health-related quality of life measure. Med Care 1998; 36:1002. 43. Krongrad A, Perczek RE, Burke MA, et al: Reliability of Spanish translations of select urological quality of life instruments. J Urol 1997; 158:493. 44. Litwin MS, Fink A, Hays RD, et al: Quality of life in men with prostate cancer: a pilot study. J Urol 1993; 149:494A. 45. Wei JT, Dunn RL, Litwin MS, et al: Development and validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer. Urology 2000; 56:899. 46. Ware J Jr, Kosinski M, Keller SD: A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care 1996; 34:220. 47. Curran D, Fossa S, Aaronson N, et al: Baseline quality of life of patients with advanced prostate cancer. European Organization for Research and Treatment of Cancer (EORTC), Genito-Urinary Tract Cancer Cooperative Group (GUT-CCG). Eur J Cancer 1997; 33:1809. 48. Kim SP, Bennett CL, Chan C, et al: QOL and outcomes research in prostate cancer patients with low socioeconomic status. Oncology 1999; 13:823. 49. Herr HW, O’Sullivan M: Quality of life of asymptomatic men with nonmetastatic prostate cancer on androgen deprivation therapy. J Urol 2000; 163:1743. 50. Green HJ, Pakenham KI, Headley BC, et al: Coping and health-related quality of life in men with prostate cancer randomly assigned to hormonal medication or close monitoring. Psychooncology 2001; 11:401. 51. 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. 52. Litwin MS, Shpall AI, Dorey F, et al: Quality-of-life outcomes in long-term survivors of advanced prostate cancer. Am J Clin Oncol 1998; 21:327. 53. Moinpour CM, Savage MJ, Troxel A, et al: Quality of life in advanced prostate cancer: results of a randomized therapeutic trial [see comments]. J Natl Cancer Inst 0998; 90:1537. 54. Tyrrell CJ: Tolerability and quality of life aspects with the anti-androgen Casodex (ICI 176,334) as monotherapy for prostate cancer. International Casodex Investigators. Eur Urol 1994; 26:15. 55. 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 [see comments]. J Clin Oncol 1999; 17:1654. 56. 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. 57. Turner SL, Gruenewald S, Spry N, et al: Less pain does equal better quality of life following strontium-89 therapy for metastatic prostate cancer. Br J Cancer 2001; 84:297.

58. Bacon CG, Giovannucci E, Testa M, et al: The association of treatment-related symptoms with qualityof-life outcomes for localized prostate carcinoma patients. Cancer 2002; 94:862. 59. Penson DF, Feng Z, Kuniyuki A, et al: General quality of life 2 years following treatment for prostate cancer: what influences outcomes? Results from the Prostate Cancer Outcomes Study. J Clin Oncol 2003; 21:1147. 60. Steineck G, Helgesen F, Adolfsson J, et al: Quality of life after radical prostatectomy or watchful waiting. N Engl J Med 2002; 347:790. 61. 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. 62. Steiner MS: Current results and patient selection for nerve-sparing radical retropubic prostatectomy. Semin Urologic Oncol 1995; 13:204. 63. Kao T, Cruess D, Garner D, et al: Multicenter patient self-reporting questionnaire on impotence, incontinence and stricture after radical prostectomy. J Urol 2000; 163:858. 64. Murphy G, Mettlin C, Menck H, et al: National patterns of prostate cancer treatment by radical prostatectomy: results of a survey by the American College of Surgeons Commission on Cancer. J Urol 1994; 152:1817. 65. Fransson P, Widmark A: Late side effects unchanged 4–8 years after radiotherapy for prostate carcinoma: a comparison with age-matched controls. Cancer 1999; 85:678. 66. Franklin CI, Parker CA, Morton KM: Late effects of radiation therapy for prostate carcinoma: the patient’s perspective of bladder, bowel and sexual morbidity. Australas Radiol 1998; 42:58. 67. Crook J, Esche B, Futter N: Effect of pelvic radiotherapy for prostate cancer on bowel, bladder, and sexual function: the patient’s perspective. Urology 1996; 47:387. 68. 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 age-matched control population. Cancer 1994; 74:2520. 69. Mantz CA, Nautiyal J, Awan A, et al: Potency preservation following conformal radiotherapy for localized prostate cancer: impact of neoadjuvant androgen blockade, treatment technique, and patientrelated factors [see comments]. Cancer J Scientific Am 1999; 5:230. 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 Radiation Oncol Biol Phys 2000; 46:77. 71. 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. 72. Arterbery VE, Frazier A, Dalmia P, et al: Quality of life after permanent prostate implant. Semin Surg Oncol 1997; 13:461.

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73. 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. 74. Brandeis J, Litwin M, Burnison C, et al: Quality of life outcomes after brachytherapy for early stage prostate cancer. J Urol 2000; 163:851. 75. 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. 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; 166:962. 77. 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. 78. Bjerre BD, Johansen C, Steven K: Health-related quality of life after cystectomy: bladder substitution compared with ileal conduit diversion. A questionnaire survey. Br J Urol 1995; 75:200. 79. Hunt Raleigh ED, Berry M, Montie JE: A comparison of adjustments to urinary diversions: a pilot study. JWOCN 1995; 22:58. 80. Hara I, Miyake H, Hara S, et al: Health-related quality of life after radical cystectomy for bladder cancer: a comparison of ileal conduit and orthotopic bladder replacement. Br J Urol Int 2002; 89:10. 81. Fujisawa M, Isotani S, Gotoh A, et al: Health-related quality of life with orthotopic neobladder versus ileal conduit according to the SF-36 survey. Urology 2000; 55:862. 82. Boyd S, Feinberg SM, Skinner DG, et al: Quality of life survey of urinary diversion patients: comparison of ileal conduits versus continent Kock ileal reservoirs. J Urol 1987; 138:1386. 83. Dutta SC, Chang SC, Coffey CS, et al: Health related quality of life assessment after radical cystectomy: comparison of ileal conduit with continent orthotopic neobladder. J Urol 2002; 168:164. 84. Hardt J, Filipas D, Hohenfellner R, et al: Quality of life in patients with bladder carcinoma after cystectomy: first results of a prospective study. Quality Life Res 2000; 9:1. 85. McGuire MS, Grimaldi G, Grotas J, et al: The type of urinary diversion after radical cystectomy significantly

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impacts on the patient’s quality of life. Ann Surg Oncol 2000; 7:4. Litwin MS, Fine JT, Dorey F, et al: Health related quality of life outcomes in patients treated for metastatic kidney cancer: a pilot study. J Urol 1997; 157:1608. Kroger MJ, Menzel T, Gschwend JE, et al: Life quality of patients with metastatic renal cell carcinoma and chemoimmunotherapy–a pilot study. Anticancer Res 1999; 19:1553. Heinzer H, Mir TS, Huland E, et al: Subjective and objective prospective, long-term analysis of quality of life during inhaled interleukin-2 immunotherapy. J Clin Oncol 1999; 17:3612. Osband ME, Lavin PT, Babayan RK, et al: Effect of autolymphocyte therapy on survival and quality of life in patients with metastatic renal-cell carcinoma. Lancet 1990; 335:994. Shinohara N, Harabayashi T, Sato S, et al: Impact of nephron-sparing surgery on quality of life in patients with localized renal cell carcinoma. Eur Urol 2001; 39:114. Clark PE, Schover LR, Uzzo RG, et al: Quality of life and psychological adaptation after surgical treatment for localized renal cell carcinoma: impact of the amount of remaining renal tissue. Urology 2001; 57:252. Pace KT, Dyer SJ, Stewart RJ, et al: Health-related quality of life after laparoscopic and open nephrectomy. Surg Endosc 2003; 17:143. Joly F, Heron JF, Kalusinski L, et al: Quality of life in long-term survivors of testicular cancer: a populationbased case-control study. J Clin Oncol 2002; 20:73. Fossa SD, De Wit R, Roberts JT, et al: Quality of Life in Good Prognosis Patients With Metastatic Germ Cell Cancer: A Prospective Study of the European Organization for Research and Treatment of Cancer Genitourinary Group/Medical Research Council Testicular Cancer Study Group (30941/TE20). J Clin Oncol 2003; 21:1107. Arai Y, Kawakita M, Hida S, et al: Psychosocial aspects in long-term survivors of testicular cancer. J Urol 1996; 155:574. Weissbach L, Bussar-Maatz R, Flechtner H, et al: RPLND or primary chemotherapy in clinical stage IIA/B nonseminomatous germ cell tumors? Results of a prospective multicenter trial including quality of life assessment. Eur Urol 2000; 37:582.

C H A P T E R

7 Image-Guided Minimally Invasive Therapy Agnieszka Szot Barnes, M.D., M.S., and Clare M.C. Tempany, M.B., B.A.O., B.Ch.

The field of image-guided minimally invasive procedures has undergone a revolutionary change in the past decade. We have seen the development of advanced imageguided therapies for treatment of many different diseases, ranging from brain tumor resection and treatment to magnetic resonance (MR)-guided prostate brachytherapy and MR-monitored thermal therapies, such as cryotherapy. In the field of urologic oncology, today there are many image-guided procedures for obtaining diagnoses and guiding and delivering treatment. These range from simple biopsies to image-guided tumor ablations. Minimally invasive therapy is used to treat the disease by operating through natural body openings or small incisions, thereby reducing the cosmetic or loco-regional tissue damage and the potential complications of open surgery. By reducing the need for invasive surgery, hospitalization is shortened, with fewer complications and faster recovery. These procedures have been allowed by the development of improved surgical techniques and, perhaps more importantly, improved imaging techniques. Because direct visualization without surgical intervention is not possible, the ability to combine multiple imaging modalities to plan and execute the surgery has permitted the full use of the new surgical techniques. This combination of imaging and therapy is known as image-guided therapy (IGT). The purpose of IGT is to integrate the anatomic and physiologic information acquired before treatment with the therapy methods and allow the control and guidance of the treatment while it is being performed to improve the accuracy of treatment delivery. Not only can imageguidance improve targeting of cancer tissue during therapy but it can also spare adjacent tissues and organs from being damaged during treatment. IGT is a multidisciplinary field in which surgeons, radiologists, oncologists,

and computer experts combine efforts to integrate imaging systems with therapy systems. Image-guided minimally invasive therapy is experiencing rapid growth driven by the introduction of new imaging modalities and significant improvement of existing ones as well as improving computer performance. The most important advancements of this field include integrating preprocedure and intraprocedure imaging, further improving image quality, and testing the usability of the techniques in clinical settings. HISTORY IGT evolved over the years with major advances in imageguided neurosurgery spreading to other disciplines, including urologic oncology. In many cases, brain tumors may visually resemble healthy tissue to the naked eye or the extent of tumor invasion may be obscured by overlying healthy tissue. Before image guidance the procedures were performed without proper visualization of the extent of the tumor or its specific geometry. In the past decade or so, MR imaging (MRI) and computed tomography (CT) techniques have improved enormously. We have seen rapid MR scanners with high field strengths become standard clinical tools in many radiology departments around the world. New multidetector CT scanners allow rapid acquisition of high-resolution CT data sets that can now be reconstructed in coronal or sagittal planes. As the technology has advanced, the impact of the image data has expanded. Now imaging alone diagnoses nearly all renal cell carcinomas. Imaging alone stages the extent of vascular invasion by a renal cell tumor and plans the surgical approach. Three-dimensional (3D) reconstructions allow the surgeon to determine the feasibility of a partial nephrectomy.

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The imaging of solid organs, both to identify pathology and to accurately locate critical structures, has become the province of x-ray CT and MRI. CT has been used primarily for guiding biopsies, although the advent of “CT fluoroscopy” has stimulated use in guiding interventional procedures, such as radiofrequency (RF) ablation. Intraoperative ultrasound (US) has been used with increasing success for many decades, particularly in the imaging of solid organs, which can be directly contacted by the probe, giving both excellent imagery and explicit orientation of the image. US is particularly useful in observing vascular structures, which are both important landmarks and vital structures to be avoided during the resection of solid organs. Laparoscopic US shares the imaging advantages of intraoperative use, but due to the small size of the imaging head and the offset required for endoscopic insertion, it could be more difficult to interpret the content and orientation of the images. The penetration of real-time CT and MRI into the broad range of surgical procedures has been slow, due to the complexity and cost of their implementation and difficult access to the patient. In the case of MRI, additional obstacles have been the incompatibility of surgical tools, devices and operating room equipment with the magnetic field environment and the challenge of interpreting the MR image, which may require extensive training and/or expert consultation. The attractiveness of MRI for guiding simple procedures, such as biopsies, was recognized as early as the mid-1980s. Many of the initial obstacles of real-time MRI guidance were overcome when an open MR scanner was introduced to guide neurosurgical procedures in Brigham and Women’s Hospital in Boston in December 1993. This new revolutionary method was envisioned by Dr. Ferenc Jolesz—radiologist and neurosurgeon—in 1987 when he began to put together a team of collaborators to create the “operating room of the future.”1 The 0.5 T intraoperative MR scanner was designed by GE Medical Systems (Signa SP) and installed in a designated MR therapy (MRT) suite.2 The scanner has a vertical gap that allows the physician to enter between the two magnets and makes it easy to access the patient to perform treatment (Figure 7-1). Images are generated using fast sequences resulting in near real-time imaging without disruption of the procedure. Initially, the scanner was used to guide percutaneous or transcranial biopsies but currently it is utilized in a variety of procedures from neurosurgery to prostate brachytherapy and biopsy. Since then, many other open configuration magnets have been introduced, including 0.2 T vertical-type magnets (Picker, Siemens) and shorter-bore magnets (Philips, Picker). Conventional 1.5 T magnets are also used to guide various procedures. The main disadvantage of

Figure 7-1 Open 0.5 T MR system for performing imageguided procedures.

these scanners is the difficulty they pose to accessing the patient during the procedure, while their main advantage is higher field strength and therefore better image quality. In the field of urology, IGT has advanced significantly from lithotripsy—shockwave removal of kidney stones under US or fluoroscopy guidance—to MR-guided procedures. While fluoroscopy remains a very popular method of image guidance in urology, it can expose both the patient and the physician to radiation. The advances in CT imaging made it possible to perform CT fluoroscopy in real time. These advances, including 3D reconstruction, play a large role in the guidance of urologic procedures, including CT-guided tumor ablations and CT-guided prostate brachytherapy and biopsy. Ultrasound guidance still remains very popular in clinical urology mainly because of its lower cost and portability, the possibility of real-time imaging, and the safety for both patient and urologist. Currently, many centers successfully use transrectal US (TRUS) to guide prostate biopsies and brachytherapy. MR has unique assets as a guidance modality, allowing not only target identification but also therapy monitoring. This is best illustrated by MR-guided focused ultrasound (MRgFUS). Finally, advances in MR imaging include image reconstruction in multiple planes, a higher signal-to-noise ratio that allows excellent differentiation between tissues, and new contrast agents to make feasible MRguided diagnostic techniques, such as MR angiography and MR spectroscopy. The creation of open interventional MR also made MR guidance possible for several urologic procedures, including prostate brachytherapy and biopsy.3

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OVERVIEW OF CURRENT MR-GUIDED IMAGE-GUIDED THERAPY APPLICATIONS The field of MR imaging for guiding interventions and therapy is attracting considerable research attention. MRI is superior to any other method in brain tumor localization and assessment and therefore is an excellent method for surgical guidance. Tumor margins and extent can be well defined, which in turn provides the possibility of complete tumor eradication with minimal damage to healthy brain tissue. MR-guidance for neurosurgery provides substantial help in performing brain tumor surgery.3 The use of computerized navigation and 3D modeling further enhances precise tumor resection. These improvements in MR-guided neurosurgery techniques, including 3D modeling, have provided a framework for an MR-guided prostate intervention program guiding prostate cancer therapy with interstitial brachytherapy—the permanent placement of radioactive sources (commonly I-125) directly into the prostate. Prostate MRI, especially with combined endorectal and phase-array coils, provides images of even higher resolution and is used in prostate cancer staging, as well as in determination of extraprostatic disease with up to 82% accuracy.5,6 The T1- and T2-weighted images are helpful in differentiating between postbiopsy hemorrhage, which presents as a high T1 and a low T2 lesion, and prostate cancer, which presents as a low T1 and a low T2 lesion. Contrast-enhanced images and prostate spectroscopy are of great importance in distinguishing between normal and cancerous tissues. Bladder and prostate cancers may experience higher perfusion than does normal tissue, which is detected as signal enhancement following intravenous

injection of MR contrast agents (such as GadoliniumDTPA); relative peak enhancement, time to peak, and washout are of great importance in distinguishing and characterizing cancer.7–9 Added value comes from spectroscopy, where metabolic differences can distinguish between cancer and healthy tissues. Normal prostate metabolism is characterized by high citrate and low choline/creatinine levels, whereas in cancerous tissue these ratios are reversed.10 Prostate multivoxel spectra conveying metabolic information are superimposed on endorectal and multiphase-array MR anatomic images, allowing for precise localization of the tumor. Prostate imaging is now moving towards use of higher-field 3 T scanners, which provide images with higher signal-to-noise ratio, which in turn allow for better visualization of prostatic substructures and increased MR-spectroscopy resolution. The development of an interventional MR therapy (MRT) system has made it possible to perform prostate brachytherapy under MR guidance. Even at lower field strength than is routinely used for prostate cancer imaging (0.5 T versus 1.5 T), MRI provides images of good quality for target visualization, as well as identification of the urethra and rectum (see Figure 7-2 for comparison of 1.5 T and 0.5 T images). Computer software has been developed to provide dosimetry analysis, used for both treatment planning and monitoring based on intraoperative MR images.11 Image-processing methods adapted from brain surgery are available to further facilitate precise radiation delivery to the prostate gland while sparing surrounding tissues. Currently, treatment delivery with a robot assistance system is being developed and tested to improve radioactive seed placement.

Figure 7-2 Prostate gland segmentation and registration. Segmentation identifies PZ (solid arrow) and central gland (hollow arrow) in pre-therapy endorectal coil MR (1.5 T, left) and MR-guided therapy images 0.5 T, right). Registration matches the segmented areas in the different images.

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After installation of the first interventional magnet at Brigham and Women’s hospital in 1993, several other centers were created at teaching hospitals around the country, including Stanford University and the University of Mississippi. Since then the number of centers has grown and now includes many more sites in the U.S. and overseas. A great strength of MRI lies in its sensitivity to temperature changes.12–14 This sensitivity allows specialists to monitor in real-time the delivery of several thermal energy treatments, including RF and laser therapy for brain tumors, and cryotherapy and high-intensity FUS for breast, prostate, liver, and uterine lesions. Currently, MRI is a very useful guidance method for cryotherapy— tumor ablation by use of freezing—because it allows for monitoring of the location and size of the ice ball in multiple dimensions.4 Intraoperative MR images are used to depict the slow expansion of the ice ball, as well as tissue damage caused by the freezing process. MR-guided FUS is a very promising method for noninvasive cancer treatment. While other minimally invasive therapies require direct insertion of special probes to reach the tumor, this method uses a high-intensity US beam focused on the target lesion (as seen on the MR image) without disruption of skin and other tissues. FUS is based on the use of acoustic energy and its secondary thermal effect, which cause thermal coagulation of the target tissue. As early as 1955, it was clinically shown that FUS was capable of destroying mammalian tissues.15 Broad use of this treatment method has been hindered by a lack of appropriate image-guidance techniques for the tumor-targeting, and most importantly for the real-time monitoring of temperature changes. The introduction of MR guidance provided an excellent method for monitoring treatment planning and delivery with direct temperature mapping (using MR phase-contrast techniques), as well as posttreatment confirmation of necrotic tissue changes.6 Using the MR images, the physician can identify the target lesions; temperature change during treatment delivery is monitored using MR temperature maps. A special transducer moves from one spot to another, following a pretreatment plan, until the entire volume is treated. To date, this method has been successfully used in the treatment of breast fibroadenomas, breast cancers, and uterine leiomyomas.16–18 Application of this treatment to prostate cancer, liver lesions, and brain tumors is currently under investigation. IMAGE-GUIDED THERAPY: ROLE OF IMAGE PROCESSING The key to IGT is the integration of a coordinated image process with the therapy process. Early problems with IGT included lack of integration of the imaging with therapy instruments, as well as difficulties with image

display and processing, especially when using MR processing. As the image processing technology improved, feedback from imaging to the therapy became possible and the role of imaging became more prominent, using MRI for intraoperative guidance as well as diagnosis. As the processing improved, imaging became almost instantaneous or “real-time,” allowing for tight integration of imaging and therapy. There are several components critical to all imageguided therapies; these are: planning, targeting, navigation, control, and monitoring. Pretreatment planning allows for the assessment of the approach that will provide the most effective eradication of the tumor and at the same time the least damage to the surrounding vital organs. For example, when delivering radiation therapy, pretreatment dosimetry planning determines the volume of the target and the placement of radiation sources. Targeting during IGT refers to precise pretreatment localization of all tumor targets that need to be treated and is essential for precise navigation of equipment during treatment delivery. Navigation refers to the guidance of surgical equipment during procedures to target the tumors precisely and spare healthy tissue. Current research efforts in the field of navigation are directed towards automatization of the procedure and increasing the use of surgical robots.19,20 Real-time controlling and monitoring of the treatment delivery by means of intraoperative imaging allows for necessary adjustments of the therapy to reflect movement of the tissues and permits alterations of he plan in response to initial therapy. Many different image postprocessing techniques have been developed to allow use of anatomic and functional information to improve tumor detection and treatment planning. These techniques include image segmentation, fusion, and registration. The purpose of image segmentation is to distinguish organs or structures of interest (e.g., prostate or its peripheral zone [PZ]) from the surrounding organs and tissue in order to perform volumetric and shape analyses, as well as treatment planning (see Figure 7-2). This is currently done by either manual outlining of the structure of interest or by semiautomated methods.21 The future of medical image segmentation is to automate the process and replace manual segmentation.22,23 Registration is a technique used to match images taken using different modalities, the same modality at different time points, or different imaging sequences (see Figure 7-2). The process involves mapping one image into the coordinate system of another image. Fusion is the merging of the anatomic and functional information provided by different imaging modalities into a single volume in order to provide better information about the underlying anatomy and tissue characteristics (Figure 7-3). Applications for fused images include not only IGT but also minimally invasive diagnosis and treatment planning.


Figure 7-3 MR-CT image fusion of prostate gland. Registration allows fusion of MR image (left) with CT image to yield fused image (right). Black arrows indicate radioactive seeds.

IMAGE-GUIDED MINIMALLY INVASIVE THERAPY IN UROLOGY Many of the image-guided minimally invasive therapies in urologic oncology are directed toward diagnosis and treatment of prostate cancer. In prostate procedures, IGT and diagnosis can be guided by different image modalities; transrectal TRUS (TRUS) is the most widely used method. TRUS provides good delineation of the prostate margin, simplicity of imaging, relatively low cost compared to other modalities, and availability. TRUS is a widely used technique for guidance of both prostate biopsies and brachytherapy. However, for prostate cancer diagnosis, the positive predictive value of this method remains quite low (17% to 57% for hypoechoic lesions, as summarized by Boges et al.24). Currently, research focuses on improving the accuracy of TRUS in the detection and staging of prostate cancer, including features such as power and color Doppler, 3D imaging, and elastography. CT guidance was used primarily for prostate biopsies but has also been introduced in prostate cancer therapy guidance.25 CT provides visualization of prostate boundaries and with the placement of a Foley catheter in the bladder allows for good visualization of the urethra that helps avoid urethral damage during treatment delivery. MR guidance of prostate procedures grew in importance after the development of the interventional MR scanner described earlier. Compared to US and CT imaging, MR imaging provides superior visualization of the prostate and its zonal anatomy, tumor location, and surrounding vital organs like the rectum, neurovascular bundles (NVBs), and urethra.

Minimally invasive image-guided procedures for early stage organ-confined prostate cancer include diagnosis using US-, CT- and MR-guided biopsy; and therapy using cryotherapy, CT-guided brachytherapy (CTBT), 2D transrectal US-guided brachytherapy (USBT)—both with and without external beam radiation therapy, with and without neo-adjuvant hormonal therapy; MR-guided brachytherapy (MRBT), with and without external beam radiation therapy; and FUS. In general, the group of patients that may benefit from IGT as monotherapy for prostate cancer is comprised of men with organ-confined disease. Lieberfarb et al.26 showed that in low-risk patients with clinical stage ≤ T2a (according to the American Joint Commission on Cancer Staging—AJCC system), PSA ≤10 ng/ml, and ≤ 50% positive biopsies, the likelihood of extracapsular extension (ECE) with or without positive margins was 18%, and seminal vesicle involvement was 2%. These patients may be “ideal” candidates for IGTs. For an overview of prostate therapy outcomes see Jani and Hellman (2003)27 and Peschel and Colberg (2003).28 Cryotherapy Cryotherapy refers to the application of low temperatures to necrotize the tumor. In addition to its use as a primary treatment for prostate cancer it has also been used as a salvage therapy after failure of radiation therapy.29–31 Cryosurgery was first proposed as a treatment for prostate disease in 1966.30 In the following years, several open transperineal procedures were performed under visual control. Because of many serious posttherapy

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complications, including urethro-cutaneous and urethrorectal fistulas, cryosurgery was not commonly used until its revival with US guidance in 1993.33 Procedure Cryotherapy is usually performed with the patient placed in the lithotomy position and placed under general anesthesia. The specific technique and the number of freezing cycles vary slightly between centers, with 2 cycles used most commonly. After positioning of the TRUS probe, multiple suprapubic cryoprobes are placed using US guidance. To prevent damage to the urethra, a warming urethral catheter is placed. Thermal sensors are placed around the periphery of the gland to allow good temperature control in critical locations. At the end of the procedure, the cryoprobes are thawed and removed. A newer approach to the use of cryotherapy in imageguided interventions is MR-guided cryotherapy, which has the major advantage of allowing clear visualization of the “ice-ball” induced in the tissue, as it occurs. This allows for direct thermal monitoring of the treatment effect (Figure 7-4).

Because of the fairly recent revival of cryotherapy due to image guidance improvements, the long-term treatment results are still being investigated. Several groups reported their preliminary results following TRUS-guided cryotherapy. At 5 years, the progression-free rate defined as undetectable PSA (< 0.3 ng/ml) ranged from 48% to 77%, depending on patients’ risk factors.34,35

Outcomes

Figure 7-4 Axial MR image showing a percutaneous cryotherapy probe in the lateral aspect of the left kidney during an MR-guided cryoablation of a small renal cell carcinoma. The “black” ice-ball is clearly seen (solid arrow); note the close proximity of the left colon (hollow arrow).

Complications of the treatment included incontinence, urethral sloughing, rectal fistula, and perirectal abscess.34–36 Patients self-reporting erectile dysfunction (ED) following cryosurgery were many compared to other minimally invasive prostate cancer treatments, ranging from 53% to 87%.34–37 A recent study showed pilot results on a new “nerve sparing” cryosurgery with the preservation of potency in 7 of 9 treated men at a median follow-up of 36 months (range from 6 to 72 months).38 Brachytherapy Interstitial brachytherapy refers to the permanent placement of small radioactive sources directly into the prostate. These are typically iodine (I-125) or palladium sources contained within a titanium-jacket and measure about 4 mm in length. Similar to cryosurgery, interstitial brachytherapy can be used as a primary treatment or as a salvage therapy after external beam radiation or initial implant failure. 39–41 Interstitial brachytherapy for prostate cancer was introduced in the 1960s by Scardino and Carlton.42 The placement of radioactive seeds was performed using a freehand technique that did not provide homogenous seed distribution and resulted in both underdosing of tumors and overdosing of vital structures (rectum, urethra, NVBs). This resulted in many posttreatment complications, and the procedure was discontinued until its revival with US image guidance in 1983 by Holm and colleagues.43 Further improvements in imaging techniques and technology resulted in the first MR-guided implant being performed at 1997 at Brigham and Women’s Hospital in Boston.44

Ultrasound-Guided Brachytherapy Procedure A patient is placed in the lithotomy position, a Foley catheter is inserted, and general or spinal anesthesia is administered. The TRUS probe and probe stabilizer are positioned and the probe stepper is attached to the stabilizer. US images are obtained every 5 mm from the apex to the base. Some centers use designated treatment planning software for preplanning of the procedure.45 The images are transferred to a laptop computer connected to the US equipment. A 3D reconstruction of the prostate, urethra, and rectum is produced, and the dose of radiation to those structures is visualized. Dosevolume histograms and the number of radioactive seeds per needle are then calculated. The template for needle guidance is placed against the patient’s perineum. After insertion of each needle a sagittal mode of the US acquisition is also used to determine the depth of the needle insertion. Some centers use fluoroscopy to visualize seed placement.45


Although investigators used slightly different definitions of biochemical failure, the overall results of similar studies are quite consistent. At present, there are only a few studies presenting 10-years outcome data for prostate USBT. Biochemical disease-free survival rates after 10 years following treatment ranged from 70% to 87%.46–48 At 5 years, relapse-free survival rates reached 85% to 94% for the low-risk group, 77% to 82% for the intermediate-risk group, and 62% to 65% for the highrisk group.49–51 Reported complications following USBT included urinary incontinence, urethral strictures, cystitis, urinary retention, prostatitis, proctitis, rectal ulceration, and rectal fistulas. Transient irritation and obstruction of the urinary tract 2 to 6 months after treatment were common and about 10% of patients showed symptoms of acute urinary retention (AUR).52 Preservation of potency ranged from 64% to 79% at 3 years to 39% at 6 years. Pretreatment ED and a higher implant dose caused greater impotence.53–55 Outcomes

CT-Guided Brachytherapy Procedure The prostate gland immobilization before the procedure is similar to US-guided therapy. A Foley catheter, with radio-opaque wire to fluoroscopically localize the urethra, is placed, and general anesthesia is administered. Preoperative CT images collected using 5 mm slices are used to outline the prostate gland for treatment planning. Posteroanterior and lateral fluoroscopic images are used to determine needle position before seeds are deposited. The seeds are placed under fluoroscopic control. Recently, CT-guided transischiorectal stereotactic brachytherapy has been introduced and tested.56–58 This approach can be used in patients with larger prostates. Transischiorectal CT images acquired every 5 mm are used for pretreatment planning. The patient is placed in the prone position, a Foley catheter is inserted and spinal or epidural anesthesia is administered. A 3D stereotactic template used to guide needle placement is attached to the CT table and tilted at the same angle as the gantry. Electronic grids are superimposed on every second CT image to determine needle depth. CT images are used for needle visualization, placement corrections are introduced if necessary, and radioactive seeds are deposited. Biochemical disease-free survival rates reached 99% for low, 96% for intermediate, and 90% for the high-risk group at a median follow-up of 4.5 years (2 to 8 years).59 Treatment complications included urinary retention, incontinence, and rectal symptoms. Outcomes

MR-Guided Brachytherapy Patient Selection The patient selection criteria for this program in our institution are clinical stage T1cNXM0 (according to AJCC), PSA less than 10 ng/ml, biopsy Gleason score not more than 3 + 4, low cancer volume, and endorectal MRI demonstrating organ-confined disease. Patients with prior transurethral resection of the prostate (TURP) are excluded. We do not exclude men with larger-volume prostates, as pubic arch interference can be avoided in this approach. All patients undergo endorectal coil MRI for prostate cancer staging prior to the treatment visit (Figures 7-5 and 7-6). An MR radiologist assesses prostate gland volume, tumor location and volume, the presence or absence of extraglandular disease, seminal vesicle invasion (SVI), and possible spread to pelvic lymph nodes or bones. Procedure This multidisciplinary procedure uses many different computer, imaging and technical skills and therefore requires the cooperation of specialists from various medical and nonmedical fields, including radiation oncologists, medical physicists, radiologists, anesthesiologists, urologists, nurses, radiology technologists, and computer scientists. For the procedure the patient is placed in an open configuration 0.5 T Signa SP MR scanner in the lithotomy position. The patient is positioned on the table between two magnets with vertically oriented open space for easier access to the patient during the treatment (see Figure 7-1). A Foley catheter is inserted, skin prepared, the template for needle guidance placed against the patient’s perineum and secured, and a rectal obturator is inserted (Figure 7-7). T2-weighted MRI images are acquired in the axial, coronal, and sagittal planes. The radiologist uses the T2-weighted images (see Figure 7-2, right) to identify the peripheral zone (PZ), urethra, and anterior rectal wall on each axial MR slice. These are then outlined using the 3D Slicer surgical simulation software designed and operated by members of the Surgical Planning Laboratory (SPL) at Brigham and Women’s Hospital in Boston (Figure 7-8). The 3D Slicer is free, open-source software for two- and three-dimensional display, registration, and segmentation of medical images (see www.slicer.org for more information on 3D Slicer). Pretreatment planning, as well as calculation of the MRI-based peripheral zone as a clinical target volume (CTV), is then performed by the medical physicists using designated planning software.11 The number of I-125 seeds per catheter and the depth of catheter insertion are calculated. The physicians then insert each preloaded catheter into the prostate gland. After every catheter insertion, axial gradient-echo MR images are obtained in real-time and compared to the catheter’s expected location according to the plan. Dose volume

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Figure 7-5 Endorectal coil MRI of prostate. Axial (left) and coronal (right) T2-weighted images provide superior visualization of the prostate and its zonal anatomy. White solid arrows indicate PZ, hollow arrows indicate central gland, and striped arrows indicate endorectal coil.

Figure 7-6 Prostate cancer. Axial T2-weighted erMRI image shows low signal lesion located in PZ (white arrow).

Figure 7-7 Close up view of a patient in the open 0.5T Signa SP magnet, during MR-guided prostate brachytherapy. The patient is in the lithotomy position and the perineal template used for catheter guidance is seen in the center.

histograms (DVH) for the CTV, anterior rectal wall, and urethra are recalculated, adjustment of the catheter placement is performed when necessary, and seeds are deposited. Approximately 6 weeks after the procedure, MRI and CT imaging of the prostate is performed to identify the location of radioactive seeds and calculate final DVHs. Since seeds can be well visualized on CT images, and the underlying anatomy is better depicted on MR images, MR-CT fused images are used to calculate dose distribution to the surrounding tissues (Figure 7-9).

Outcomes

Long-term biochemical outcomes were compared for similar patients over similar time frames between MR-guided brachytherapy and radical prostatectomy by D’Amico et al.60 At 5 years, PSA control was 95% for brachytherapy and 93% for RP patients (median follow-ups were 3.95 and 4.2 years for brachytherapy and RP patients, respectively). The percentage of positive prostate biopsies was found to be a significant predictor of the time to postbrachytherapy PSA failure. Short-term toxicity following MR-guided brachytherapy was rare, and no patient reported gastrointestinal or


Figure 7-8 Image segmentation using 3D Slicer surgical navigation software. PZ (solid arrow), rectal wall (hollow arrow), and urethra (striped arrow) are identified on T2-weighted image acquired in a 0.5 T scanner for MRBT planning.

Figure 7-9 MR-CT fusion of post-MRBT images. Post-therapy MR image (left) and CT image (middle) are fused resulting in MR-CT image (right) to allow better visualization of individual seeds and facilitate dose distribution calculation. Black arrows indicate radioactive seeds.

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sexual dysfunction during the first month after treatment.61 Acute urinary retention (AUR) was observed in 12% of men within 24 hours of removal of the Foley catheter and was self-limiting within 1 to 3 weeks. MRdetermined prostate volume, transitional zone (TZ) volume, and total number of seeds were found to be significant predictors of AUR on univariate analysis. The TZ volume was the only significant predictor of AUR on multivariate logistic regression analysis. The authors concluded that benign prostatic hyperplasia (BPH) that results in larger TZ volume is the most important predictor of AUR. No urinary incontinence was seen at a median follow-up of 14 months (from 9 months to 2 years).62 MR-guided brachytherapy is a very new approach; thus, there is only one report to date summarizing long-term toxicity.63 Albert et al.63 found low incidence of rectal bleeding (8%) and no urethral strictures at a median follow-up of 2.8 years (0.5 to 5 years). While ED reached 82%, two-thirds of the patients reported good erectile function after sildenafil (Viagra). No radiation cystitis was estimated at 4 years after MRBT. Quality of life (QoL) outcomes collected using a previously validated questionnaire64 are currently being assessed, and early reports indicate that MR-guided prostate brachytherapy has better symptomatic outcomes than the conventional US-guided approach (J. Talcott, personal communication). Current research projects will continue to study the radiation dose distribution to vital organs and its impact on the side effects. Image-segmentation techniques are used to identify those important organs on endorectal coil MR images. Radiation dose to the organs can then be correlated with changes in patientreported QoL. Focused Ultrasound Surgery US-Guided High-Intensity Focused Ultrasound for Prostate Cancer This approach uses a high-intensity US beam that is focused on the target lesion, which then undergoes thermal coagulation. In 1996, Galet et al.65 were the first to evaluate clinical application of FUS for treatment of organ-confined prostate cancer. Procedure For the treatment the patient is placed in the lateral position and anesthetized. A suprapubic catheter is placed to assure urinary drainage, and an imaging and treatment probe is inserted into the rectum. The probe is surrounded with a balloon filled with cooling fluid to avoid overheating of the rectal wall. Target areas are identified using biplanar US imaging and the

treatment is planned. Therapy is performed using a 2.25 to 3-MHz transducer. Early results showed 56% to 100% therapy response rates when using Ablatherm probes; however, the criteria of PSA failure after FUS are still under debate.66–72 Blana et al.73 reported outcomes following FUS for localized prostate cancer at a median follow-up of 22.5 months (4 to 62 months). After a follow-up for 22 months, 87% of patients had a PSA level below 1ng/ml, and 93.4% had negative control biopsies. Reported treatment adverse effects included urinary tract infection, stress incontinence, rectal burn, rectourethral fistulas, urethral stricture, and impotence. MR-guided FUS for treatment of prostate disease is currently under investigation; initial animal tests appear very promising. FUS treatment can be monitored by thermal maps and contrast-enhanced MRI (Figure 7-10). Outcomes

Diagnosis US-Guided Prostate Biopsy Currently, diagnosis of prostate cancer is aided using TRUS to guide the biopsy and is a widely used and accepted procedure.74–76 However, the sensitivity and positive predictive value of sextant biopsy remain quite low, 60% and 25%, respectively.77–79 The first transperineal prostate biopsies under US control were performed in the mid-1980s, and a few years later TRUS become the primary modality for biopsy guidance.80 Initially, the sextant biopsy technique recommended the collection of six samples from the base, mid-gland, and apex on both sides. Subsequent literature, however, showed the advantages of increasing the number of samples to 10, 11, or even 12 to detect cancer with up to a 96% success rate. It was also recommended that the number of core biopsies increase with the prostate volume, since bigger gland sizes introduced high sampling error and therefore required more sampling.81–85 However, the ideal number of cores is still not clear. Procedure Prior to the insertion of the endorectal probe, the patient undergoes a digital rectal exam (DRE). The patient is positioned on the table in either litothomy or lateral decubitus position. The ultrasound probe is inserted and stabilized and the prostate volume is calculated using transverse and sagittal imaging. If the procedure is performed in lithothomy position, the template for needle guidance is placed against the patient’s perineum. The positions of needles are identified by grid coordinates on the template and the depth by the probe stepper attached to the probe stabilizer. These coordinates are used to guide biopsy under real-time US imaging. Biopsy is performed using an 18-gauge biopsy gun.


MR-Guided Prostate Biopsy In addition to being an excellent method for guiding prostate cancer therapy, MR imaging also appears to be useful for guiding diagnostic biopsy.86 Similar to its use in therapy, metabolic information from spectroscopy and dynamic contrast MR data can be combined with routine MR images to allow precise tumor targeting. Our group has adapted the interventional MR system to perform MR-guided prostate biopsy.86,87 This transperineal technique eschews endorectal devices and provides an excellent diagnostic alternative for patients who have undergone rectal surgeries and in whom US-guided procedure is impossible to perform. An additional group of men who can be benefited from MR-guided procedure are those with persistently rising PSA values and have had prior negative US-guided biopsies. Preliminary feasibility results of this method for facilitating prostate cancer diagnosis are promising.73 One of the unique aspects of this approach is the interactive imaging provided by using the 3D Slicer, as reported by Hata et al.86, which facilitates T2 imaging in “near-real time.” D’Amico et al.88 reported results of the procedure from two MRI-targeted lesions in a patient who could not undergo US-guided procedure because of previous rectal surgery. Several transurethral biopsies yielded negative results in this patient. Following MRguided biopsy, cancer was confirmed in 15% and 25% of the 2 cores. Figure 7-10 MR-focused US surgery of uterine fibroid. A, Coronal T2-weighted FSE image (4000/90) used for treatment planning. The sonication locations and sizes (circles and grid) were determined by the planning software from this prescription (and the tissue depth) and displayed on top of the treatment plan. During the treatment, the accumulated thermal dose (hollow arrow) was displayed on top of the treatment planning images. A dose threshold of 240 equivalent minimum at 43 ˚ C is displayed. B, Sagittal T2weighted image (2500/98) showing the treatment plan and the area that achieved the threshold thermal dose. C–D, Temperature sensitive phase-difference FSPGR images (39.9/19.7) acquired at peak temperature rise during two sonications, one imaged perpendicular to the direction of the US beam (Coronal, C), and one imaged parallel to the direction of the beam (sagittal, D). These images were used to estimate the thermal dose (white line) for each sonication. E–F, Result of the treatment. E, Sagittal contrast-enhanced gradient-echo image (245/1.8) acquired 2 days after US therapy. The nonenhancing area (white arrow) is clearly seen. F, Gross pathologic cut specimen showing the central area of hemorrhagic necrosis. (From Tempany MC et al: Radiology 2003; 226(3):902.)

Procedure Prior to the procedure, each patient undergoes endorectal coil MRI using a 1.5 T imaging system. The T1- and T2-weighted and contrast-enhanced images are collected, and multivoxel spectroscopy is performed. Using this information, the radiologist identifies biopsy targets. Patient positioning for the procedure and initial preparation is similar to MRBT except that an endorectal obturator may not be used in some cases with previous rectal surgery. Subsequently, T2-weighted images are collected at 3.5 mm intervals in a 0.5 T interventional system. The information from preprocedure and intraprocedure images are correlated and target lesions are identified. Computer software is used to calculate appropriate coordinates on the perineal template for the needle insertion, as well as needle insertion depth. Additionally, 0.5 T T2weighted images and intraprocedure fast gradient-echo images are loaded into the 3D Slicer software and displayed in an alternating fashion to provide real-time image guidance during biopsy. All target locations along with sextant biopsies of the PZ from the right and left apex, mid-gland, and base are sampled using MR-compatible 18 gauge biopsy guns. Figure 7-11 shows an axial view of the needle tip artifact in PZ after needle insertion and just before

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A

B Figure 7-11 Biopsy needle artifact. Axial (A) and coronal (B) view of prostate gland on pre(left) and intra-MR-guided biopsy images (middle and right). The black arrow indicates the tip of the biopsy needle. (From D’Amico Av, Loeffter JS, Harris JR. Image guided diagnosis and treatment of cancer. Totowa, NJ, Humana Press, 2003.)

biopsy. This procedure is currently done under anesthesia as a day surgical procedure. It is well tolerated and offers a second-line biopsy approach in selected patients. SUMMARY

Figure 7-12 Biopsy needle antifact. Real-time 3D view of prostate gland on intra-MR-guided biopsy images.

The areas covered in this chapter serve to illustrate the significant advances that have occurred in image-guided procedures and therapy for both diagnosis and treatment of prostate cancer. These are only some of the many new IGT applications available today. As the imaging techniques continue to improve and as surgical approaches become even less invasive or completely noninvasive (as with FUS), the future looks very exciting for both urology patients and their doctors.


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49. Blasko JC, Grimm PD, Sylvester JE, et al: Palladium-103 brachytherapy for prostate carcinoma. Int J Radiat Oncol Biol Phys 2000; 46(4):839–850. 50. Potters L, Cha C, Oshinsky G, et al: Risk profiles to predict PSA relapse-free survival for patients undergoing permanent prostate brachytherapy. Cancer J Sci Am 1999; 5(5):301–306. 51. Beyer DC, Brachman DG: Failure free survival following brachytherapy alone for prostate cancer: comparison with external beam radiotherapy. Radiother Oncol 2000; 57(3):263–267. 52. Merrick GS, Butler WM, Tollenaar BG, Galbreath RW, Lief JH: The dosimetry of prostate brachytherapyinduced urethral strictures. Int J Radiat Oncol Biol Phys 2002; 52(2):461–468. 53. Merrick GS, Butler WM, Galbreath RW, et al: Erectile function after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002; 52(4):893–902. 54. Stock RG, Kao J, Stone NN: Penile erectile function after permanent radioactive seed implantation for treatment of prostate cancer. J Urol 2001; 165(2):436–439. 55. Talcott JA, Clark JA, Stark PC, Mitchell SP: Long-term treatment related complications of brachytherapy for early prostate cancer: a survey of patients previously treated. J Urol 2001; 166(2):494–499. 56. Koutrouvelis P, Lailas N, Katz S, et al: High- and low-risk prostate cancer treated with 3D CT-guided brachytherapy: 1- to 5-year follow-up. J Endourol 2000; 14(4):357–366. 57. Koutrouvelis PG, Three-dimensional stereotactic posterior ischiorectal space computerized tomography guided brachytherapy of prostate cancer: a preliminary report. J Urol 1998; 159(1):142–145. 58. Molloy JA, Williams MB: Treatment planning considerations and quality assurance for CT-guided transischiorectal implantation of the prostate. Med Phys 1999; 26(9):1943–1951. 59. Koutrouvelis PG, Lailas N, Katz S, et al: Prostate cancer with large glands treated with three-dimensional computerized tomography guided pararectal brachytherapy: up to 8 years of followup. J Urol 2003; 169(4):1331–1336. 60. D’Amico AV, Tempany CM, Schultz D, et al: Comparing PSA outcome after radical prostatectomy or magnetic resonance imaging-guided partial prostatic irradiation in select patients with clinically localized adenocarcinoma of the prostate. Urology 2003;62(6):1063–1067. 61. D’Amico A, Cormack R, Kumar S, Tempany CM: Realtime magnetic resonance imaging-guided brachytherapy in the treatment of selected patients with clinically localized prostate cancer. J Endourol 2000; 14(4):367–370. 62. Thomas MD, Cormack R, Tempany CM, et al: Identifying the predictors of acute urinary retention following magnetic-resonance-guided prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 47(4):905–908. 63. Albert M, Tempany CM, Schultz D, et al: Late genitourinary and gastrointestinal toxicity after magnetic resonance image-guided prostate brachytherapy with or without neoadjuvant external beam radiation therapy. Cancer 2003; 98(5):949–954.

Chapter 7 Image-Guided Minimally Invasive Therapy 127 64. Clark JA, Talcott JA: Symptom indexes to assess outcomes of treatment for early prostate cancer. Med Care 2001; 39(10):1118–1130. 65. Gelet A, Chapelon JY, Margonari J, et al: Prostatic tissue destruction by high-intensity focused ultrasound: experimentation on canine prostate. J Endourol 1993; 7(3):249–253. 66. Gelet A, Chapelon JY, Bouvier R, et al: Treatment of prostate cancer with transrectal focused ultrasound: early clinical experience. Eur Urol 1996; 29(2):174–183. 67. Gelet A, Chapelon JY, Bouvier R, et al: Transrectal high intensity focused ultrasound for the treatment of localized prostate cancer: factors influencing the outcome. Eur Urol 2001; 40(2):124–129. 68. Gelet A, Chapelon JY, Bouvier R, et al: Transrectal highintensity focused ultrasound: minimally invasive therapy of localized prostate cancer. J Endourol 2000; 14(6):519–528. 69. Chaussy CG, Thuroff S, High-intensive focused ultrasound in localized prostate cancer. J Endourol 2000; 14(3):293–299. 70. Gelet A, Chapelon JY, Bouvier R, Pangaud C, Lasne Y: Local control of prostate cancer by transrectal high intensity focused ultrasound therapy: preliminary results. J Urol 1999; 161(1):156–162. 71. Beerlage HP, Thuroff S, Debruyne FM, Chaussy C, de la Rosette JJ: Transrectal high-intensity focused ultrasound using the Ablatherm device in the treatment of localized prostate carcinoma. Urology 1999; 54(2):273–277. 72. Uchida T, Sanghvi NT, Gardner TA, et al: Transrectal high-intensity focused ultrasound for treatment of patients with stage T1b-2n0m0 localized prostate cancer: a preliminary report. Urology 2002; 59(3):394–398 (Discussion 398-9). 73. Blana A, Walter B, Rogenhofer S, Wieland WF. Highintensity focused ultrasound for the treatment of localized prostate cancer: 5-year experience. Urology 2004;63(2):297–300. 74. Lee F, Gray JM, McLeary RD, et al: Prostatic evaluation by transrectal sonography: criteria for diagnosis of early carcinoma. Radiology 1986; 158(1):91–95. 75. Lee F, Gray JM, McLeary RD, et al: Transrectal ultrasound in the diagnosis of prostate cancer: location, echogenicity, histopathology, and staging. Prostate 1985; 7(2):117–129. 76. Rifkin MD, Kurtz AB, Goldberg BB: Prostate biopsy utilizing transrectal ultrasound guidance: diagnosis of nonpalpable cancers. J Ultrasound Med 1983; 2(4):165–167.

77. Keetch DW, McMurtry JM, Smith DS, Andriole GL, Catalona WJ: Prostate specific antigen density versus prostate specific antigen slope as predictors of prostate cancer in men with initially negative prostatic biopsies. J Urol 1996; 156(2 Pt 1):428–431. 78. Terris MK: Sensitivity and specificity of sextant biopsies in the detection of prostate cancer: preliminary report. Urology 1999; 54(3):486–489. 79. Terris MK, McNeal JE, Freiha FS, Stamey TA: Efficacy of transrectal ultrasound-guided seminal vesicle biopsies in the detection of seminal vesicle invasion by prostate cancer. J Urol 1993; 149(5):1035–1039. 80. Applewhite JC, Matlaga BR, McCullough DL, Hall MC. Transrectal ultrasound and biopsy in the early diagnosis of prostate cancer. Cancer Control 2001; 8(March–April; 2): 141–150. 81. Eskew LA, Bare RL, McCullough DL. Systematic 5 region prostate biopsy is superior to sextant method for diagnosing carcinoma of the prostate. J Urol 1997; 157(January; 1):199–202 (Discussion 202-3). 82. Chang JJ, Shinohara K, Bhargava V, Presti JC Jr: Prospective evaluation of lateral biopsies of the peripheral zone for prostate cancer detection. J Urol 1998; 60(December; 6 Pt 1):2111–2114. 83. Chen ME, Troncoso P, Johnston DA, Tang K, Babaian RJ: Optimization of prostate biopsy strategy using computer based analysis. J Urol 1997; 58(December; 6): 2168–2175. 84. Babaian RJ, Toi A, Kamoi K, et al: A comparative analysis of sextant and an extended 11-core multisite directed biopsy strategy. J Urol 2000; 163(January; 1):152–157. 85. Naughton CK, Miller DC, Mager DE, Ornstein DK, Catalona WJ. A prospective randomized trial comparing 6 versus 12 prostate biopsy cores: impact on cancer detection. J Urol 2000; 164(August; 2):388–392. 86. Hata N, Jinzaki M, Kacher D, et al: MR imaging-guided prostate biopsy with surgical navigation software: device validation and feasibility. Radiology 2001; 220(1):263–268. 87. Cormack RA, D’Amico AV, Hata N, et al: Feasibility of transperineal prostate biopsy under interventional MR guidance. Urology 2000; 56(4):663–664. 88. D’Amico AV, Tempany CM, Cormack R, et al: Transperineal magnetic resonance image guided prostate biopsy. J Urol 2000; 164(2):385–387.

C H A P T E R

8 Adrenal Tumors E. Darracott Vaughan, Jr, MD

The major adrenal tumors that will be discussed in this chapter include adrenal cortical adenomas producing primary hyperaldosteronism and Cushing’s syndrome, adrenal cortical carcinoma, the incidentally identified adrenal mass, and pheochromocytoma. Actually, the most common tumors involved in the adrenal gland are metastatic tumors to the adrenal, and the management of such lesions generally is dependent on the treatment of the primary disease entity. It is fortunate that the diagnosis of adrenal disorders is extremely accurate using the combination of precise analytical methods for the measurement of the abnormal secretion of adrenal hormones and sophisticated radiographic techniques for the localization and characterization of specific adrenal lesions.1,2 The management of patients with adrenal tumors requires a clear understanding of the normal physiology of the adrenal medulla and cortex; a three-dimensional concept of the adrenal anatomy, as well as adjacent structures; and the knowledge of the various pathologic entities that may involve the adrenal. Moreover, the operating surgeon must be well aware of the nuances involved in the diagnosis of the different adrenal entities, be aware of potential intraoperative phenomena that are unique to these patients, and be alert to specific postoperative complications that may occur.3 This chapter will review the preoperative, intraoperative, and postoperative aspects of each of these specific entities and will outline surgical approaches with operative hints to guide those interested in adrenal surgery. The adrenal glands are paired retroperitoneal organs that lie within the perinephric fat, at the anterior, superior, and medial aspects of the kidneys. Their location in juxtaposition with other organs, as well as the periadrenal fat, renders them ideal for sectional imaging by computed tomography (CT). Thin-cut CT scanning allows precise identification of lesions as small as 0.5 cm. The CT scan remains the best imaging device for the identification of small adrenal lesions, whereas magnetic reso-

nance imaging (MRI) gives information concerning cell type and aids in the differentiation of adenomas from medullary tumors or metastatic carcinoma.4 Other advantages of MRI scanning will be discussed later. The right adrenal lies above the kidney posterior and lateral to the inferior vena cava (IVC) and its solitary venous drainage is via a short sturdy vein that enters the IVC in a posterior fashion. Hence, the right adrenal gland is best approached through a posterior or modified posterior incision.5 The left adrenal is in more intimate contact with the kidney, overlying the upper pole of the kidney with its anterior and medial surfaces behind the pancreas and splenic artery. It is best exposed through a flank approach or a thoracoabdominal approach if the lesion is large. The adrenals have a delicate, rich blood supply estimated to be 6 to 7 ml/g/min without a dominant adrenal artery. The inferior phrenic artery is the main blood supply with additional branches from the aorta and renal arteries. The small arteries penetrate the gland in a circumferential stellate fashion leaving both the anterior and posterior surfaces avascular (Figure 8-1). During adrenalectomy, an important technical goal is to divide the superior and lateral blood supplies to the adrenal first, allowing the adrenal to remain attached to the kidney, which can be used to draw the adrenal gland inferiorly and anteriorly during the resection. On the left side, the adrenal vein drains into the left renal vein; however, there is also a medially located phrenic drainage branch, which, if not appropriately ligated, can cause troublesome bleeding (Figure 8-2). The left adrenal vein is also a guide to the left renal artery, which often lies dorsal to the vein. One potential complication of left adrenalectomy is the inadvertent ligation of the apical renal arterial branch to the upper pole, which lies in close contact to the inferior border of an adrenal tumor. The basic physiology of the adrenal cortex and medulla, as well as the various pathologic entities, will be discussed under specific disorders.

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132

Part II Adrenal Gland

Figure 8-1 Arterial supply of left and right adrenal glands.

CUSHING’S SYNDROME Cushing’s syndrome is the term utilized to describe the symptom complex caused by excessive circulating glucocorticoids. We must remember that the term is allencompassing and includes: patients with pituitary hypersecretion of adrenocorticotrophic hormone (ACTH) (corticotropin); Cushing’s disease, which accounts for 75% to 80% of patients with endogenous Cushing’s; adrenal adenomas or carcinomas; ectopic secretion of ACTH, or corticotropin-releasing hormone (CRH) syndrome.6 Before assuming that a patient has one of these pathologic entities, there should be a thorough questioning of the patient about the use of steroidcontaining preparations. At times patients are unaware that a substance they use, particularly creams or lotions, contains steroids, and if the patient is on any type of medication at all, it should be carefully reviewed for steroid content. There are few diseases in which the clinical appearance of the patient can be as useful in suspecting the diagnosis. Old photographs are helpful in documenting recent changes in appearance that occurred. The more common clinical manifestations of Cushing’s syndrome found in different series of patients are shown in Table 8-1. The clinical findings do not distinguish patients with Cushing’s disease from those with adrenal adenoma; however, patients with adrenal carcinoma are more likely to show virilization in the female or feminization in the male. Patients with ectopic ACTH may present with manifestations of the primary tumor. It is also important to remember that some nonendocrine

Figure 8-2 Venous drainage of left and right adrenal glands with particular attention to the intercommunicating vein on the left.

disorders mimic the clinical and even the biochemical manifestations of Cushing’s syndrome. These patients have been termed to have “pseudo”-Cushing’s syndrome; this may exist in patients with major depression or in patients with chronic alcoholism.6 There are a myriad of tests both to diagnose the presence of Cushing’s syndrome and then to identify which subentity is present. Fortunately, due to recent development of extremely accurate assays for urinary and plasma cortisol, as well as plasma corticotropin, this task has become much easier. The approach that has recently been reported by Orth6 is shown in Figure 8-3. The clinical diagnosis of Cushing’s syndrome is confirmed by the demonstration of cortisol hypersecretion. At the present time the determination of 24-hour urinary excretion of cortisol in the urine is the most direct and reliable index of cortical secretion. Orth recommends that urinary cortisol should be measured in two and preferably three consecutive 24-hour urine specimens, collected on an outpatient basis. Once the diagnosis has been established, the next chore is to determine whether there is Cushing’s disease due to hypersecretion of plasma corticotropin (ACTH) from the pituitary or primary adrenal disease. Herein is the major change in our approach to patients with Cushing’s disease. In the past, high- and low-dose dexamethasone suppression tests have been used to accomplish this task. At present, the low-dose dexamethasone is generally used to rule out pseudo-Cushing’s syndrome. The differentiation of corticotropin-dependent Cushing’s

Chapter 8 Adrenal Tumors 133

Table 8-1 Clinical Manifestations of Cushing’s Syndrome All* Disease† (%) (%)

Adenoma/ Carcinoma‡ (%)

Obesity

90

91

93

Hypertension

80

63

93

Diabetes

80

32

79

Centripetal obesity

80

—

—

Weakness

80

25

82

Muscle atrophy

70

34

—

Hirsutism

70

59

79

Menstrual abnormal/ sexual dysfunction

70

46

75

Purple striae

70

46

36

Moon facies

60

—

—

Osteoporosis

50

29

54

Early bruising

50

54

57

Acne/pigmentation

50

32

—

Mental changes

50

47

57

Edema

50

15

—

Headache

40

21

46

Poor healing

40

—

—

From Scott HW Jr: In Scott HW (ed): Surgery of the Adrenal Glands. Philadelphia, JB Lippincott Co, 1990, with permission. *Hunt and Tyrell, 1978. †Wilson, 1984. ‡Scott, 1973.

syndrome versus corticotropin-independent Cushing’s syndrome is determined by the concurrent late afternoon or midnight measurement of collection of blood for the simultaneous measurement of plasma corticotropin and cortisol. Thus, if the patient’s cortisol concentration is above 50 μg/dl and the corticotropin concentration is below 5 pg/ml, then the cortisol secretion is ACTH independent and the patient has a primary adrenal problem. In contrast, if the plasma corticotropin concentration is greater than 50 pg/ml, then the cortisol secretion is ACTH dependent and the patient has Cushing’s syndrome or ectopic ACTH or CRH syndrome.5 In situations where the two-site immunoradiometric assay test is not available, the high-dose dexamethasone suppression test has always been used as the standard test to differ-

entiate between pituitary and adrenal Cushing’s syndrome. Patients are given high-dose dexamethasone (2 mg every 6 hours for 2 days), and plasma cortisol and urinary free cortisol levels are measured. In patients with pituitary disease, there should be a 50% or greater suppression in cortisol. Patients with adrenal adenomas or carcinomas fail to suppress cortisol secretion. The highdose dexamethasone suppression test may also be useful to identify ectopic ACTH syndrome, where there is usually complete resistance to high-dose dexamethasone suppression. Treatment is obviously dependent on the underlying lesion. Patients with adrenal adenomas or carcinomas are generally treated with surgical extirpation of the lesions. Patients with Cushing’s disease have confirmation with pituitary CT or MRI and usually are treated with transsphenoidal pituitary tumor removal, and patients with ectopic ACTH have treatment directed towards the primary tumor. The surgical approach and preparation of patients with adrenal Cushing’s disease will be discussed later. If the patient is identified as having adrenal Cushing’s, the next step is radiographic localization with CT scanning.7 Adrenal adenomas are usually larger than 2 cm, solitary, and associated with atrophy of the opposite gland. The density is low because of the high concentration of lipid (Figure 8-4). Adrenal carcinomas are often indistinguishable from adenomas except for the larger size, carcinomas usually being greater than 6 cm.8 Necrosis and calcification are also more common in association with adrenal carcinomas but are not specific. Clearly, large irregular adrenal lesions with invasion represent carcinoma; however, metastatic carcinoma to the adrenal has the same appearance. MRI is not usually necessary in patients with Cushing’s syndrome unless the lesion is large; the rationale for MRI is to obtain anatomic information concerning surrounding structures or invasion of the IVC, a rare but well-recognized entity.9 Adrenal cortical scanning with iodinated cholesterol agents is no longer routinely utilized but can be helpful in differentiating functional adrenal tissue from other retroperitoneal lesions.10 INCIDENTALLY DISCOVERED ADRENAL MASSES The increased utilization of abdominal ultrasound and CT scanning has led to a new classification of adrenal lesions termed the “incidentally identified unsuspected adrenal mass” or “incidentaloma.”8 Our approach to the incidentally identified adrenal mass is shown in Figure 8-5. Several points do not warrant controversy. First, there is an agreement that all patients with solid adrenal masses should undergo biochemical assessment. If biochemical abnormalities are identified, the lesions should be treated as described elsewhere in the chapter, usually by removal

134


Figure 8-3 Identifying Cushing’s syndrome and its causes.

of the offending lesion. However, the extent of biochemical assessment has been reviewed, and a selective approach has been outlined that markedly limits cost without sacrificing diagnostic accuracy.11 A very limited evaluation is recommended, including tests only to rule out pheochromocytoma, potassium levels in hypertensive cases, and glucocorticoid evaluation only in the presence of clinical stigmata of Cushing’s syndrome or virilization. The second point that is not controversial is that nonfunctioning solid lesions larger than 5 cm should be removed. This is based on the finding that adrenal malignancies are almost always larger than 6 cm. However, we

feel that CT scanning may underestimate the size of an adrenal, and we suggest that exploration be performed when lesions are more than 5 cm on CT or MRI.12 Furthermore, if lesions are purely cystic by CT or MRI, cyst puncture is often not necessary and these lesions can be followed (Figure 8-6). The controversy arises in the management strategy for the solid adrenal lesions smaller than 5 cm in size. The current approach has been to use MRI imaging in this situation. Most adenomas appear slightly hypointense or isointense relative to the liver or spleen on T1-weighted images and slightly hyperintense or isointense relative to hepatic or splenic parenchyma


Figure 8-4 CT scan of a patient with right adrenal adenoma.

Figure 8-5 Evaluation of incidentally found adrenal mass.

Figure 8-6 Multilocular benign renal cyst in an asymptomatic patient that was incidentally identified. A, CT scan showing left adrenal cyst. B, Coronal MRI showing the lobular suprarenal adrenal cyst. In this case, exploration was carried out because of multilocular nature. The cyst was benign.

136


on T2-weighted images. There is little change in the intensity from T1- to T2-weighted studies. In contrast, the general notion is that adrenal cortical carcinoma is hypointense relative to liver or spleen on T1-weighted images and hyperintense to the liver or spleen on T2weighted images. Thus, if the mean signal intensity ratio between the lesion and the spleen is over 0.8, it is unlikely that the lesion is a benign adenoma. However, it should be remembered that there are a number of entities other than adrenal carcinoma that can cause high intensity, including neural tumors, metastatic tumors to the adrenal, adrenal hemorrhage, and other retroperitoneal lesions.4,13,14 An additional study that has shown accuracy is the fine-needle adrenal biopsy guided by ultrasound or CT. In a large series from Finland, significant cytologic material was obtained in 96.4% and the accuracy to differentiate benign from malignant disease was 85.7%.15 However, the utilization of aspiration cytology requires an extremely experienced cytologist, and in fact there is often inability to distinguish an adrenal adenoma from a carcinoma even on pathologic review of the entire specimen. It is our general approach that if there is either any radiographic evidence that argues against a characteristic benign adenoma or any change in size of an adrenal lesion with repeated studies, then we feel that adrenalectomy is indicated. This fairly aggressive approach is justified in view of the extremely poor prognosis of patients when adrenal carcinoma is diagnosed, even when the lesion is localized. ADRENAL CARCINOMA Adrenal carcinoma is a rare disease with a poor prognosis. The incidence is estimated as 1 case per 1.7 million, accounting for only 0.02% of cancers. A practical subclassification for adrenal carcinomas is according to their ability to produce adrenal hormones. In a series by Luton et al.,16 79% of adrenal tumors were functional, a higher percentage than previously reported due to more sensitive assays. The varieties of functioning tumors are shown in Table 8-2. However, this classification is some-

Table 8-2 Classification of Adrenal Carcinoma Functional Cushing’s syndrome Virilization in females Increased DHEA, 17-ketosteroids Increased testosterone Feminizing syndrome in males Hyperaldosteronism Mixed combination of above Nonfunctional DHEA, dehydroepiandrosterone.

what contrived, since many of these tumors will produce multiple adrenal hormones and also because of the clear evidence that a tumor may secrete one hormone at one point in its natural history and additional hormones at a later phase when there is increased tumor mass. The most commonly identified functional tumor is one causing Cushing’s syndrome. The most common characteristic to delineate Cushing’s syndrome due to carcinoma rather than adenoma has been the presence of virilization with elevated 17-ketosteroid levels. More recently, the measurement of DHEA has been useful in identifying these patients. Other rare functional tumors include both testosterone- and estrogen-secreting adrenal cortical tumors. Rarely, virilization can occur in the absence of elevated urinary 17-ketosteroids and raises the possibility of pure testosterone-secreting ovarian or adrenal lesions.17 Of the two sites of origin, adrenal cortical tumors secreting testosterone are exceedingly rare. In contrast to other tumors described in this section, these tumors are usually small, less than 6 cm, and many behave in a benign fashion. In contrast, most feminizing tumors occur in males 25 to 50 years of age, and they are usually larger, often palpable, and highly malignant.18 Characteristically, the patients present with gynecomastia; in addition they may exhibit testicular atrophy, impotence, or decreased libido. We have also seen a presentation with infertility and oligospermia. These tumors secrete androstenedione, which is converted peripherally to estrogen. Other steroids may also be secreted, and the clinical picture may be mixed with associated cushingoid features. The management of adrenal cortical carcinoma is surgical removal of the primary tumor. The most common sites of metastasis include lung, liver, and lymph nodes.19 Often these tumors extend directly into adjacent structures, especially the kidney, and surgical removal may require removal of the primary tumor and adjacent organs, including the kidney, spleen, as well as local lymph nodes. Unfortunately, despite en bloc resection even in patients without evidence of metastatic disease, the 5-year survival rate is only approximately 50% with complete resection and 25% overall.20 Because of the poor prognosis there has been an intense search for effective adjunctive chemotherapy, but this search has been frustrating and it is generally believed that conventional chemotherapy is not effective, probably because of P-glycoprotein expression.21 The most success has been reported with the adrenolytic 1,1-dichloro2-(o-chlorophenyl)-2-(p-chlorophenyl)-ethane(o,p¢-DDD) or Mitotane. This DDT derivative has been shown to induce tumor response in 35% in a review of 551 cases reported in the literature.22 However, despite these response rates, survival time has not been prolonged and there is intense toxicity. Recently, it has been suggested that patients even without the presence of metastatic


disease be given adjunctive o,p¢-DDD, and trials are currently in progress to determine if this approach is efficacious. In general, there is an extremely poor prognosis in patients with adrenal cortical carcinoma and an obvious need for the development of new treatment strategies.

of primary hyperaldosteronism is now identified by the combined findings of hypokalemia, suppressed plasma renin activity (PRA) despite sodium restriction, and a high urinary and plasma aldosterone level after sodium repletion in hypertensive patients. The current evaluation of patients suspected of having hyperaldosteronism is shown in Figure 8-7. The primary physiologic control of aldosterone secretion is angiotensin II (Figure 8-8). Other control mechanisms are ACTH and potassium. A clear knowledge of the physiology of the renin– angiotensin–aldosterone system (RAAS) is mandatory in order to understand the pathophysiology and evaluate patients with primary hyperaldosteronism.25,26 The critical sensor in the RAAS resides in the juxtaglomerular apparatus within the kidney. Thus, in response to a variety of stimuli, but primarily decreased renal perfusion, or a decreased intake of sodium, there is an increased renin release, formation of angiotensin II, and subsequent

HYPERALDOSTERONISM The term hyperaldosteronism originally was coined by Dr. Jerome Conn to describe the clinical syndrome characterized by hypertension, hypokalemia, hypernatremia, alkalosis, and periodic paralysis due to an aldosteronesecreting adenoma.23 We now realize that this metabolic syndrome can be caused by either a solitary adrenal adenoma or by bilateral adrenal zona glomerulosa hyperplasia. One of the clinical chores is to delineate patients with hyperplasia from those with adenoma.24 The syndrome

Hypertension

>3.6

Serum K

ⱕ3.6

ⱕ1.0

PRA

>1.0

Replete K and Na

1⬚ aldosteronism is unlikely

1⬚ aldosteronism is unlikely

24-hour urine: K > 40 mEq and Aldosterone > 15 mcg No

Check urine: Cortisol DOC

Adrenal CT scan

Hyperplasia or normal

Equivocal

Unilateral adenoma

Postural stimulation test (+) (or) Plasma 18 OHB > 100 ng% (or) Elevated urinary 18 OH-F, 18 oxo-F No

Yes Adrenal sampling

Not Lateralized

Medication

Lateralized

Adrenalectomy

Figure 8-7 Identifying primary hyperaldosteronism.

138


Effective circulating blood volume

RENAL potassium excretion

Renal perfusion pressure

Renal sodium retention

History physical exam BP x 3 > 140/90 Basic lab tests

Suspect pheochromocytoma

Juxtaglomerular apparatus

Aldosterone secretion

Angiotensinogen Angiotensin II Potassium balance

Converting enzyme

Renin release

Plasma norepinephrine Epinephrine

Elevated

Diagnosis pheochromocytoma

Dopamine Urinary catechols

Angiotensin I

Normal

Figure 8-8 Control of aldosterone secretion by means of interrelationships between the potassium and reninangiotensin feedback loops.

Localize CTT

− −

Venous sampling

MIBG

aldosterone secretion. Therefore, the term secondary hyperaldosteronism is utilized when there is increased renin secretion and secondary aldosterone production.27,28 The most common examples of secondary hyperaldosteronism would be renovascular hypertension and malignant hypertension. In contrast, with an adrenal adenoma or adrenal hyperplasia there is primary secretion of aldosterone and subsequently the sodium retention that occurs leads to a suppression of plasma renin activity. Therefore, returning to Figure 8-7, the hallmark of the entity is hypokalemia. However, some patients realize that weakness occurs with increased sodium intake and therefore restrict their sodium, and may have a more normal potassium than that first observed. Therefore, the entity should not be ruled out until the patient has sodium loading with 10 g of sodium a day for several weeks and repeat potassium measurements. A small subset of patients exhibits normokalemic hyperaldosteronism, and if there is a high index of suspicion for the disease, these patients should be studied further. If there is hypokalemia, a 24-hour urine should be collected demonstrating that there is urinary loss of potassium. The critical test is the measurement of plasma renin activity at a time when the patient is either on a low-sodium diet or is challenged with a diuretic. If the patient has hyperaldosteronism, the plasma renin activity remains inappropriately low despite sodium depletion. Because potassium is also a stimulus of aldosterone, the patient should be potassium repleted before measuring 24-hour urine and plasma aldosterone levels. Both of these values should be elevated in hyperaldosteronism. At this point the question is whether the patient has a unilateral adenoma or bilateral adrenal hyperplasia, and the imaging study of choice is an adrenal CT scan with 3 to 5-mm cuts through both adrenal glands. The next step that is traditionally performed would be adrenal vein sampling. The difficulty with adrenal vein sampling is obtaining adequate collections from the short, stubby, right adrenal vein, and when samples are collected, cortisol levels should also always be collected to ensure proper

MRI

Evaluate for other causes

+ +

α- blockade, then remove

Figure 8-9 Identifying pheochromocytoma.

catheter placement. An appropriate way of analyzing aldosterone levels is with comparative aldosterone/cortisol ratios from each side. It is our general policy to have positive lateralizing information, as well as a positive CT scan, before recommending exploration and unilateral adrenalectomy. However, more recently, in patients who have elevated plasma 18-hydroxy-B levels and elevated urinary 18-hydroxy-F levels, at times we have not required sampling when a clear adenoma was demonstrated on CT scan. In contrast, we have demonstrated a subset of patients with radiographic bilateral hyperplasia who will lateralize adrenal vein sampling for aldosterone. In this setting, we have performed unilateral adrenalectomy and a significant number of those patients have favorable biochemical and blood pressure responses, although most have required the continuation of some antihypertensive medication.24 Finally, in patients who have normal CT scans yet lateralize on sampling, if they show elevated 18-hydroxy products, we will operate; if not, we will follow those patients. The majority of patients with bilateral hyperplasia will not lateralize with adrenal vein sampling for aldosterone. Those patients are treated with spironolactone at an appropriate dose to control blood pressure. Often, they will need other medications, such as calcium channel blockers. PHEOCHROMOCYTOMA Pheochromocytoma is an uncommon entity, but one that has potentially lethal sequelae for the patient if not diagnosed. Therefore, it is generally felt that all patients with sustained hypertension should have the appropriate studies performed to rule out pheochromocytoma (Figure 8-9).29,30


The clinical manifestations exhibited by patients with pheochromocytoma are due to the physiologic effects of the catecholamines, dopamine, epinephrine, and norepinephrine. However, other signs and symptom complexes exhibited may be extremely variable, including the asymptomatic patient in whom a lesion is picked up simply on CT scan. In all reported series, hypertension is by far the most common sign (Table 8-3). As far as the type of hypertension, the patients may have either sustained hypertension, paroxysmal or dramatic attacks of hypertension, or sustained hypertension with superimposed paroxysms. Most series have shown this latter constellation of findings to be the most common in patients with pheochromocytoma. In addition, the frequency of attacks among patients is quite variable, ranging from a few times a year to multiple daily episodes. In addition, the duration may be minutes or hours and the nature of the attacks can vary dramatically. Most patients will exhibit a paroxysm or an episode once a week, and most of the attacks will last less than an hour. Usually, the attacks occur in the absence of recognizable stimuli, but a number of factors—particularly exercise, posture, trauma, or a variety of other situations—may precipitate an attack. One specific entity is noteworthy: catecholamineinduced cardiomyopathy. 31 Patients with catecholamine-induced cardiomyopathy will present with decreased cardiac function and congestive heart failure, and it is mandatory that their cardiac status be stabilized with the use of appropriate a- and b-adrenergic blocking agents as well as a-methylparatyrosine (a tyrosine hydroxylase inhibitor) (Figure 8-10) to cut down on catecholamine production before surgery is contemplated. Generally, the cardiomyopathy is reversible, and the patients can be operated on within weeks or months after the initial diagnosis and treatment is instituted. An appreciable number of pheochromocytomas have been found in association with other disease entities and hereditary syndromes. These entities include the association of tumors of the glomus jugulare region, neurofibromatosis, Sturge-Weber syndrome, and the von Hippel-Landau and familial multiendocrine adenopathy (MEA) syndromes. Pheochromocytomas occur in MEA2, a triad including pheochromocytoma, medullary carcinoma of the thyroid, and parathyroid adenomas (Sipple’s syndrome). Pheochromocytomas may also be a part of MEA-3, which also includes medullary carcinoma of the thyroid, mucosal neuromas, thickened corneal nerves, ganglioneuromatosis, and frequently marfanoid habitus. It is now believed that the relatives of patients with all of these syndromes should be evaluated for the presence of occult pheochromocytoma. In addition, there is a wellknown entity of familial pheochromocytoma in which multiple members of the kindred will be found to have multiple lesions and all members of such families should be both screened and then followed for the appearance of

these tumors. The mechanism of the increased incidence of pheochromocytomas in association with neuroendocrine dysplasias and medullary carcinoma of the thyroid may be explained by the amine precursor uptake and decarboxylation (APUD) cell system of Pierce. The APUD cells derived from the neural crest of the embryo share common ultrastructural and cytochemical features and elaborate amines by precursor uptake and decarboxylation.32,33 The laboratory diagnosis of pheochromocytoma is now extremely accurate, utilizing the urinary plasma measurements of catecholamines and their by-products (see Figure 8-9). Extremely accurate assays exist for these amines.34 At the present time it is felt that urinary catecholamines remain the measurement of choice with the measurement of total urinary catecholamines and metanephrines. Approximately 95% of patients will have elevated levels of these substances. In the patient with a severe paroxysmal hypertension who presents in the midst of hypertensive crisis, the plasma catecholamines are almost always elevated and can be utilized. Stimulation or suppression tests are generally not utilized at the present time. The one situation where they may be useful is in the patient who appears to have essential hypertension but borderline elevated catecholamines, and in this setting a clonidine suppression test may be useful. Following a single 0.3-mg oral dose of clonidine the patients with neurogenic hypertension at rest show a fall in norepinephrine, whereas patients with pheochromocytomas do not.34 The radiographic test that is most useful in both identifying and characterizing neuroendocrine adrenal tumors, and in identifying surrounding structures, is the MRI scan. We have been impressed with the multiple uses of MRI scans in patients with pheochromocytoma. Therefore, the test is as accurate as a CT scan in identifying lesions and also has a characteristic bright light bulb appearance on the T2-weighted study (see Figure 8-10).3 In addition, sagittal and coronal imaging can provide excellent anatomic information concerning the relationship between the tumor and the surrounding vasculature. Therefore, we feel that the MRI should be the initial scanning procedure in patients with the biochemical findings of pheochromocytoma. An alternative approach that also is useful at times, particularly for residual or multiple pheochromocytomas, is the metaiodobenzylguanidine (MIBG) scan that images medullary tissue.35,36 This test may be more sensitive than CT or MRI picking up small extra-adrenal lesions and has major use in patients where multiple lesions are suspected. ADRENAL SURGERY Adrenalectomy is the treatment of choice in most patients who have undergone appropriate metabolic evaluation

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Table 8-3 Symptoms Reported by 76 Patients (Almost all Adults) with Pheochromocytoma Associated with Paroxysmal or Persistent Hypertension Symptoms

Paroxysmal (37 Patients) (%)

Symptoms Presumably Due to Excessive Catecholamines or Hypertension Headache (severe) 92 Excessive sweating (generalized) 65 Palpitations ± tachycardia 73 Anxiety or nervousness (± fear of impending death, panic) 60 Tremulousness 51 Pain in chest, abdomen (usually epigastric), lumbar regions, lower abdomen, or groin 48 Nausea ± vomiting 43 Weakness, fatigue, prostration 38 Weight loss (severe) 14 Dyspnea 11 Warmth ± heat intolerance 13 Visual disturbances 3 Dizziness or faintness 11 Constipation 0 Paresthesia or pain in arms 11 Bradycardia (noted by patient) 8 Grand mal 5

P e r s i s t e n t (39 Patients) (%)

72 69 51 28 26 28 26 15 15 18 15 21 3 13 0 3 3

Manifestations Due to Complications Congestive heart failure ± cardiomyopathy Myocardial infarction Cerebrovascular accident Ischemic enterocolitis ± megacolon Azotemia Dissecting aneurysm Encephalopathy Shock Hemorrhagic necrosis in a pheochromocytoma Manifestations Due to Coexisting Diseases or Syndromes Cholelithiasis Medullary thyroid carcinoma ± effects of secretions of serotonin, calcitonin, prostaglandin, or ACTH-like substance Hyperparathyroidism Mucocutaneous neuromas with characteristic facies Thickened corneal nerves (seen only with slit lamp) Marfanoid habitus Alimentary tract ganglioneuromatosis Neurofibromatosis and its complications Cushing’s syndrome (rare) Von Hippel-Lindau disease (rare) Virilism, Addison’s disease, acromegaly (extremely rare) Symptoms Caused by Encroachment on Adjacent Structures or by Invasion and Pressure Effects of Metastases From Manger WM, Gifford RW Jr: Pheochromocytoma. In Laragh JH, Brenner BM (eds): Hypertension Pathophysiology Diagnosis and Management. New York, Raven Press, 1990, with permission.


Figure 8-10 MRI of pheochromocytoma.

and have been found to have a surgical lesion. Although most adrenal tumors are removed with a laparoscopic approach, the principles of open adrenal surgery apply and warrant review. However, the surgeon must be aware that there are unique aspects to the care in these patients, including specific preoperative management as outlined in Table 8-4. Accordingly, patients with hyperaldosteronism who are generally healthy require spironolactone 100 to 400 mg/day to restore their potassium supply. Patients with Cushing’s syndrome have severe systemic effects from the hyperglucocorticoidism. They are often obese, have diabetic tendencies, are poor wound healers, easily sustain bony fractures, and are susceptible to infection. Thus, they are at high risk for complications. In selected patients with markedly elevated cortisol levels the preoperative use of metabolic blockers, such as metyrapone, is required to reverse some of the clinical findings prior to adrenalectomy. Certainly, glucocorticoid replacement is required throughout the surgical procedure and postoperatively until the function of the contralateral adrenal gland occurs. Finally, in patients with a pheochromocytoma, adrenergic blockade generally with Dibenzyline is required, and at times the blockade of catecholamine production with metyrosine is also useful as previously discussed. The additional preoperative evaluation that is mandatory in patients with

pheochromocytoma is consultation with the anesthesiologist, who can be well aware of the patient and can plan strategy for management.37 Thus, the management of patients with an adrenal disorder is approached on a team basis, including experienced endocrinologists, radiologists, anesthesiologists, and urologists or general surgeons. Numerous approaches can be made to the adrenal gland (Table 8-5). The proper approach depends on the underlying cause of adrenal pathology, the size of the adrenal, the side of the lesion, the habitus of the patient, and the experience and preference of the surgeon. In most cases, there are a number of different options available, and a careful review of all the variables is required before a choice is made. Thus, each case should be considered individually, although some approaches are preferable for a given disease. For example, in patients with large adrenal tumors, a thoracoabdominal approach is often utilized. In contrast, a posterior or modified posterior approach is preferred for small localized lesions. Finally, in patients with multiple lesions, either extra-adrenal or bilateral will be explored using a transabdominal chevron incision. Before describing the specific techniques, a number of unifying concepts warrant attention. First, adequate visualization is imperative, as the adrenal glands lie high in the retroperitoneum and quite posterior. Therefore, the

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Table 8-4 Preoperative Management

Table 8-5 Surgical Approaches in Adrenal Disorder Approach

Treatment Primary hyperaldosteronism

Spironolactone, 100–400 mg/ day, 2–3 weeks Follow K+ until normal Blood pressure should fall

Primary hyperaldosteronism Posterior (left or right) Modified posterior (right) Eleventh rib (left > right) Posterior transthoracic

Cushing’s syndrome

Control of glucose abnormalities Documentation of osteoporosis Glucocorticoid replacement (before, during, and after surgery) Perioperative antibiotics

Cushing’s adenoma

Eleventh rib (left or right) Thoracoabdominal (large) Posterior (small)

Cushing’s disease Bilateral hyperplasia

Bilateral posterior Bilateral eleventh rib (alternating)

Adrenal carcinoma

Thoracoabdominal Eleventh rib Transabdominal

Bilateral adrenal ablation

Bilateral posterior

Pheochromocytoma

Transabdominal (chevron) Thoracoabdominal (large, usually right) Eleventh rib

Neuroblastoma

Transabdominal Eleventh rib

Pheochromocytoma

Adrenergic blockade Phenoxybenzamine (Dibenzyline), 20–160 mg/day Metyrosine (if needed) Volume expansion Crystalloid β-Blockade if cardiac arrhythmias (only after α-blockade established) Anesthesia consultation

From Vaughan ED Jr: Adrenal surgery. In Marshall FF (ed): Textbook of Operative Urology. Philadelphia, WB Saunders Co, 1996, with permission.

use of a headlight by both the surgeon and first assistant is critical, and hemostasis should be rigorously maintained. The operator should bring the adrenal down by initially exposing the cranial attachments and dividing the rich blood supply between either right-angled clips or utilizing a forceps cautery or the harmonic scalpel. Thus, it is often simplest to begin the dissection laterally, identifying the vascular supply and working around the cranial edge of the gland. The posterior surface is generally devoid of vasculature and after the gland is freed superiorly with gentle traction on the kidney, the gland can be brought inferiorly for control of the adrenal vein. The only tumor handled in a different fashion would be a pheochromocytoma where intent should be made to obtain control of the adrenal vein early so as to stabilize the patient from a burst of catecholamine release during manipulation. The adrenal gland is extremely friable and fractures easily, which can cause troublesome bleeding. Therefore, tension or traction should be maintained on the kidney or surrounding structures and not on the adrenal itself. The concept has been stated that the “patient should be dissected from the tumor,” a view that is particularly true for pheochromocytomas, in which the glands should not be manipulated (Figure 8-11).

From Vaughan ED Jr: Adrenal surgery. In Marshall FF (ed): Textbook of Operative Urology. Philadelphia, WB Saunders Co, 1996, with permission.

Posterior Approach The posterior approach can be used for either bilateral adrenal exploration or unilateral removal of small tumors (Figure 8-12). The bilateral approach is rarely utilized today because of our excellent localization techniques. It is now utilized primarily for ablative total adrenalectomy. The options for incisions are shown in Figure 8-12; generally rib resection is preferable to gain high exposure. After standard subperiosteal rib resection, care should be taken with the diaphragmatic release, and the pleura should be avoided, and the diaphragm swept cranially. The fibrofatty tissues within Gerota’s fascia are swept away from the paraspinal musculature, exposing a subdiaphragmatic “open space” that is at the posterior apex of the resection. The liver within the peritoneum is dissected off the anterior surface of the adrenal and the cranial blood supply is divided. Medially on the right, the IVC is visualized. The short, high adrenal vein entering the cava in a dorsolateral position is identified and can be clipped or ligated. The adrenal can then be drawn caudally by traction on the kidney. The adrenal arteries will issue from behind the IVC and these must be carefully clipped; otherwise, troublesome bleeding can occur.


Figure 8-11 MRI of recurrent pheochromocytoma with an excellent demonstration of anterior crossing right renal vein, feeding lumbar vein, and involvement of right renal artery.

Finally, the adrenal is removed from the superior aspect of the kidney and care must be taken to avoid apical branches of the renal artery. On the left, the approach is similar with division of the splenorenal ligament given initial lateral exposure. The posterior approach can be modified for a transthoracic adrenal exposure to the diaphragm38; however, this more extensive approach is rarely necessary for small adrenal tumors. Modified Posterior Approach

Figure 8-12 Posterior approach to the adrenals.

Although the posterior approach has the advantage of rapid adrenal exposure and low morbidity, there are definite disadvantages. This approach may impair respiration, the abdominal contents are compressed posteriorly, and the visual field is limited. In addition, if bleeding occurs, it is difficult to extend the incision to gain a better exposure. Therefore, we have developed a modified posterior approach for right adrenalectomy utilizing the Gil-Vernet position.39 The approach is based on the anatomic relationship with the right adrenal, which lies deep posterior and high in the retroperitoneum behind the liver (Figure 8-13A). In addition, the short, stubby right adrenal vein enters the IVC posteriorly at the apex of the adrenal. Hence, we utilize an approach that is posterior, but the patient is in a modified position, similar to that used for a Gil-Vernet dorsal lumbotomy incision.40 The patient is first placed in a formal lateral flank position and then allowed to fall forward into the modified posterior position (see Figure 8-13B). Subsequently, the 11th or 12th rib is resected

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Figure 8-13 Modified posterior approach to the right adrenal.

with care to avoid the pleura. The diaphragm then is dissected off the underlying peritoneum and liver in order to gain mobility. Similarly, the inferior surface of the peritoneum, closely associated with the liver, is sharply dissected from Gerota’s fascia, which is gently retracted inferiorly. It is of note that the adrenal gland is not identified during the early portion of the dissection, and because of the modified posterior approach, the surgeon can become disoriented if not thoroughly familiar with anatomic relationships. The adrenal will become visible in the depth of the incision as the final hepatic attachments are divided. The

lateral, empty space can be found exposing the posterior abdominal musculature and often the IVC. Multiple small arteries course behind the IVC and emerge over the paraspinal muscles, and these are clipped and divided. At this point the adrenal can usually be moved posteriorly against the paraspinal muscles exposing the anterior surface of the IVC below the adrenal gland. The major advantage of this approach is that the adrenal vein is easily identified because it emerges from the segment of the IVC exposed and courses up to the adrenal, which now rises toward the surgeon. In other flank or anterior positions the adrenal vein resides in its poste-


rior relationship, requiring caval rotation and the chance of adrenal vein avulsion. After adrenal vein exposure, it is doubly tied and divided or clipped with right-angle clippers and divided (see Figure 8-13D). The remaining removal of the adrenal is as we previously described for the posterior approach. On the left side we do not use this modified approach and use a standard flank approach with a fairly small incision. We have used the modified posterior approach for all patients with right adrenal aldosterone-secreting tumors and for other patients with benign adenomas of less than 6 cm. We do not recommend the approach for patients with large lesions or malignant adrenal neoplasms. The approach has been used for patients with relatively small pheochromocytomas. Flank Approach The standard extrapleural, extraperitoneal 11th rib resection is excellent for either left or right adrenalectomy. After completion of the incision, the lumbocostal arch is utilized as a landmark showing the point of attachment of the posterior diaphragm to the posterior abdominal musculature. Gerota’s fascia, containing the adrenal and kidney, can be swept medially and inferiorly, giving exposure to the splenorenal ligament on the left, which should be divided to avoid splenic injury (Figure 8-14). Working anteriorly on the left, the spleen and pancreas within the peritoneum can be lifted cranially, exposing the anterior surface of the adrenal gland. On the right side, a similar maneuver is used to lift the liver within the peritoneum off the anterior surface of the adrenal. Quite often the adrenal gland cannot be identified precisely until these maneuvers are performed. One should not attempt to dissect into the body of the adrenal or to dissect the inferior surface of the adrenal off the

Figure 8-14 Release of splenorenal ligament early in exposure of left adrenal.

kidney. The kidney is useful for retraction. The dissection should continue from lateral to medial along the posterior abdominal and diaphragmatic musculature, with precise ligation or clipping of the small but multiple adrenal arteries. While the operator clips these arteries with one hand, the opposite hand is employed to retract both adrenal and kidney inferiorly. With release of the superior vasculature, the adrenal becomes easily visualized. On the left medially, the phrenic branch of the venous drainage must be carefully clipped or ligated (Figure 8-15). This vessel is not noted in most atlases but can cause troublesome bleeding if divided. The medial dissection along the crus of the diaphragm and aorta will lead to the renal vein; finally, the adrenal vein is controlled, doubly tied, and divided. The adrenal is then removed from the kidney with care to avoid the apical branches of the renal artery (see Figure 8-15). On the right side, the dissection is similar. However, after release of the adrenal from the superior vasculature, it is helpful to expose the IVC and divide the medial arterial supply. This maneuver allows mobilization of the cava for better exposure of the high posterior adrenal vein, which is doubly tied or clipped and divided (Figure 8-16).

Figure 8-15 Further exposure of left adrenal including phrenic vein.

146


Figure 8-16 Exposure of right adrenal with and without nephrectomy.

Patients with large adrenal carcinomas may require an en bloc resection of the adrenal and kidney following the principles of radical nephrectomy (see Figure 8-16). A major deviation from this technique is used for the patient with pheochromocytoma, in whom the initial dissection should be aimed toward early control and division of the main adrenal vein on either side. Obviously, in this setting, the anesthesiologist should be notified when

the adrenal vein is divided because a marked drop in blood pressure often occurs, even when the patient is adequately hydrated. After removal of the adrenal, inspection should be made for any bleeding and for pleural tears of the diaphragm. The kidney should also be inspected. The incision is closed without drains with interrupted 0 polydioxanone sutures.


Thoracoabdominal Approach The thoracoabdominal 9th or 10th rib approach is utilized for large adenomas; for some large adrenal carcinomas, and for well-localized pheochromocytomas. The incision and exposure are standard, with a radial incision through the diaphragm and a generous intraperitoneal extension. The techniques described for adrenalectomy with the 11th rib approach are used. Transabdominal Approach The transabdominal approach is commonly selected for patients with pheochromocytomas, for children, and for some patients with adrenal carcinomas. The concept is to have the ability for complete abdominal exploration to identify either multiple pheochromocytomas or adrenal metastases. I use the transverse or chevron incision, which I believe gives better exposure of both adrenal glands than a midline incision. The rectus muscles and lateral abdominal muscles are divided, exposing the peritoneum. Upon entering the peritoneal cavity, the surgeon should gently palpate the para-aortic areas and the adrenal areas. Close attention is given to blood pressure changes in an attempt to identify any unsuspected lesions if the patient has a pheochromocytoma. This maneuver is less important today because of the excellent localization techniques previously discussed. In fact, with precise preoperative localization of the offending tumor, the chevron incision does not need to be completely symmetric and may be limited on the contralateral side. If the patient has a lesion on the right adrenal, the hepatic flexure of the colon is reflected inferiorly. The incision is made in the posterior peritoneum lateral to the kidney and carried superiorly, allowing the liver to be reflected cranially (Figure 8-17). Incision in the peritoneum is carried downward, exposing the anterior surface of the IVC to the entrance of the right renal vein. Once the cava is cleared, one or two accessory hepatic veins are often encountered, which should be secured (Figure 8-18B). These veins are easily avulsed from the cava and may cause troublesome bleeding. Ligation of these veins gives 1 to 2 cm of additional caval exposure of the short posterior right adrenal vein. Small accessory adrenal veins may also be encountered. The cava is then rolled medially, exposing the adrenal vein, which should be doubly tied or clipped and divided (Figure 8-18C). After control of the adrenal vein, it is simplest to proceed with the superior dissection, lifting the liver off the adrenal and securing the multiple small adrenal arteries arising from the inferior phrenic artery, which is rarely seen. The adrenal can be drawn inferiorly with retraction on the kidney, and the adrenal arteries traversing to the adrenal from under the cava can be secured with rightangled clips. The final step is removing the adrenal from the kidney.

Figure 8-17 Exposure of right adrenal and left adrenal utilizing a transabdominal approach.

Figure 8-18 Further transabdominal exposure of the right adrenal with ligation of an accessory right hepatic vein.

148


The left adrenal vein is not as difficult to approach because it lies lower, partially anterior to the upper pole of the kidney, and the adrenal vein empties into the left renal vein. Accordingly, on the left side, the colon is reflected medially, exposing the anterior surface of Gerota’s capsule; the initial dissection should involve identification of the renal vein (see Figure 8-17B). In essence, the dissection is the same as for a radical nephrectomy for renal carcinoma. Once the renal vein is exposed, the adrenal vein is identified, doubly ligated, and divided. After this maneuver the pancreas and splenic vasculature are lifted off the anterior surface of the adrenal gland. Because of additional drainage from the adrenal into the phrenic system, I generally continue the medial dissection early to control the phrenic vein. I then work cephalad and lateral to release the splenorenal ligament and the superior attachments of the adrenal. The remainder of the dissection is carried out as previously described. After removal of the tumor, regardless of size, careful inspection is made to ensure hemostasis and the absence of injury to adjacent organs. Careful abdominal exploration is carried out, after which the wound is closed with the suture material of choice. No drains are used. Patients with multiple endocrine adenopathy of family histories of pheochromocytoma, as well as pediatric patients, should be considered at high risk for multiple

lesions. Preoperative evaluation should identify these lesions, but, regardless, a careful abdominal exploration should be carried out. In patients with suspected malignant pheochromocytomas, en bloc dissections may be necessary to obtain adequate margins, a concept that also applies in patients with adrenal carcinomas. Evaluation with MRI to obtain transverse, coronal, and sagittal images is extremely useful to define clearly the adrenal relationships to the IVC and renal vessels as well as to localize the adrenal vein. In patients with pheochromocytomas, postoperative management includes maintenance of arterial and venous lines in an intensive care setting until they are stable. Often, 24 to 48 hours are required for the full effect of phenoxybenzamine, the α-blocking agent commonly given, to wear off and for normal α-receptor activity to be restored. PARTIAL ADRENALECTOMY The standard treatment for patients with the adrenal lesions described has been total adrenalectomy. However, there recently has been reported an excellent paper showing the utility of partial adrenalectomy in patients with primary hyperaldosteronism.41 I have not used partial adrenalectomy in a patient for normal contralateral adrenal, but certainly have used the technique in patients with bilateral disease (Figure 8-19). Thus, in

Figure 8-19 MRI showing bilateral adrenal pheochromocytoma in a patient with bilateral glomus jugulare tumors. A, Small right adenoma that was enucleated and which was partially resected. B, Large left bright pheochromocytoma that was totally removed.


one patient with a pheochromocytoma on one side and a nonfunctioning adenoma on the other, the adenoma was simply enucleated from the adrenal. In a second patient with bilateral pheochromocytomas, the larger lesion was totally excised with partial adrenalectomy was utilized to remove the contralateral tumor. Care has to be taken to obtain thorough hemostasis when performing a partial adrenalectomy because of the vascular nature of the adrenal. Partial adrenalectomy or adrenal sparing surgery is most useful in patients at risk for multiple adrenal tumors, such as von Hippel-Landau kindreds.42,43,44 CRYOSURGERY Cryoablation is currently used as a surgical alternative for the treatment of prostatic, lung, brain, pharyngeal, and liver tumors. We have demonstrated in a canine model45 that adrenal cryoablation is effective in destroying adrenal tissue and is safe. We have successfully used the technique in one patient with primary hyperaldosteronism. Adrenal laparoscopic cryoablation may shorten operative time and be as effective as total adrenalectomy in patients with small lesions. ABLATION Successful adrenal ablation using transcatheter arterial infusion of ethanol has been described in 33 cases of primary hyperaldosteronism; the approach was successful in 27 cases (82%). Five patients required surgical adrenalectomy. This technique may be useful in the patient who is at high risk with use of general anesthesia.46 More recently, direct percutaneous tumor injection with ethanol has given excellent results in 41 patients with pheochromocytoma with reversal of hormonal abnormalities.47 LAPAROSCOPIC ADRENALECTOMY Laparoscopic adrenalectomy, first reported in 1991,48 is now the surgical approach of choice for adrenal removal in the majority of patients.49 The exceptions are patients with large irregular adrenal carcinoma where adjacent organs may be involved, large pheochromocytomas, patients with large adrenal hemorrhage, and in some cases of metastatic disease.

A variety of laparoscopic approaches to the adrenal exist.50,51 The lateral transperitoneal, anterior transperitoneal, lateral retroperitoneal, and posterior retroperitoneal techniques have been described similar to the rationale for an open approach. The laparoscopic approach depends on the patient’s habitus, the underlying pathology and the skill and experience of the operating surgeon.1 The results of these approaches mirror the results of open adrenalectomy with less morbidity and hospitalization time for the patient.52 The lateral transperitoneal approach is the technique most often reported in the literature. Most laparoscopic surgeons have extensive experience identifying, dissecting, and mobilizing the adjacent organs required in order to obtain adrenal exposure and removal. For this approach the patient is placed in a full lateral position (Figure 8-20A and B). Bilateral adrenalectomy requires repositioning and redraping. In contrast, the retroperitoneal approaches avoid dissection and mobilization of intra-abdominal viscera (Figure 8-21A and B). The major limitation is the small working space that compromises instrument placement and crossing of instruments can occur. The approach is best for patients with small adrenal tumors. Balloon inflation is used to dissect the retroperitoneal space. During this procedure, close blood pressure monitoring is necessary in patients with pheochromocytoma since the expanding balloon may compress the tumor with catechol release. Regardless of the approach utilized the principles of adrenal surgery previously described are the same. SUMMARY We are fortunate that our ability to diagnose the specific adrenal entities that mandate a surgical approach is extremely accurate. The combination of analytic methodology to measure the appropriate adrenocortical and medullary hormonal production and the radiologic techniques for localization are superb. The management of these adrenal disorders usually employing a laparoscopic approach following localization is highly successful, resulting in a reversal of both metabolic abnormalities and the hypertension that often accompanies these diseases. Indeed, this is a true success story with the evolution of these different techniques over the past 50 years.

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Figure 8-20 A, Trocar placement for left transperitoneal adrenalectomy. The distribution is a mirror image of that used for the left side. Dissection of the left adrenal gland: the spleen (3), pancreas (4), left lobe of the liver (2), renal vein (5), and kidney are shown. The left adrenal vein (1) has been isolated. A clip is applied to the adrenal vein before dividing it (inset, right). The inset (left) shows the patient’s position on the operating table. B, Trocar placement for a right transperitoneal adrenalectomy: supra-umbilical trocar for camera (if only three trocars are used) or splenic retractor (if four trocars are used). Trocars at anterior axillary line and midaxillary line for instruments for dissection. Fourth trocar halfway between midline and anterior is shown. A clip is applied to the adrenal vein before dividing it (inset, right). The inset (left) shows the patient’s position on the operating table.

Figure 8-21 A, The retroperitoneal approach for the left adrenal gland (1): the adrenal vein (2) is seen anterior to the renal artery (4); the renal artery (4) and vein (6) are identified early in the dissection. The kidney (7) and ureter (8) are also depicted. The inset (left) shows the patient’s position on the operating table. Continued


Figure 8-21 cont’d B, The retroperitoneal approach for the right adrenal gland (1): the adrenal vein (2) is seen at its takeoff from the vena cava (5); the renal artery (4) and vein (6) are identified early in the dissection. The kidney (7) and ureter (8) are also depicted. The inset (left) shows the patient’s position on the operating table.

REFERENCES 1. Vaughan ED Jr, Blumenfeld JD, Del Pizzo J, Schichman SJ, Sosa RE: The adrenals. In Walsh PC, Retik AB, Vaughan ED Jr, Wein AJ (eds): Campbell’s Urology, 8th edition. Philadelphia, WB Saunders Co, 2002. 2. Belldegrun A, Ritchie A, Figlin R, Oliver R, Vaughan ED Jr (eds): Renal and Adrenal Tumors. Oxford, Oxford University Press, 2003. 3. Taneja SS, Smith RB, Ehrlich RM (eds): Complications of Urologic Surgery Prevention and Management. Philadelphia, WB Saunders Co, 2001. 4. Lee MJ, Mayo-Smith WW, Hann PE, et al: State-of-theart MR imaging of the adrenal gland. Radiographics 1994; 14:1015–1029. 5. Vaughan ED Jr: Adrenal surgery. In Marshall FF (ed): Textbook of Operative Urology. Philadelphia, WB Saunders Co, 1996. 6. Orth DN: Cushing’s syndrome. N Engl J Med 1995; 32:791. 7. Teeger S, Papanicolaou N, Vaughan ED Jr: Imaging of adrenal masses. In Belldegrun A, Ritchie A, Figlin R, Oliver R, Vaughan ED Jr (eds): Renal and Adrenal Tumors. Oxford, Oxford University Press, 2003. 8. Murai M, Marumo K: Selection of patients with incidentally discovered adrenal masses for operation. In Belldegrun A, Ritchie A, Figlin R, Oliver R, Vaughan ED Jr (eds): Renal and Adrenal Tumors. Oxford, Oxford University Press, 2003. 9. Ng L, Libertino JM: Adrenal cortical carcinoma: diagnostic evaluation and treatment. J Urol 2003; 169: 1—11. 10. Nakajo M, Nakabeppu Y, Yonekura R, et al: The role of adrenocortical scintigraphy in the evaluation of unilateral

11.

12.

13.

14.

15.

16.

17.

18.

19. 20.

21.

incidentally discovered adrenal and juxtaadrenal masses. Ann Nucl Med 1993; 7(3):157–166. Ross NS, Aron DC: Hormonal evaluation of the patient with an incidentally discovered adrenal mass. N Engl J Med 1990; 323:1401. Cerfolio RJ, Vaughan ED Jr, Brenan TC, Hiruela ER: Accuracy of computed tomography in predicting adrenal tumor size. Surg Gynecol Obstet 1993; 176:307. Mayo-Smith WW, Lee MJ, McNicholas MM et al: Characterization of adrenal masses (400,000) when controlling for pathologic stage, nuclear grade, and cell type.29,30,31 Anemia and serum iron have also been useful as tumor markers for initial evaluation and follow-up.29,32 Normochromic and normocytic anemia and anemia of chronic diseases are the most common hematologic abnormalities associated with RCC.29 MOLECULAR MAKERS The search for better markers has increasingly moved toward the molecular level. The prognosis for patients with locally confined RCC is known to be variable and emphasis on morphologic character, proteins, antigens and other prognostic markers is being sought to aid in the diagnosis and prognosis of RCC.29 Molecular markers of proliferation like Ki-67, silver staining nucleolar organizer regions (AgNOR), and proliferating cell nuclear antigen (PCNA) are present in cycling cells and therefore have potential utility in estimating the biologic aggressiveness of a given tumor. AgNOR reflect transcription activity of ribosomal RNA and cellular mitotic activity. For some authors the AgNOR score is an independent prognostic factor associated with survival,33–35 whereas for others it is associated with histologic grade but is not an independent factor.36 PCNA is a protein synthesized during the late G1 and S phases of the cell cycle. For some authors a low PCNA index (less than 10%) is an independent positive predictor of disease-free survival but not of overall survival,37 whereas for others it

is associated with good survival.35,38,39 Ki-67 identifies an antigen of 395 kDa whose expression is detectable during the G1 phase, increases during S phase and rapidly decreases after mitosis. There is an agreement that Ki-67 is an excellent maker of proliferation in histologic material analyzed immunohistochemically. According to the result of several studies, the Ki-67 index is correlated with the histologic grade and stage,35,36,37 and might be a more powerful prognostic factor than the PCNA index. Rini and Vogelzang39 concluded that because Ki-67 is present in cells during all cell cycle phases, it provides a more accurate determination of the proliferation rate than the PCNA index but more multivariate studies are needed.29,35,39,40 Cell adhesion molecules and angiogenesis factors have also been evaluated. Cadherins are a large family of transmembrane proteins responsible for mediating cell-to-cell adhesion, and when expression decreases, their inherent ability to modulate and preserve epithelial integrity diminishes. Lack of E-cadherin expression correlates with aggressiveness in several tumors, but in RCC, only 20% express this glycoprotein.41 E-cadherin is localized to Bowman’s capsule and other tubular segments rather than the proximal tubular epithelium, calling into question whether it plays an integral role in RCC carcinogenesis.29 Shimazui42 has shown that cadherin-6 is the major one in the proximal renal tubules and the tumors themselves. His group found that aberrant expression of cahderin-6 connoted poor survival.29,42,43 Paul et al.44 have reproduced these data wherein the majority of RCCs with histology-associated poor prognosis (i.e., high-grade clear cell cancers and sarcomatoid renal tumors) showed aberrant expression. The tumor with a historically good prognosis (low-grade clear cell carcinomas and papillary cancers) exhibited normal cadherin-6 expression.29,44 Studies investigating the role of angiogenesis, using microvessel density (MVD) as a marker, as a correlate with the development of metastases have not been rewarding. There was no correlation to clinical stage, pathologic stage, or tumor grade.29,45 RCC is a vascular tumor, and its direct relationship to angiogenesis has yet to be completely determined.29 The p53 protein has also been studied in RCC. The p53 protein binds DNA and is believed to regulate transcription, acting as a “checkpoint” to induce cell cycle arrest.29,46 This tumor suppressor gene, when mutated, inactivates the normal function of DNA damage surveillance. Aneuploid cells originate, carcinogenesis occurs, and tumor progression can ensue.47 Mutant p53 proteins have a prolonged half-life and with accumulation are detectable with immunohistochemical analysis.48 However, controversy exists with regards to the frequency of the mutation in RCC, ranging from 4% to 40% of RCC specimens tested, and its resultant

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prognostic power. The clinical significance of p53 and other apoptotic markers has yet to be determined.29,49,50 Carbonic anhydrase IX (CAIX) protein, a member of the carbonic anhydrase family, is thought to play a role in the regulation of cell proliferation in response to hypoxic conditions and may be involved in oncogenesis and tumor progression.51–54. Constitutive expression of CAIX as a result of von Hippel-Lindau (VHL) protein mutations has been described for RCC.55 Recent studies now indicate that expression of CAIX is regulated by the hypoxia-inducible factor (HIF) 1 transcriptional complex that mediates expression of a number of genes in response to hypoxic conditions.56 It has been postulated that cell surface carbonic anhydrase regulate acid-base balance to optimize conditions in the tumor invasiveness.54 Acidification of the extracellular matrix is known to induce expression of angiogenic factors57 and may inhibit cellular immunity,58 which additionally promotes tumor aggressiveness. In addition, there is some evidence for the association of CAIX with loss of contact inhibition and anchorage dependence of cancer cells.59 Bui et al.51 have investigated CAIX as kidney cancer marker as an independent predictor of progression and survival. Immunohistochemical analysis using a CAIX monoclonal assay was performed on tissue microassays constructed from paraffin-embedded specimens from 321 patients treated by nephrectomy for clear cell RCC. CAIX staining was correlated with response to treatment, clinical factors, pathologic features, and survival. CAIX staining was present in 94% of clear cell RCCs. Survival tree analysis determined that a cutoff of 85% CAIX staining provided the most accurate prediction of survival. Low CAIX (≥85%) staining was an independent poor prognostic factor for survival for patients with metastatic RCC, with a hazard ratio of 3.10 ( p < 0.001). CAIX significantly substratified patients with metastatic disease when analyzed by T stage, Fuhrman grade, nodal involvement, and performance status ( p < 0.001, p = 0.001, p = 0.009, p = 0.005, respectively). For patients with nonmetastatic RCC and at high risk for progression, low CAIX predicted a worse outcome similar to patients with metastatic disease ( p = 0.058). CAIX status may potentially aid in the selection of patients who might benefit from IL-2 or CAIX-targeted therapies. Furthermore, patients with high-risk localized RCC and low CAIX may be potential candidates for adjuvant immunotherapy.51 MOLECULAR GENETICS To date, four major dominantly inherited forms of RCC have been described. RCC occurs in association with VHL disease. About 45% of patients with VHL disease have RCC, which is metastatic in half of the cases at diagnosis, often bilateral and multifocal, occurs in younger patients,

and has an equal male to female ratio. Tumors associated with VHL are predominantly of the clear cell type and are associated with germline mutations of the tumor suppressor gene, VHL gene, located on chromosome 3p. After extensive work, the VHL gene has been mapped to the 3p25–26 region and VHL inactivation by point mutation and allelic loss has been reported to occur in both sporadic and VHL-associated RCC. Specific sites or types of mutations within the VHL gene appear to correlate with specific phenotypic expression of the gene: VHL type I (VHL without pheochromocytomas) and VHL type II (VHL with pheochromocytomas). VHL disease is characterized by renal cysts, RCC (clear cell histology), retinal hemangiomas, hemangioblastomas of the cerebellum and spinal cord, pancreatic carcinomas and cysts, epididymal cysts and cystadenomas, and pheochromocytomas.60–68 The VHL gene product forms a complex that degrades two α subunits of HIF, an intracellular protein that plays an important role in regulating cellular responses to hypoxia, starvation, and other stresses.16,69 The HIFα subunits are transcription factors that regulate the expression of a number of proteins, including vascular endothelial growth factor (VEGF), the primary proangiogenic growth factor in RCC, contributing to the pronounced neovascularity associated with RCC,16,63,70 glucose transporter (GLUT-1), and transforming growth factor (TGF)-α. Hereditary papillary renal carcinoma (HPRC) is a hereditary cancer syndrome, which generally develops in older patients (50s and 60s). The affected individuals are at risk to develop bilateral, multifocal papillary RCC. Linkage analysis of the families led to the discovery of the HPRC gene on chromosome 7.71–73 This syndrome, which has an autosomal dominant inheritance pattern, is caused by missense mutations in the tyrosine kinase domain of the MET proto-oncogene at 7q31.73 Patients with germline or somatic mutations in the MET protooncogene develop a specific subtype of papillary renal carcinoma—papillary renal carcinoma type 1. In vitro and in vivo studies suggest that MET functions as a dominantly acting oncogene in HPRC and in sporadic papillary renal carcinoma.74 Patients with hereditary hair follicle tumors (fibrofolliculomas) on their face and neck have a high risk for developing kidney cancer (20% to 30%), lung cysts (90%), and pneumothorax (20%). Inherited fibrofolliculoma is called Birt-Hogg-Dubé syndrome (BHD). The BHD gene has been localized to the short arm of chromosome 17. BHD patients are at risk for the development of chromophobe RCC, oncocytic renal carcinoma, and oncocytoma.75–78 Familial renal oncocytoma is an entity currently undergoing evaluation and definition, in which multiple bilateral renal oncocytomas develop in affected family members. The genetic defect involved in the pathogenesis of familial renal oncocytoma has not yet been identi-

Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 177

fied. However, clues to the location of this gene have come from cytogenetic studies: one characterized by the loss of chromosomes 1 and Y,79 and the other by translocations involving the breakpoint region 11q13.68,80–82 The untreated natural history of familial renal oncocytoma is currently being studied.83 Hereditary leiomyomatosis renal carcinoma (HLRC) is another type of hereditary renal carcinoma. Affected HLRC individuals are at risk for the development of cutaneous leiomyomas, uterine leiomyomas (fibroids), and renal carcinoma. The HLRC renal tumors are of varying histologic type, but the predominate histologic phenotype is type 2 papillary renal carcinoma.84 PATHOLOGY RCCs originate from renal tubular cells. Renal cancer has an equal frequency on the right and left and is distributed equally throughout the kidney. Fifteen percent of tumors extend to the renal vein, and 8% extend to the vena cava. The histologic classification of RCC has undergone a major revision since 1990. Traditionally, renal cancers have been classified as clear cell, granular, sarcomatoid, and papillary types. Malignant renal epithelial neoplasms are now subdivided under the new classification system (Table 10-2) based on prominent morphologic features.85 Major changes include the addition of a new histologic subtype, the chromophobe cell carcinoma; the reclassification of granular cell tumors into other categories; and the recognition that sarcomatoid lesions represent poorly differentiated elements derived from other histologic subtypes, rather than a distinct tumor type.16,85–87 Common or conventional RCC accounts for approximately 70% to 80% of all RCCs. They are highly vascular and are typically yellow when

Table 10-2 Classification of Renal Cell Carcinoma Subtype

Incidence (%)

Affected Chromosomes

Conventional

70–80

3p, 17

Papillary

10–15

3q, 7, 12, 16, 17, 20, Y

Chromophobe

4–5

1, 2, 6, 10, 13, 17, 21

Collecting duct

50%

20 10 0 0

1

2

83 45 59

50 23 36

24 6 16

4

5

6

7

8

9 10 11 12

Time in years

Time in years 96 49 62

3

12 4 8

8 3 3

206 175

155 153

79 89

37 38

6 12

13 3

Number at risk Number at risk Figure 25-5. Prostate-specific antigen outcome following external beam radiation therapy stratified by the percent of positive prostate biopsies for intermediate-risk patients with clinically localized disease.

(such as microvessel density and ploidy), imaging approaches (such as color Doppler), PSA derivatives (such as PSA velocity, PSA density, and free PSA), and reverse transcriptase polymerase chain reaction (rtPCR) to examine PSA-expressing cells in the peripheral blood, bone marrow, and pelvic lymph nodes all have been examined11–15 to assess their ability to predict PSA outcome following definitive local therapy for patients with clinically localized disease. While many of these factors have been predictive of PSA outcome on univariable analysis, they await testing in a multivariable model that accounts for the established prognostic factors to determine their clinical significance. Radiologic Staging The ability of computerized tomography, pelvic coil magnetic resonance imaging (MRI), and transrectal ultrasound (TRUS) to identify extracapsular extension (ECE) and/or seminal vesicle invasion (SVI) for patients with clinically localized disease based on the DRE is limited. The accuracy of these studies does not exceed 60%,16,17 and therefore none of these studies is recommended for staging patients with clinical stage T1 or stage T2 disease. Patients with more advanced disease (stage T3 or stage T4) as determined by DRE should have a computed tomographic (CT) scan or MRI scan of the pelvis to assess

Figure 25-6. Prostate cancer-specific survival following external beam radiation therapy stratified by the percent of positive prostate biopsies for intermediate-risk patients with clinically localized disease.

for pelvic lymphadenopathy. A bone scan is generally recommended to identify metastatic disease and is indicated for patients with either clinical stage T3 or stage T4 disease, biopsy Gleason score of 4 + 3 or higher, a PSA level greater than 20 ng/ml, or clinical symptoms. The role of endorectal MRI (erMRI) has been evaluated for patients with clinical stage T1c or stage T2 disease to assess whether information regarding pathologic stage and PSA outcome following RP was provided.18 In experienced hands, the erMRI finding of T3 versus T2 disease was 80% accurate in predicting pathologic stage. However, the erMRI did not add clinically meaningful information for the vast majority of the patients (low risk and high risk) after accounting for the pretreatment PSA level, biopsy Gleason score, clinical T-category, and the percent positive prostate biopsies. In the intermediate risk patients, however, the erMRI provided a clinically relevant stratification of 5-year PSA outcome as shown in Figure 25-7. At present, however, outside of high risk localized of locally advanced prostate cancer, imaging of the pelvis with erMRI to assess for evidence of pelvic lymphadenopathy or evidence of ECE or SVI remains under investigation. Pretreatment Nomograms A popular tool for predicting outcomes in prostate cancer is the nomogram. Strictly speaking, a nomogram is a series of lines with point values, which one manipulates

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Part V Prostate Gland and Seminal Vesicles

nomograms have been developed and validated for predicting biochemical failure for patients treated with surgery, brachytherapy, and external beam RT.3,21–7 They are presented in Figures 25-8 to 25-10. They predict biochemical failure, and future nomograms are necessary for predicting more distant and clinically relevant endpoints, such as metastasis and death. These prediction models are available in software for the palm and desktop computers from http://www.nomograms.org.

100 90 % bNED Survival

80 70 60 50 40 30

MR T2 MR T3

20

SUMMARY

10 0 0

1

2

3

4

5

46 4

28 4

The 2002 AJCC staging system is limited in its ability to provide accurate information regarding time to PCSM for individual patients who present with the most common clinical category of T1c disease. However, algorithms for predicting PSA outcome following RP or external beam RT that are based on pretreatment clinical parameters that include the PSA level, biopsy Gleason score, and 2002 AJCC clinical T-category have been validated.1–3 Nevertheless, given the competing causes of mortality that exist in men undergoing definitive treatment for localized prostate cancer, many men who sustain PSA failure will not live long enough to develop clinical evidence of distant disease and far fewer will die from the disease. Although pretreatment riskbased staging systems predicting the endpoint of PCSM7,26 have been published, none has been validated in the PSA era. Studies are currently ongoing to define a validated pretreatment staging system that can accurately predict time to PCSM following surgery or RT for prostate cancer.

Time in years 162 29

137 19

100 14

64 4

Number at risk Figure 25-7. Prostate-specific antigen outcome following radical prostatectomy stratified by the erMRI T-category for intermediate-risk patients with clinically localized disease.

by drawing straight lines to obtain a prediction.19 The term is attributed to Professor Maurice d’Ocagne in 1889.20 The primary advantage of nomograms, relative to other paper-based approach, such as tables, is that nomograms maintain a continuous prediction model, resulting in greater predictive accuracy. Pretreatment

Preoperative nomogram for PSA recurrence Points PSA

0

10

20

40

50

60

1

23 4 6 7 8 9 101 2

T2c

T3a

0.1 T2a

30

70

80

90

100

16 20 30 45 70 110

Clinical stage T1c

T1ab T2b 2+3 3+2

Biopsy gleason sum

2+2

3+3

4+ 3+4

Total points 0

20

40

60

80

100

120

140

160

180

200

60-month recurrence free prob. .96

.93 .9 .85 .8

.7 .6 .5 .4 .3 .2 .1 .05

Figure 25-8. Pretreatment nomogram for patient considering surgery. (Adapted with permission from Kattan MW, Eastham JA, Stapleton AMF, et al: J Natl Cancer Inst 1998; 90(10):766–771.)

Chapter 25 Cancer of the Prostate: Detection and Staging 463

3D conformal radiation therapy nomogram for PSA recurrence 0

Points

10

20

30

40

50

60

70

80

4

5 6 7

910

90

100

Pretreatment PSA 0.3

1 T2a T3ab T3c

2

3

80

100

25 50 100

Clinical stage T1c

T2b T2c

357

9

Bx. gleason sum 24 6

Dose (Gy)

8

10

86.4 72 No

68 64.8

Hormones Yes

Total points 0

20

40

60

120

140

160

180

60 month Rec. free prob. 0.99

0.98 0.95

0.9

0.8 0.7 0.5 0.3 0.1 0.01

Figure 25-9. Pretreatment nomogram for patient considering external beam radiation. (Adapted with permission from Kattan MW, Zelefsky, Kupelian PA, et al: J Clin Oncol 2000; 18:3352–3359.

Brachytherapy nomogram for PSA recurrence 0

10

20

30

40

50

60

70

80

90

100

Points 0.8

Pretreatment PSA 0.6

1

42

2

3

4 5 6

8 10

15 20

30 40

60 80 100

7

Biopsy GI.Sum 536

8 T2a

97 clinical stage T2b T1c No

XRT

Yes

Total points 0

10

20

30

40

50

60

70

80

90 100 110 120 130

60-month Rec. free prob. 0.99

0.98

0.96 0.93 0.9

0.8 0.7 0.6 0.5 0.4 0.25 0.12

Figure 25-10. Pretreatment nomogram for patients considering brachytherapy. (Adapted with permission from Kattan MW, Potters, L, Blasko JC, et al: Urology 2001; 58(3):393–399.)

464


REFERENCES 1. Kattan MW, Eastham JA, Stapleton AMF, Wheeler TM, Scardino PT: A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. JNCI 1998; 90:766–771. 2. D’Amico AV: Combined-modality staging for localized adenocarcinoma of the prostate. Oncology 2001; 15:1049–1059. 3. Graefen M, Karakiewicz PI, Cagiannos I, et al: A validation of two preoperative nomograms predicting recurrence following radical prostatectomy. Urol Oncol 2002; 7:141–146. 4. From the National Center for Health Statistics: National Vital Statistics 2002; 50:1–120. 5. Greene FL, Page DL, Fleming ID, et al: American Joint Committee on Cancer, Manual for staging cancer, 6th edition, pp 337–346. New York, Springer, 2002. 6. Catalona WJ, Smith DS, Ratliff TL, Basler JW: Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993; 270:948–954. 7. D’Amico AV, Cote K, Loffredo M, Renshaw AA, Chen MH: Pre-treatment predictors of time to cancer specific death following prostate specific antigen failure. J Urol 2003; 169(4):1320–1324. 8. D’Amico AV, Whittington R, Malkowicz SB, et al: Clinical utility of the percentage of positive prostate biopsies in defining biochemical outcome after radical prostatectomy for patients with clinically localized prostate cancer. J Clin Oncol 2000; 18:1164–1172. 9. D’Amico AV, Schultz D, Silver B, et al: The clinical utility of the percent positive prostate biopsies in predicting biochemical outcome following external beam radiation therapy for patients with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2001; 49:679–684. 10. D’Amico AV, Keshaviah A, Manola J, et al: The clinical utility of the percent of positive prostate biopsies in predicting prostate cancer specific and overall survival following radiation therapy for patients with localized prostate cancer. Int J Radiat Oncol Biol Phys 2002; 53:581–587. 11. Ismail MT, Petersen RO, Alexander AA, Newschaffer C, Gomella LG: Color Doppler imaging in predicting the biologic behavior of prostate cancer: correlation with disease-free survival. Urol 50:906–912. 12. Yang RM, Naitoh J, Murphy M, et al: Low P27 expression predicts poor disease-free survival in patients with prostate cancer. J Urol 1998; 159:941–945. 13. Stapleton AM, Zbell P, Kattan MW, et al: Assessment of the biologic markers p53, Ki-67, and apoptotic index as

14.

15.

16.

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19. 20. 21.

22.

23.

24.

25.

26.

predictive indicators of prostate carcinoma recurrence after surgery. Cancer 1998; 82:168–174. Waltregny D, de Leval L, Menard S, de Leval J, Castronovo V: Independent prognostic value of the 67-kd laminin receptor in human prostate cancer. J Natl Cancer Inst 1997; 89:1224–1228. Berruti A, Dogliotti L, Mosca A, et al: Circulating neuroendocrine markers in patients with prostate carcinoma. Cancer 2000; 88:2590–2597. Platt JF, Bree RL, Schwab RE: The accuracy of CT in the staging of prostatic carcinoma. Am J Radiol 1987; 149:315–321. Rifkin MD, Zerhouni A, Gatsonis CA, et al: Comparison of magnetic resonance imaging and ultrasonography in staging early prostate cancer. Results of a multi-institutional cooperative trial. NEJM 1990; 323:621–629. D’Amico AV, Whittington R, Malkowicz SB, et al: Endorectal magnetic resonance imaging as a predictor of biochemical outcome following radical prostatectomy for men with clinically localized prostate cancer. J Urol 2000; 164:759–763. Hankins TL: Blood, dirt and nomograms. Hist Sci Soc 1999; 90:50–80. Banks J. Nomograms, Vol 6. New York, Wiley, 1985. Kattan MW, Eastham JA, Stapleton AMF, Wheeler TM, Scardino PT: A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 1998; 90(10):766–771. Kattan MW, Potters L, Blasko JC, et al: Pretreatment nomogram for predicting freedom from recurrence after permanent prostate brachytherapy in prostate cancer. Urology 2001; 58(3):393–399. 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; 18:3352–3359. Graefen M, Karakiewicz P, Cagiannos I, et al: A validation of two preoperative nomograms predicting recurrence following radical prostatectomy in a cohort of European men. Urol Oncol 2002; 7(4):141–146. Graefen M, Karakiewicz PI, Cagiannos I, et al: International validation of a preoperative nomogram for prostate cancer recurrence following radical prostatectomy. J Clin Oncol 2002; 20(15):3206–3212. Roach M, Lu J, Pilepich MV, et al: Four prognostic groups predict long-term survival from prostate cancer following radiotherapy alone on radiation therapy oncology group clinical trials. Int J Radiat Oncol Biol Phys 2000; 47:609–615.

C H A P T E R

26A Clinically Localized (Stage T1a-T2c) Adenocarcinoma of the Prostate: Surgical Management and Prognosis Maxwell V. Meng, MD, and Peter R. Carroll, MD

Prostate cancer remains a major health concern in the U.S. and throughout the world. The institution of screening protocols, based on the combination of digital rectal examination and serum prostate specific antigen (PSA) testing, has increased the opportunity for cancer cure by allowing earlier diagnosis at lower stages of disease. Over the past decade, advances in both surgical and therapeutic radiation therapy techniques have revolutionized the ability to adequately treat prostate cancer while simultaneously reducing treatment-related morbidity. This chapter focuses on the management and outcomes of patients with clinically localized (stages T1a to T2c) cancer of the prostate. RADICAL PROSTATECTOMY Rationale for Treatment Proponents of screening for prostate cancer cite the disease prevalence and mortality, ability to effectively treat localized cancers, and inability to cure metastatic disease as compelling reasons for this practice.1 Despite the numerous factors supporting early prostate cancer detection, controversy continues to surround the need for, and specific choice of, intervention.2 This is particularly true for radical prostatectomy. Definitive surgery is not only curative for most organ-confined tumors (stages T1 to T2) but is also associated with limited morbidity and is amenable to selective use with adjuvant therapy in high-risk patients. Nevertheless, the potential for operative and postoperative morbidity exists and surgery may not be necessary in men with lower-risk disease who may be candidates for surveillance alone.

Natural History of Prostate Cancer Ultimately, the role and necessity of surgical removal of the prostate from men with cancer can only be determined in appropriately designed clinical trials. The most relevant endpoint of these studies is the impact of prostatectomy on overall survival. Prior published reports evaluating various prostate cancer treatments are not applicable to contemporary patients. Currently, there are several ongoing randomized trials seeking to compare active therapy with watchful waiting.3 The results of a recent study from the Scandinavian International Union against Cancer provide evidence that radical prostatectomy significantly reduces disease-specific mortality.4 A total of 695 men with clinical stages T1b, T1c, or T2 prostate cancer were randomized to either watchful waiting or prostatectomy. During a median follow-up of 6.2 years, there was no difference between the two groups with respect to overall survival; however, death due to prostate cancer in the surveillance cohort (8.9%) was greater than that observed in the surgery cohort (4.6%, p = 0.02). In addition, men after surgery had a lower risk of distant metastases (hazard ratio 0.63). Although there was no reduction in overall mortality, a difference is likely to be noted with longer follow-up given the significant reduction in metastases in those managed with surgery. This important study supports the utility of early detection and treatment of prostate cancer in selected patients. Although it appears that surgery for localized prostate cancer impacts disease-specific outcomes, the rational selection of therapy remains complex, and examination of other data provides information regarding the natural history of untreated prostate cancer. Chodak et al.5 analyzed the pooled data of 823 men (cT1-2) from six

465

466


nonrandomized studies treated prior to the era of PSA testing. The risk of metastases was significant and dependent on tumor grade—2.1% per year, 5.4% per year, and 13.5% per year for well differentiated, moderately differentiated, and poorly differentiated tumors, respectively. At 15 years, the fraction of patients with metastatic disease was 40%, 70%, and 85% in these groups, respectively (Table 26A-1). Albertsen et al.6 analyzed the long-term outcome of 451 men with clinical stage T1-2 tumors managed with immediate or delayed hormonal therapy. Again, tumor grade was the important factor determining patient outcome. The cancer-specific mortalities in men with Gleason sums 2 to 4, 5 to 7, and 8 to 10 were 9%, 28%, and 51%, respectively. Overall, 46% of men treated expectantly living 15 years or more will die of prostate cancer and lose approximately one-third of their remaining life expectancy, even at older age of diagnosis (i.e. >75 years).6,7 Fleming et al.8 attempted to address questions regarding the selection of surveillance or definitive therapy using decision analysis. In their Markov model, they incorporated estimates of progression to metastatic disease with watchful waiting from review of the literature, efficacy of radical prostatectomy based on pathologic stage, and arbitrary reductions in survival after surgery due to impact on quality of life to determine which strategy resulted in a greater survival advantage. Based on the data selected for their model, the authors reported that surgical intervention for prostate cancer provided limited benefit to the patient, relative to expectant management, with well-differentiated tumors. In men with moderate or poorly differentiated tumors, they stated that treatment offered less than 1-year improvement in qualityadjusted life expectancy in those men 60 to 65 years old and that treatment was harmful in men over age 70. Thus, they conclude that selection of watchful waiting in men with localized prostate cancer is a feasible alternative to radical prostatectomy. Application of the model by other investigators, using other estimates of disease progression and efficacy of treatment, resulted in much different results. Beck et al.9 utilized progression data from Table 26A-1 Development of Metastases in Men with Localized Prostate Cancer Treated Conservatively PERCENT Histologic Grade

WITH

METASTASES

10 Years

15 Years

1

19

40

2

42

70

3

74

85

From Chodak GW, Thisted RA, Gerber GS, et al: N Engl J Med 2002; 330: 781–789.

the work of Chodak et al. and calculated survival benefit from surgery. In contrast to the study of Fleming et al., the estimated survival advantage in men with well differentiated, moderately differentiated, and poorly differentiated tumors increased to 1.0, 2.4, and 2.7 years, respectively. Selection of Patients for Radical Prostatectomy Despite the disparate result of the various publications and controversy regarding the “best” treatment, it is clear that selection of therapy needs to be based on several patient and tumor factors. In general, radical prostatectomy is considered in men with a life expectancy greater than 10 years, a duration during which an untreated cancer may progress and/or metastasize. In addition, the patients should be free of serious comorbidities and be able to tolerate a major operation. With respect to cancer variables, the tumor should be both clinically significant and at a stage where surgical extirpation is likely to be curative. These aspects of tumor behavior and biology are often difficult to assess based on traditional measures, such as digital rectal examination, serum PSA, and Gleason grade. Thus, more accurate determinations of outcome have been developed and are currently commonly applied to aid in the appropriate selection of men for radical prostatectomy, as well as other definitive treatments. Pretreatment Risk Stratification The most commonly used risk assessment criteria include serum PSA, clinical tumor stage (T stage), and Gleason grade on biopsy. Recently, the extent of disease, assessed by systematic biopsy (e.g., percent positive biopsies), has been shown to have prognostic significance and such information may be incorporated into the assessment of pretreatment risk. In general, the role of imaging modalities, such as transrectal ultrasonography, computed tomography (CT), and magnetic resonance imaging/spectroscopy, is limited in initial risk stratification, except in those with advanced disease. Due to widespread screening efforts, men are increasingly diagnosed with early stage disease (i.e., T1c). The risk for disease recurrence after radical prostatectomy increases with higher clinical stage. In men with stage T1c, 5-year PSA-free survival after radical prostatectomy is greater than 85%, while those with palpable but localized (cT2) have disease-free rates between 70% and 80%.10 Serum PSA levels can vary within any clinical stage but usually correlate with tumor volume and, therefore, pathologic stage and outcome after surgery. As reported by Ohori and Scardino,11 progression-free survival 5 years after prostatectomy in men with PSA ≤ 4.0 ng/ml, 4.1 to 10 ng/ml, 10.1 to 20 ng/ml, and >20 ng/ml was 94%, 85%, 66%, and 38%, respectively. These values are

Chapter 26A Clinically Localized (Stage T1a-T2c) Adenocarcinoma of the Prostate 467

comparable to those reported by others. In the study from Catalona et al.,12 7-year progression-free survival was 93% in men with serum PSA ≤ 2.5 ng/ml, 80% with PSA 2.5 to 4.0 ng/ml, 76% with PSA 4.1 to 10 ng/ml, and 40% with PSA >10 ng/ml. Walsh et al.13,14 reported 10-year rates of 87%, 75%, 30%, and 28% for PSA groups of 20 ng/ml, respectively. Gleason grade, as determined by biopsy, is a significant predictor of outcomes after radical prostatectomy. With increasing tumor grade, the likelihood of disease recurrence increases. Five and 10-year disease-free survival in patients with Gleason sum 2 to 4 are approximately 90% but drop to approximately 60% for those men with sum of 7. Over half of men with Gleason sum 8 to 10 will develop PSA recurrence at 5 years.10 In addition to clinical factors, pathologic information obtained from the prostatectomy specimen can provide prognostic information. This includes variables, such as pathologic stage, total tumor volume, surgical margin status, and tumor grade in the specimen. The development of predictive nomograms and models has allowed the prediction of both pathologic stage and clinical outcome (i.e., PSA-free survival), based on standard pretreatment variables, and may increase the accuracy of risk assessment over the use of clinical stage, PSA level, and Gleason score alone.15–17 The nomograms published by Partin et al.18 predict the pathologic stage of disease, thus helping one decide the role of surgery based on the categorical estimation of organ-confined, established capsular penetration, seminal vesical invasion, and lymph node involvement.15,16 In applying the Partin nomograms, it is important to point out that adverse pathologic features alone, such as seminal vesicle invasion or extracapsular disease, may not preclude surgical therapy. From the experience of Catalona et al.,12 over 70% of patients with unconfined disease and 35% of those with seminal vesicle invasion have long-term (10 years) cancer-free survival with prostatectomy alone (no adjuvant therapy). Kattan and colleagues, rather than estimating pathologic stage as an outcome, created a continuous scale, based on PSA, clinical stage, and Gleason grade, to calculate the probability that a patient remains free of biochemical recurrence at 5 years after surgery.17 They have created a similar postoperative nomogram, predicting freedom from progression 7 years after surgery based on PSA, Gleason sum in the prostatectomy specimen, and individual pathologic features.19 These models can be easily applied in the clinical setting using a web-based (www.mskcc.org/nomograms/prostate) or computer calculation. In order to simplify pretreatment risk stratification, a three-group system has been developed based on PSA, clinical stage, and biopsy Gleason score. One that is commonly applied categorizes patients as low-risk patients

(cT1c or T2a and Gleason sum 2 to 6 and PSA 20 ng/ml).20 In low-risk patients, it should be mentioned that excellent outcomes might be achieved with a variety of modalities, including watchful waiting in selected patients. Although progression occurs slowly within this population, eventual active treatment is likely in men who are young or have elevated PSA levels.21 High-risk patients can undergo radical prostatectomy with acceptable morbidity and reasonable rates of local control; however, long-term cure is less likely and if surgery is selected, the patient must realize that adjuvant or secondary treatment may be necessary. Although categorization of patients into fewer (e.g., 3 or 4) risk groups simplifies the situation, it is important to point out that prognostic power can be reduced. This is particularly true for those patients with intermediate- and high-risk disease, where significant overlap occurs and discrimination of clinical outcome is less accurate.22,23 The development of additional models incorporating novel and/or molecular determinants of tumor behavior will allow identification of patients most likely to benefit from prostatectomy, as well as those who may benefit from adjuvant treatments. Pelvic Lymph Node Dissection Contemporary series of patients undergoing radical prostatectomy demonstrate that the risk of pelvic lymph node metastases is low, typically between 4% and 9%.24,25 This is largely due to the earlier detection of cancers at lower stage, as well as the refined selection of patients undergoing surgery with reduced likelihood of nodal involvement. Thus, pelvic lymphadenectomy may not be routinely indicated for all patients undergoing radical prostatectomy. However, the detection of positive lymph nodes provides important prognostic information and should be performed in those patients at higher risk, as determined by nomogram or risk-group stratification. Traditionally, it was thought that all patients with lymph node metastases experience recurrence after prostatectomy and therefore identification would spare patients an ineffective, and potentially morbid, operation. Recent data question the paradigm and may renew interest in both pelvic lymphadenectomy and more aggressive surgical therapy. In addition, at the time of radical retropubic prostatectomy, the pelvic lymph nodes are easily accessible and removal can be performed with minimal morbidity; in general, unless the lymph nodes appear grossly involved, frozen section analysis is unnecessary. Heidenreich et al.26 extended the boundaries of the pelvic lymphadenectomy in 103 patients, including the external and internal iliac, obturator, common iliac, and presacral lymph nodes. They found a high rate of nodal

468


metastases (26%) in patients undergoing increased sampling, suggesting that if lymph nodes are to be sampled, the standard limits may be inadequate. Nearly all men with proven pelvic lymph node metastases will have biochemical relapse with 5 to 7 years after surgery. Thus, radical prostatectomy with distant disease has been avoided because of limited benefit to the patient. In a retrospective, nonrandomized study, Cadeddu et al.27 compared 10-year survival in men with proven lymph node involvement who did and did not undergo radical prostatectomy. Overall, men fared better if the prostate had been removed and there was a suggestion of improved survival in this cohort. Similarly, Ghavamian et al.28 demonstrated an overall survival advantage at 10 years in men with pTxN+ prostate cancer undergoing prostatectomy and orchiectomy, compared with those with orchiectomy alone. More recently, data from Messing et al.29 indirectly address this question. In a prospective randomized trial of 98 men undergoing radical prostatectomy and pelvic lymph node dissection, an improvement in survival was observed in men receiving immediate hormonal therapy for microscopic lymph node disease compared to those men receiving delayed hormonal therapy at the time of disease progression. This difference, at a median follow-up of 7.1 years, was statistically significant ( p = 0.02) with 77% of men in the immediate-therapy group alive without disease at last

evaluation. Not only does this support the concept of immediate androgen deprivation in those men with node-positive prostate cancer but also raises the issue of whether complete excision via prostatectomy and lymph node dissection plays a role in improving cancer outcomes even in those with regional metastases. Results of Radical Prostatectomy The techniques of radical retropubic and perineal prostatectomy are covered elsewhere in this book. Therefore, we describe cancer outcomes and morbidity related to such surgery in this section. Due to an improved understanding of periprostatic anatomy, increased surgeon experience, and refinement in anesthesia and perioperative patient care, morbidity from prostatectomy has been reduced from that seen in previous decades. Early and Intraoperative Complications Table 26A-2 summarizes perioperative data from contemporary series of patients undergoing radical retropubic prostatectomy. Operative mortality, defined as death within 30 days of surgery is exceedingly rare (50% PSA Decline (%)

Measurable Response (%)

153

15–33

13

134

23–24

0

14

50

NR

Aminoglutethimide

583

NR

9

Ketoconazole

204

78–80

16

Low-dose steroids

241

18–22

NR

DES

405

21–86

NR

PC-SPES

114

45–81

NR

Therapy Antiandrogen withdrawal

Number

Second antiandrogen Bicalutamide Nilutamide Adrenal androgen inhibitors

Estrogens

NR, not reported.

aminoglutethimide. Ketoconazole is effective in suppressing testicular and adrenal androgen production. In vitro experiments also suggest a possible direct cytotoxic effect of ketoconazole on prostate cancer cells. Older studies in androgen-independent prostate cancer using high-dose ketoconazole plus replacement steroids showed measurable responses in approximately 15%. Three recent trials of high-dose ketoconazole demonstrate much higher response rates using PSA endpoints. Small et al.43 treated 48 patients with 400 mg tid in a phase II trial and found PSA declines of 50% or greater in 63%. In another trial of 45 patients treated with highdose ketoconazole, Millikan et al.44 showed a 40% PSA response rate using a similar dose. In CALGB 9583, concurrent antiandrogen withdrawal and high-dose ketoconazole demonstrated a 27% PSA response rate and a 13% measurable response rate.45 Increased gastric pH decreases drug absorption, so ketoconazole should be taken on an empty stomach and, if possible, in the absence of H2 blockers or antacids. Though toxicity is generally mild or moderate, including nausea, diarrhea, fatigue, and skin changes, some patients require discontinuation of the drug because of toxicity. A recent phase II study suggests that similar response rates may be obtained with half the traditional dose (i.e., 200 mg tid), with fewer apparent side effects.46 In a review of 13 clinical trials of aminoglutethimide plus hydrocortisone, there was an overall partial response rate of 9%. Aminoglutethimide toxicity includes fatigue, nausea, skin rash, orthostatic hypotension, and ataxia.

Estrogens and their analogs also have some activity in patients with hormone-refractory disease. Using 1 mg DES in 21 men who failed with ADT, Smith et al.47 demonstrated a response rate of 43% based on more than 50% decrease in PSA level. Its utility in prostate cancer has been unfortunately limited by the risk of thromboembolic complications but nevertheless is a potentially useful drug in this setting. DES is no longer marketed in the United States but is available through compounding pharmacies. PC-SPES was supplement consisting of 8 different herbs and showed estrogenic activity. Its efficacy in both androgen sensitive and androgen insensitive prostate cancer was demonstrated in several trials.48–50 Despite of its potential, PC-SPES has been taken off the market when it was recently found to contain synthetic agents, such as warfarin and DES. CHEMOTHERAPY In the traditional view of chemotherapy in hormonerefractory prostate cancer (HRPC), there is either no or little impact in the history of the disease. Two reviews from 1985 suggested that the response with chemotherapy is poor.51,52 In the first review of 17 randomized clinical trials by Eisenberger et al.,53 total response rate was 4.5%, while a second review of 26 trials performed in the late 1980s showed an overall response rate of only 8.7%. However, recent studies with new drugs and combinations have shown that prostate cancer is in fact chemosensitive. At the same time, new endpoints of

510


paclitaxel and docetaxel have moderate activities.57,58 Estramustine, by itself, also has modest activity.59 The activity of this drug is not due to the estrogen moiety as first thought to be but rather due to its ability to disrupt mitotic activity through the binding of the microtubule assembly proteins.60 Although estramustine has been studied in combination with other chemotherapeutic agents, it is the synergism with other antimicrotubule agents (paclitaxel and docetaxel) that have generated enthusiasm. PSA response rates ranging from 50% to 65% and from 39% to 82% for estramustine plus paclitaxel or docetaxel, respectively, have been reported in several clinical studies. In spite of the high activity of the combination therapy, the optimal dose and schedule in HRPC are yet to be defined. In fact, the added value of estramustine in these combinations is counterbalanced by significant toxicity. Several groups have tested the efficacy of single agent docetaxel chemotherapy with reported PSA response ranging from 41% to 47% and less toxicity.58,61 The Southwest Oncology Group has completed a phase III study with over 600 patients randomized either to estramustine and docetaxel or mitoxantrone and prednisone. Overall survival is the primary endpoint and results are pending. Many other chemotherapeutic drugs have also been tested, including etoposide, vinblastine, and cyclophosphamide. In general, these have modest single agent activity in HRPC. On the other hand, results of triple drug combination have also been published. One such regimen consists of weekly paclitaxel, estramustine, and

treatment, such as PSA response and parameters of quality of life, as well as better supportive measures and improvement in the management of comorbid conditions, have allowed a resurgence of interest in the use of chemotherapy to palliate advance disease.54 Two randomized trials reestablished the promise of chemotherapy in HRPC, both analyzing mitoxantrone and a corticosteroid.55,56 In the first study with 161 symptomatic patients, Tannock et al.55 showed that mitoxantrone plus prednisone significantly improved pain control compared to prednisone alone (29% versus 12%; p = 0.01). The duration of palliation in the chemotherapy arm also was significantly longer (43 weeks versus 18 weeks; p < 0.0001). In a second study by Kantoff et al.56 242 patients with HRPC were randomized to receive either mitoxantrone and hydrocortisone or hydrocortisone alone. Although there was no significant difference in survival, a trend towards longer time-to-progression and time-to-treatment-failure in the combination arm was evident (3.7 months versus 2.3 months; p = 0.25). Furthermore, there was a higher percentage of patients in the combination arm who achieved a >50% maximum reduction in PSA (38% versus 22%; p = 0.008), as well as a trend for improved pain control. Despite a lack of survival benefit, mitoxantrone was approved for palliative use in HRPC patients and has become the standard of care to which future agents will be compared (Table 28-2). Taxanes combinations are among the most active regimens tested to date in phase II trials. As single agents,

Table 28-2 Chemotherapy Regimen

Number

>50% PSA Decline (%)

Measurable Response (%)

Paclitaxel

41

33–60

22–33

Paclitaxel/estramustine

62

53–61

38–44

Paclitaxel/estramustine/VP-16

40

45

65

Paclitaxel/estramustine/carboplatin

88

67–100

17–45

Docetaxel

113

41–47

28–33

Docetaxel/estramustine

131

63–82

17–57

38

71

47

199

38

NR

Vinorelbine

77

17–36

13–66

Vinorelbine/estramustine

25

24–65

NR

Vinorelbine/estramustine/VP-16

25

56

32

Docetaxel/estramustine/carboplatin Mitoxantrone/steroid

NR, not reported.

Chapter 28 Metastatic Adenocarcinoma of the Prostate 511

carboplatin. In 56 patients treated, 50% or greater PSA declines were seen in 67% and median survival was 20 months.62 Unfortunately, the trial was complicated by thromboembolic event in 25% of the patients. Current estramustine-based clinical trials now also include lowdose warfarin to decrease the risk of thromboembolism. Following hormonal therapy failure, chemotherapy may control disease progression, as well as to palliate symptoms. Although mitoxantrone chemotherapy is the first to be approved for treatment of hormone-refractory disease, the most active therapies are probably taxanebased. As chemotherapy continues to make inroads into management of prostate cancer, patients should be encouraged to participate in clinical trials. BONE-DIRECTED THERAPIES Skeletal complications are a major cause of morbidity for men with advanced prostate cancer. Over 80% of men with metastatic prostate cancer have radiologic evidence of bone involvement. Palliative external beam radiotherapy has been used for decades for relief of bone pain, but recently, bisphosphonates and radiopharmaceutical agents have been approved for use in HRPC. There are three potential uses of bisphosphonates in advanced prostate cancer: (1) to prevent osteopenia that commonly accompanies the use of ADT; (2) to prevent or delay skeletal complications in men with bone metastasis; (3) to relieve pain from bony disease as well. In the United States, zoledronic acid is a bisphosphonate approved for use in HRPC. The landmark randomized, placebo-controlled trial of zoledronic acid in patients with HRPC with bone metastasis was reported by Saad et al.63 In this trial, there were significantly more skeletalrelated events in men receiving placebo compared to zoledronic acid (44.2% versus 33.2%; p = 0.021). Skeletal-related events were defined as bone fractures, spinal cord compression, surgery to bone, radiotherapy to bone, or a change in antineoplastic agents. The time to first skeletal event was also significantly longer in the arm receiving zoledronic acid (363 days versus 321 days; p = 0.021). In another study, using high-dose clodronate as adjuvant therapy, the time to development of symptomatic bone metastasis in 311 men with prostate cancer was 23.6 months in those receiving clodronate compared with 19.3 months in placebo arm (p = 0.08).64 However, significantly more dose reductions were required in clodronate arm due to adverse events (93 versus 108, hazard ratio, 0.75). Strontium-89 (89St) chloride, samarium-153 (153Sm), and 32-phosphorus (32-P) are approved radiopharmaceutical agents for treatment of symptomatic bone metastases. There have been no comparative studies between the different radioisotopes although the pain response rates and the patterns of pain relief with differ-

ent radioisotopes appear similar. However, the main toxicity of these radiopharmaceutical agents is potentially severe and prolonged myelosuppression, which may render a patient not suitable to participate in any potential clinical trials with chemotherapy in future. SUMMARY There is no doubt that significant progress has been made in treatment of metastatic prostate cancer. ADT remains the mainstay of treatment; LHRH agonists, orchiectomy, and estrogen therapy are all standard methods of achieving ADT. Alternative methods of hormonal treatment include intermittent ADT and peripheral androgen blockade. After progression on initial ADT, secondary hormonal therapies and chemotherapy have growing promise in both palliating patients and potentially controlling disease, though randomized trials are ongoing. Current research is focused on several areas with promise of better therapeutics against prostate cancer in the future. Promising therapeutic approaches include antisense oligonucleotides, vaccines, angiogenesis inhibitors, and signal transduction inhibitors.65–69

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Chapter 28 Metastatic Adenocarcinoma of the Prostate 513 40. Veldscholte J, Berrevoets CA, Mulder E: Studies on the human prostatic cancer cell line LNCaP. J Steroid Biochem Mol Biol 1994; 49:341–346. 41. Joyce R, Fenton MA, Rode P, et al: High dose bicalutamide for androgen independent prostate cancer: effect of prior hormonal therapy. J Urol 1998; 159:149–53. 42. Scher HI, Liebertz C, Kelly WK, et al: Bicalutamide for advanced prostate cancer: the natural versus treated history of disease. J Clin Oncol 1997; 15:2928–2938. 43. Small EJ, Baron AD, Fippin L, et al: Ketoconazole retains activity in advanced prostate cancer patients with progression despite flutamide withdrawal. J Urol 1997; 157:1204–1207. 44. Millikan R, Baez L, Banerjee T, et al: Randomized phase 2 trial of ketoconazole and ketoconazole/doxorubicin in androgen independent prostate cancer. 2001; 6:111–115. 45. Oh WK: Secondary hormonal therapies in the treatment of prostate cancer. Urology 2002; 60:87–92 (Discussion 93). 46. Harris KA, Weinberg V, Bok RA, et al: Low dose ketoconazole with replacement doses of hydrocortisone in patients with progressive androgen independent prostate cancer. J Urol 2002; 168:542–545. 47. Smith DC, Redman BG, Flaherty LE, et al: A phase II trial of oral diethylstilbestrol as a second-line hormonal agent in advanced prostate cancer. Urology 1998; 52:257–260. 48. Oh WK, George DJ, Hackmann K, et al: Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen-independent prostate cancer. Urology 2001; 57:122–126. 49. DiPaola RS, Zhang H, Lambert GH, et al: Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med 1998; 339:785–791. 50. Small EJ, Frohlich MW, Bok R, et al: Prospective trial of the herbal supplement PC-SPES in patients with progressive prostate cancer. J Clin Oncol 2000; 18:3595–3603. 51. Tannock IF: Is there evidence that chemotherapy is of benefit to patients with carcinoma of the prostate? J Clin Oncol 1985; 3:1013–1021. 52. Eisenberger MA, Simon R, O’Dwyer PJ, et al: A reevaluation of nonhormonal cytotoxic chemotherapy in the treatment of prostatic carcinoma. J Clin Oncol 1985; 3:827–841. 53. Oh WK, Kantoff PW: Management of hormone refractory prostate cancer: current standards and future prospects. J Urol 1998; 160:1220–1229. 54. Dawson NA, McLeod DG: The assessment of treatment outcomes in metastatic prostate cancer: changing endpoints. Eur J Cancer 1997; 33:560–565. 55. 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; 14:1756–1764.

56. Kantoff PW, Halabi S, Conaway M, et al: Hydrocortisone with or without mitoxantrone in men with hormonerefractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol 1999; 17:2506–2513. 57. Trivedi C, Redman B, Flaherty LE, et al: Weekly 1-hour infusion of paclitaxel. Clinical feasibility and efficacy in patients with hormone-refractory prostate carcinoma. Cancer 2000; 89:431–436. 58. Picus J, Schultz M: Docetaxel (Taxotere) as monotherapy in the treatment of hormone-refractory prostate cancer: preliminary results. Semin Oncol 1999; 26:14–18. 59. Hudes G: Estramustine-based chemotherapy. Semin Urol Oncol 1997; 15:13–19. 60. Stearns ME, Tew KD: Estramustine binds MAP-2 to inhibit microtubule assembly in vitro. J Cell Sci 1988; 89(Pt 3):331–342. 61. Berry W, Dakhil S, Gregurich MA, et al: Phase II trial of single-agent weekly docetaxel in hormone-refractory, symptomatic, metastatic carcinoma of the prostate. Semin Oncol 2001; 28:8–15. 62. Kelly WK, Curley T, Slovin S, et al: Paclitaxel, estramustine phosphate, and carboplatin in patients with advanced prostate cancer. J Clin Oncol 2001; 19:44–53. 63. Saad F, Gleason DM, Murray R, et al: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002; 94:1458–1468. 64. Dearnaley D, Sydes MR, et al. Preliminary evidence that oral clodronate delays symptomatic progression of bone metastases from prostate cancer: first results of MRC Pr05 trial (abstract). Proc Am Soc Clin Oncol 2001; 20:174a. 65. Signoretti S, Montironi R, Manola J, et al: Her-2-neu expression and progression toward androgen independence in human prostate cancer. J Natl Cancer Inst. 2000; 92(23): 1918–1925. 66. Simons JW, Mikhak B, Chang JF, et al: Induction of immunity to prostate cancer antigens: results of a clinical trial of vaccination with irradiated autologous prostate tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer. Cancer Res 1999; 59:5160–5168. 67. Vaishampayan U, Fontana J, Du W, et al: An active regimen of weekly paclitaxel and estramustine in metastatic androgen-independent prostate cancer. Urology 2002; 60:1050–1054. 68. O’Reilly MS, Boehm T, Shing Y, et al: Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88:277–285. 69. Murphy GP, Tjoa B, Simmons SJ, et al: Phase II prostate cancer vaccine trial: report of a study involving 37 patients with disease recurrence following primary treatment. Prostate 1999; 39:54–59.

C H A P T E R

29 Anatomic Nerve-Sparing Radical Retropubic Prostatectomy Misop Han, MD, and William J. Catalona, MD

The management of clinically localized prostate cancer has undergone substantial changes over the past two decades. Widespread screening with serum prostatespecific antigen (PSA) testing and digital rectal examination has allowed much earlier detection of prostate cancer during this era.1,2 In addition, the modification of surgical technique by Walsh has allowed better hemostasis, improved visualization during dissection, and preservation of neurovascular bundles supplying corpora cavernosa.3 As a result, a skilled surgeon can perform radical prostatectomy with a high cure rate, while preserving urinary continence and erectile potency in the majority of patients. Thus, since 1990, radical prostatectomy has been the most commonly performed treatment for clinically localized prostate cancer.4 In a landmark study, Holmberg et al.5 recently reported on the first prospective, randomized trial showing that radical prostatectomy reduces the rates of metastases and death from prostate cancer. Consequently, the rationale for treating clinically localized prostate cancer surgically is convincing. In this chapter, we discuss patient selection, surgical technique, outcomes, and complications of anatomic radical retropubic prostatectomy using the senior author’s surgical series of more than 3500 anatomic radical prostatectomies as an example. The outcomes are similar to those of other previously reported, large radical prostatectomy series in the PSA era.6,7 It is not only representative of large modern prostatectomy series but also includes all men who underwent surgery in the analysis, even those with known adverse prognostic features. PATIENT SELECTION An ideal candidate for radical prostatectomy should have a life expectancy of at least 10 years, a completely resectable and biologically significant tumor, and no

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comorbidity that might make the operation unacceptably risky. Actuarial life tables can project the life expectancy of U.S. men,8 and with appropriate adjustment for comorbidities, life expectancy can be estimated for the individual patient. After confirming the likelihood of a sufficiently long life expectancy, the next step in patient selection is to identify those with potentially curable disease. Radical prostatectomy provides the best chance for cure for men whose tumor is confined to the prostate gland. As a result of widespread screening for prostate cancer and more restrictive preoperative patient selection, the proportion of men with organ-confined or specimenconfined disease has increased in recent years. 9 However, the lack of accuracy of conventional radiographic imaging studies in staging prostate cancer has been disappointing. Therefore, nomograms predicting the pathologic stage based on preoperative clinical and pathologic parameters have been widely used to identify patients who are likely to benefit from the surgical resection and those who are not.10,11 Alternatively, nomograms predicting postsurgical or postradiation therapy recurrence-free survival probabilities also are sometimes useful for patients.12–14 For patients with a low probability of resectable disease or a short life expectancy due to age or comorbidity, an alternative treatment to surgery should be recommended. For the patient to have realistic expectations concerning postoperative potency and continence outcomes, the surgeon should provide the patient with relevant information on the nerve-sparing aspect of radical prostatectomy during the preoperative consultation. Anatomic nerve-sparing radical retropubic prostatectomy is a safe choice without compromising cancer control in appropriately selected patients. Nerve-sparing radical prostatectomy is inappropriate in men with locally advanced

Chapter 29 Anatomic Nerve-Sparing Radical Retropubic Prostatectomy 515

disease, especially if the primary goal of the surgery is cancer control. The feasibility of the nerve-sparing surgery is questionable when a patient has extensive involvement by cancer of prostate biopsies, palpable evidence on digital rectal examination of possible extraprostatic extension, a serum PSA level >10 ng/ml, a biopsy Gleason score >7, poor quality erections preoperatively, a lack of interest and/or willingness of a partner in restoring potency, or the presence of other medical conditions that may adversely affect potency, such as diabetes mellitus, hypertension, psychologic or psychiatric diseases, neurologic diseases, and medications. Therefore, it is important to review the clinicopathologic features of the tumor and the patient’s medical history and erectile function status before embarking on a nerve-sparing operation. After discussing the prospects for preservation of potency, information on the treatment of erectile dysfunction should be imparted. This should include providing information on phosphodiesterase inhibitors, intraurethral and intracorporal vasodilators, vacuum erection devices, venous flow constrictors, and artificial penile prostheses. The discussion should include the anticipated postoperative erectile rehabilitation program to be used and the timing of the return of erections that usually begins 3 to 6 months postoperatively and lasts for up to 36 months. If erectile function is of paramount importance to the patient, he can be reassured that erections can be almost always restored, regardless of whether or not nerve-sparing surgery can be successfully performed. Finally, the surgeon should discuss possible need for and potential side effects of adjuvant radiation therapy or hormonal therapy if the final pathology report reveals adverse prognostic features. At the end of the preoperative counseling session, if nerve-sparing radical retropubic prostatectomy is appropriate, the patient and his spouse or partner should sign an informed consent form authorizing a surgeon to perform the procedure. SURGICAL TECHNIQUE Before the operation, a first-generation cephalosporin antibiotic is given intravenously. After a general endotracheal or regional anesthesia is administered, thigh-high elastic hose are placed on the patient. Sequential compression devices are used only in patients with increased risk for thromboembolic complications. The patient is positioned with his legs on spreader bars, and the operating table is dorsiflexed with the break just above the patient’s anterosuperior iliac spine (Figure 29-1). The abdomen and genitalia are appropriately prepped and draped. There are eight key steps in performing anatomic nerve-sparing radical prostatectomy: (1) a limited pelvic lymphadenectomy; (2) incision of the endopelvic fascia

and the puboprostatic ligaments; (3) ligation, proximal and distal suture ligation, and transection of the dorsal venous complex; (4) dissection of the prostate from the neurovascular bundles; (5) vascular control and transection of the prostatic pedicles; (6) transection and reconstruction of the bladder neck; (7) dissection of the seminal vesicles and ampullary portions of the vasa deferentia; and (8) performance of the vesicourethral anastomosis. These steps are described in detail here with corresponding illustrations. 1. Limited Pelvic Lymphadenectomy A superficial midline (or transverse) lower abdominal incision is made with a scalpel. The linea alba is incised and the space of Retzius is entered. Taking care to avoid disrupting the lymphatic tissue lateral to the external iliac vein and to avoid compression of the vein itself, a Balfour retractor is placed. A modified pelvic lymphadenectomy is performed, removing only the lymph nodes medial to the external iliac vein. Care is taken during the lymphadenectomy to preserve any accessory arterial branches to the corpora cavernosa that arise from the distal external iliac or obturator arteries. The obturator nerve is identified and preserved. In most incidences, the patient elects to have the prostate gland removed, even if there are pelvic lymph node metastases; otherwise, the excised lymph node packet is sent for frozen-section examination. If the frozen section examination reveals metastatic cancer, it is unlikely that the patient will be cured by radical prostatectomy, and the operation is terminated. Lymphadenectomy is optional in patients who are at low risk for pelvic lymph node metastases by virtue of a low Gleason grade, low PSA, and low biopsy tumor volume. After completing the lymphadenectomy, the adipose and areolar tissues are swept gently from the anterior surface of the prostate and the endopelvic fascia to expose the puboprostatic ligaments. Care is taken to avoid injury to the perforating branches of Santorini’s plexus that pierce the endopelvic fascia between the puboprostatic ligaments and pass cephalad on the anterior surface of the prostate gland and bladder. 2. Incision of the Endopelvic Fascia and the Puboprostatic Ligaments The endopelvic fascia is incised in the groove between the levator ani muscles and the lateral border of the prostate (Figure 29-2). Inside the endopelvic fascia, the lateral surface of the prostate is covered by a smooth, glistening membrane overlying the lateral portion of Santorini’s plexus. Strands of the levator ani muscles are gently dissected off the prostate to the level of the urogenital diaphragm. Often, venous tributaries pass from

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Figure 29-1 Positioning of the patient. A,Legs are separated on spreader bars. B, The operating table is flexed with the break just above the patient’s anterosuperior iliac spine.

the levator ani muscles to the prostate just lateral to the puboprostatic ligaments. These vessels are either cauterized, secured with hemostatic clips, or ligated laterally, and then clamped medially with a delicate snub-nose right-angle clamp. After the vein is transected sharply, its medial portion is ligated. When the endopelvic fascia has been opened from the base to the apex of the prostate, the superficial branch of Santorini’s plexus is gently retracted medially, and the puboprostatic ligaments are placed on stretch and divided close to the pubic symphysis (Figure 29-3). Care is taken not to divide the puboprostatic ligaments too medially or too far under the pubic symphysis to avoid injuring the dorsal venous complex. 3. Suture Ligation and Transection of the Dorsal Venous Complex After the puboprostatic ligaments have been divided, the lateral surfaces of the urethra are palpated. The groove

between the anterior surface of the urethra and the dorsal venous complex is developed with a pinching motion of the left index finger and thumb. The plane between the urethra and the dorsal venous complex is then developed gently, first with a large right-angle clamp. This facilitates tight ligation of the dorsal venous complex. After the dorsal venous complex has been ligated, it is also suture ligated in a slightly more caudal site with a 2-0 chromic catgut suture on a CT-1 needle (Figure 29-4). A suture ligature is also placed in the anterior surface of the prostate to reduce the back-bleeding from Santorini’s plexus (Figure 29-5). The right-angle clamp is then passed behind the dorsal venous complex and the jaws of the clamp are spread. The dorsal venous complex is transected with electrocautery or a scalpel (Figure 29-6). Back-bleeding from the dorsal venous complex is controlled with figure-ofeight 3-0 sutures. It is important to obtain good hemostasis so that the apical dissection of the prostate may be


Figure 29-2 The endopelvic fascia is incised in the groove between the levator ani muscles and the lateral border of the prostate.

Figure 29-3 The puboprostatic ligaments are placed on stretch and incised.

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Figure 29-4 The dorsal venous complex is suture ligated with a 2-0 chromic catgut suture on a CT-1 needle.

Figure 29-5 To reduce back-bleeding from Santorini’s plexus, the cephalad aspect of the dorsal venous complex is suture ligated.


Figure 29-6 The dorsal venous complex is transected with a right-angle clamp jaws spread behind the complex.

performed in a relatively bloodless field. If the dorsal venous complex ligature slips off, the complex is oversewn using a 3-0 chromic catgut suture on a 5/8-circle needle. The goal in oversewing the complex is to pass the suture just through the lateral borders of the complex itself in its anterior, middle, and posterior aspects, respectively. Wide, imprecisely placed sutures may damage the neurovascular bundles. The anterior surface of the urethra is palpated between the neurovascular bundles. The circumurethral sphincter muscle and the anterior wall of the urethra are incised with a scalpel just distal to the apex of the prostate without dissecting around the lateral or posterior surfaces of the urethra (Figures 29-7 and 29-8). The incision should not be carried too far lateral, where it may injure the neurovascular bundles. The urethral catheter is exposed and carefully hooked with a delicate right-angle clamp. Gentle traction on the clamp in a cephalad direction exposes the posterior urethral wall. The catheter is divided and placed on cephalad traction, the posterior urethral wall is sharply transected. Fibromuscular bands tethering the apex of the prostate to the pelvic floor are incised using sharp dissection (Figure 29-9). The rectourethralis muscle is incised, exposing the prerectal fat. 4. Separation of the Prostate from the Neurovascular Bundles The lateral pelvic fascia is incised from the apex of the prostate to the base. A delicate right-angle clamp may be

used to elevate the lateral pelvic fascia from the underlying veins on the surface of the prostate. Small perforating vessels are secured with hemoclips, ties, or ligatures to ensure adequate hemostasis. The posterolateral groove between the prostate and the neurovascular bundles is developed using sharp and blunt dissection, allowing the prostate to assume a more anterior position in the pelvis. The lateral aspect of the prostate is then dissected from the neurovascular bundles, allowing the bundles to retract laterally. In a case of extensive fibrosis, the dissection is performed sharply. The dissection is carried cephalad until the portion of Denonvilliers’ fascia covering the ampullary portions of the vasa deferentia and the seminal vesicles is exposed (Figure 29-10). Denonvilliers’ fascia is incised with the cautery. The Metzenbaum scissors are then used to develop the proper plane of dissection for the prostatic vascular pedicles. If there is continued bleeding from the periurethral tissues and apical pedicles of the prostate, hemostatic sutures should be placed at this juncture to avoid continued blood loss during the remainder of the procedure. 5. Vascular Control and Transection of Prostatic Pedicles The prostatic pedicles are divided by inserting the rightangle clamp medial to them, with the tip of the clamp directed almost parallel to the lateral surface of the prostate. The prostatic pedicle is ligated or hemoclipped laterally, taking care to place the tie or clip medial to the

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Figure 29-7 The circumurethral external sphincter muscle fibers are incised to expose the urethra.

Figure 29-8 The anterior wall of the urethra is incised with a scalpel without dissecting around the lateral or posterior surfaces of the urethra.


Figure 29-9 The apical pedicles of the prostate may require suture ligation. Fibromuscular bands tethering the apex of the prostate to the pelvic floor are incised using sharp dissection. The prostate gland is dissected from neurovascular bundles.

Figure 29-10 The dissection is carried cephalad until the portion of Denonvilliers’ fascia covering the ampullary portions of the vasa deferentia and the seminal vesicles is exposed. Denonvilliers’ fascia is incised with the cautery. Denonvilliers’ fascia is incised to expose vascular pedicles at prostate base.

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neurovascular bundle (Figure 29-11). The pedicle is divided close to the prostate. This dissection is performed on both sides to a point just cephalad to the seminal vesicles. Care is taken when dissecting near the seminal vesicles to avoid injuring the neurovascular bundles that are situated just lateral to the seminal vesicles. The seminal vesicles are freed from the bladder base using sharp and blunt dissection, and a large right-angle clamp is used to further develop this plane. Two hemostatic sutures of 3-0 chromic catgut are placed in the lateral bladder pedicles cephalad to the seminal vesicles, one just lateral to the prostate and another just medial to the neurovascular bundles. The lateral bladder neck fibers are then partially incised with the cautery but are not incised through their entire thickness. 6. Transection and Reconstruction of the Bladder Neck The anterior bladder neck is transected with electrocautery in the natural groove between the bladder and the prostate. The bladder neck opening is enlarged with scissors, and the catheter is pulled through and used as a tractor on the prostate (Figure 29-12). The posterior bladder neck is incised with the cautery. The muscular attachments between the bladder and prostate are divided using electrocautery and/or hemostatic clips for hemostasis.

7. Dissection of Seminal Vesicles and Ampullary Portions of the Vasa Deferentia The seminal vesicles are dissected first along their lateral edges, carrying the plane of dissection medially. Many small perforating arteries enter the lateral and terminal portions of the seminal vesicles. These are secured with small hemoclips. The ampullae are freed, using sharp and blunt dissection, and then are clipped and transected. After the seminal vesicles have been dissected to their tips and the hemoclips placed, the surgical specimen is removed. At this point, the pelvis is carefully inspected for hemostasis. Small bleeders on the neurovascular bundles may require 4-0 absorbable suture ligatures. It is important not to use the cautery for hemostasis on the neurovascular bundles, to avoid cautery injury to the cavernosal nerves. Suture ligatures of 3-0 or 4-0 absorbable material are placed in the “pockets” of the seminal vesicle pedicles on the medial aspects of the neurovascular bundles to ensure good hemostasis in this difficult-tovisualize region. 8. Vesico-Urethral Anastomosis Reconstruction of the bladder neck begins by placing a continuous running everting suture of 3-0 chromic catgut that encompass bladder mucosa and underlying muscle for a distance of nearly the entire anastomotic

Figure 29-11 Prostate base pedicle is ligated or hemoclipped laterally, taking care to place the tie medial to the neurovascular bundle.


Figure 29-12 The anterior bladder neck is transected in the natural groove between the bladder and the prostate. The bladder neck opening is enlarged with scissors. The ureteral orifices are identified.

circumference (Figure 29-13). The bladder neck is then reconstructed in a tennis racket fashion, with the handle of the racket directed posteriorly. The bladder neck closure is accomplished in two layers with a continuous 3-0 chromic catgut suture on the first layer and a continuous 2-0 chromic catgut suture on the second layer. Care should be taken to avoid compromising the ureteral orifices. The bladder neck is closed to a size of approximately 22Fr to 24Fr. An 18Fr catheter with a 30-ml balloon is passed through the urethra. While an assistant exerts pressure on the perineum with a sponge forceps to better expose the cut end of the urethra (Figure 29-14), double-armed 2-0 chromic catgut sutures are used for the vesicourethral anastomosis (Figure 29-15). A 5/8-circle needle is used to place the sutures in the urethra from inside to outside, avoiding placing the suture into the neurovascular bundles. The tip of the catheter is grasped and brought out of the wound to expose the posterior lip of the cut end of the urethra. The posterior sutures are similarly placed. The anterior sutures are placed at the 10 o’clock and 2 o’clock positions and the posterior sutures are placed at the 5 o’clock and 7 o’clock positions. The other ends of the sutures containing an SH 3/8-circle needle are placed in the corresponding positions of the bladder neck from inside to outside. These sutures encompass mucosa and muscle and exit at the edge of the mucosa. The catheter tip is placed in the bladder, and

the bladder neck is guided gently toward the cut end of the urethra. The anastomotic sutures are tied carefully under direct vision. The bladder is then irrigated free of clots, a single suction drain is placed in the pelvis and brought out the lower end of the wound. The incision is closed with #1 loop Maxon running sutures on the fascia, 2-0 chromic catgut suture on the subcutaneous tissue, and a 4-0 polyglycolic acid subcuticular suture on the skin. The skin incision is covered with Steri-Strips. Postoperative Care Patients are ambulated with assistance once the night of surgery, 5 times on the first postoperative day and 7 times on the second postoperative day. A clear liquid diet is given on the night of surgery, advancing to a regular diet as tolerated on the following days. A suction drain and dressing are removed on the second postoperative day. Intravenous antibiotics are discontinued after the suction drain is removed. For analgesia, Ketorolac (30 to 60 mg) is given intravenously every 6 hours for the first 48 hours. It may be supplemented sparingly with morphine, as needed. Antibiotic ointment is applied to the urethral meatus around the catheter 4 to 6 times a day until the catheter removal. Most patients are discharged from the hospital on the second or third postoperative day. The catheter may be removed on either the seventh, 10th, or 14th postoperative day, depending on the perceived

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Figure 29-13 A continuous running mucosa-everting suture of 3-0 chromic catgut is placed for a distance of nearly the entire anastomotic circumference.

Figure 29-14 Perineal pressure is applied with a sponge forceps to better expose the cut end of the urethra.


Figure 29-15 Double-armed 2-0 chromic catgut sutures are used for the vesicourethral anastomosis.

amount of tension on the vesicourethral anastomosis. A cystogram is not performed before removing the catheter unless an anastomotic leak is suspected. The catheter should not be removed before 7 days, as 10% to 15% of men may experience urinary retention from edema and require recatheterization.15,16 Oral fluoroquinolone is given 1 day before and 1 week following the catheter removal. Daily Kegel exercises are performed in four sets of 10, before the surgery and following the catheter removal until continence returns. A protective pad or diaper is used until a complete urinary control is achieved. The first postoperative serum PSA level is measured 2 weeks or more after the operation. CANCER CONTROL OUTCOME The most important objective of radical prostatectomy is cancer control. To cure prostate cancer with radical prostatectomy, the patient must have a resectable tumor and the surgery must completely encompass the tumor.9 A rising serum PSA level is usually the earliest evidence of recurrence or progression following surgery.17 Followup data are still not sufficiently mature to effectively evaluate cancer-specific survival trends. For example, in large contemporary radical retropubic prostatectomy series, including the current series, actuarial 10-year cancerspecific survival ranged between 96% and 98%.6,7,18 Therefore, biochemical recurrence (detectable serum PSA)-free survival has been used frequently as a surrogate in evaluating the treatment efficacy in radical retropubic prostatectomy series.

An analysis of the senior author’s series, including more than 3170 men who underwent anatomic radical retropubic prostatectomy between 1983 and 2002, including those with adverse prognostic features, has been presented.18,19 Cancer progression was defined as detectable serum PSA (>0.2 ng/ml), local recurrence, or distant metastases. With a median follow-up of 4.5 years (mean 5.3, range 0 to 18), cancer progression occurred in 19% of the men following radical prostatectomy. Actuarial 10-year cancer progression-free survival probability was 67%. Cancer progression following radical prostatectomy was strongly associated with many clinical and pathologic parameters, including Gleason grade, clinical, and pathologic tumor stage, era of treatment, and patient age. For example, preoperative serum PSA level was inversely associated with both the rate of organ-confined disease and the 10-year progression-free survival rate. Patient selection and the duration and frequency of follow-up monitoring are critical in determining outcomes as well. Therefore, factors other than treatment effectiveness can influence treatment outcomes. Accordingly, caution is indicated in comparing the results of contemporary radical prostatectomy series using different patient selection criteria and follow-up protocols. URINARY CONTINENCE OUTCOME The overall urinary continence outcome following nerve-sparing radical retropubic prostatectomy was excellent in the current series. More than 93% of men

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achieved complete urinary continence, defined as requiring no protection for daily activities.19 The return of urinary continence was strongly associated with the age of the patient. For example, more than 95% of men younger than age 50 were continent following surgery. In contrast, 85% of men above age 70 were continent postoperatively. There was no significant difference in continence rate according to the era. Only 4 men (0.2%) eventually required an artificial urinary sphincter placement for stress urinary incontinence. POTENCY OUTCOME There are several possible goals of the nerve-sparing aspect of radical retropubic prostatectomy. Patients with intact libido and erectile potency want to maintain current quality of erections or erections sufficient for penetration with the help of oral medication, such as phosphodiesterase inhibitors. Others with poor quality erections preoperatively might accept erections that at least offer some rigidity to provide sensory satisfaction for both sexual partners. The erectile potency in the current series was defined as an ability to maintain erections strong enough for penetration with or without the help of oral phosphodiesterase inhibitor. The return of erectile potency following radical retropubic prostatectomy was strongly associated with the age of the patient, preoperative potency status, nervesparing status (bilateral sparing versus partial sparing), and the era of surgery (1980s versus 1990s).19 More than 75% of men younger than age 60 regained potency following bilateral nerve-sparing radical retropubic prostatectomy. For men below age 50, more than 95% recovered potency following surgery, in the modern era. Between 62% and 72% of men in their 60s became potent following bilateral nerve-sparing surgery. Finally, there was a significant improvement in recovery of potency in men treated in the 1990s compared to those treated in the 1980s, even after correcting for the age and nerve-sparing status. COMPLICATIONS The hospital cancer registry survey performed by the American College of Surgeons reported a perioperative (within 30 days of surgery) mortality rate of 0.4% following radical prostatectomy.20 There was no intraoperative or immediate postoperative mortality in the current series. With a careful selection of patients and performance of necessary cardiovascular evaluation, perioperative mortality can be largely avoided. The overall complication rate of radical prostatectomy was 8% in the current series. Initially, the complications occurred more commonly in older men, but the overall complication rate gradually decreased with the surgeon’s

experience. The most common complications of anatomic nerve-sparing radical retropubic prostatectomy included anastomotic stricture/bladder neck contracture, thromboembolic complications (deep vein thrombosis and pulmonary embolism), and postoperative inguinal hernia occurrence. In the current series, the rate of anastomotic stricture/bladder neck contracture decreased from 8% in the 1980s to 0.2 ng/ml) at 5 years for the entire cohort was 41% and at 10 years was 30%. Ten-year cause specific for the pT3c group was 60%. Several other reports of men who underwent radical prostatectomy with seminal vesicle involvement demonstrate similar results26–30 (Table 33-2). Adjuvant radiation therapy has been used in the setting of positive margins and seminal vesicle involvement

with mixed results. The lack of randomized data comparing adjuvant versus no treatment have hampered decisionmaking. Choo et al.31 analyzed 125 patients with a positive resection margin or pT3 disease of whom 73 were treated with adjuvant radiation therapy and 52 were followed expectantly. Radiation therapy was delivered a median of 3.4 months post-RP with a 4-field technique to a dose of 60 to 66 Gy. The clinical target volume (CTV) was limited to the prostate bed, and if the seminal vesicles were pathologically involved, they were also included in the CTV. The treatment volume included a 1-cm margin around the CTV. A Cox proportional hazards model of relapse-free probability versus time demonstrated adjuvant radiation therapy (0.22, p = 0.0008), PSA preprostatectomy (1.022, p = 0.029) and seminal vesicle involvement (2.03, p = 0.09) as important variables. Unfortunately, there was no independent seminal vesicle analysis. Patients with seminal vesicle involvement are at risk for local and systemic recurrence. The exact incidence of each and whether local failure presages systemic relapse has never been fully defined. Gibbons et al.32 reported a 44% local failure rate following radical prostatectomy in patients with seminal vesicle involvement. In a 15-year follow-up study, up to 83% of patients have been reported with local recurrence if the radical prostatectomy specimen contained pT3 disease.33 In looking for local recurrence, Medini et al.34 analyzed 40 men who were found to have elevated PSA 9 to 96 months postprostatectomy. Of the 40 patients, 25 had a positive surgical margin and 6 had involvement of the seminal vesicles. Twenty-eight were found to have recurrent local disease as determined by transrectal biopsy. Zeitman et al.35 performed a review of residual disease after radical surgery or radiation therapy in patients with prostate cancer. He noted a 12% to 68% risk of local

Table 33-2 Comparison of Current Series of Patients with Seminal Vesicle Implant to Biochemical Freedom from PSA Failure Following Radical Prostatectomy with Vesicle Involvement Study

Number

Definition

Rate (%)

Years

Catalona and Bigg26

86

>0.6

32

5

D’Amico et al.27

39

>0.2

5

2

Kupelian et al.28

60

>0.2

20

6

Sofer et al.22

66

>0.4

35

5

Trapasso et al.29

93

>0.4

56

5

Zeitman et al.30

12

>0.2

4

4

Van den Ouden et al.23

83

2 increases above 0.1

29

5

Current

32

ASTRO

74

7

558


Figure 33-2 A, Axial image showing two implant needles at “C1” and “c1” positions within the seminal vesicles. The bladder with Foley balloon can be seen just above. Arrow points to anterior rectal wall. B, Longitudinal image of implant needle in anterior seminal vesicle wall. The bladder is above and to the left. The arrow points to the posterior wall of the SV. A Mick applicator will be used to deposit two seeds, one proximal and one just above prostate base.

recurrence, which was associated with a poorer prognosis. In a review of patients with T2 to T3 disease receiving radiation therapy, between 27% and 100% were found to have positive biopsies, including 27% treated with EBRT plus AU-198 seeds and 28% with EBRT plus I-125 seeds.36,37 Planning a radiation treatment field that adequately boosts dose to encompass disease that has extended into the seminal vesicles has not been addressed. While dose escalation trials have been performed on high-risk prostate cancer patients and have demonstrated an advantage to doses in excess of 75 Gy, no studies have specifically addressed these higher doses in the seminal vesicles.38,39 The problem in adequately targeting the seminal vesicles with the higher doses and sparing the rectum, bladder base, and ureters has probably prevented an adequate treatment to this region. Centers that choose to treat high-risk prostate cancer with a combination of brachytherapy and beam irradiation risk under treatment if the disease has extended into the seminal vesicles. Stock et al.40 have shown that the implant provides very little radiation dose to the seminal vesicles if the implant is limited to the prostate. The most proximal 20% of seminal vesicle tissue (SV1) received a median of 35% of the prostate dose while the next cephalad 20% (SV2) received just 3%. With external radiation dose of 45 Gy in this situation, adequate treatment of the seminal vesicle extension would be inadequate. In the same study, Stock et al.40 demonstrated in a small cohort of 5 patients with seminal vesicle tumor how to boost the SV dose with an implant technique developed for this purpose (Figure 33-2A and B). The postimplant prostate D90/SV1 D90 ranged from 63% to 97% (median 80%) and the

prostate D90/SV2 D90 ranged from 19% to 88% (median 52%). A multimodality treatment program has been developed to address these high-risk prostate cancer patients with biopsy proven SV involvement.41,42 The protocol consists of three parts: neoadjuvant and concomitant hormonal therapy, partial palladium-103 implant (planning dose 83 to 90 Gy) with seeds placed in the prostate and seminal vesicles followed 2 months later with 45 Gy of conformal EBRT, which includes a 1.5-cm margin around the prostate and seminal vesicles (Figure 33-3). High-risk patients undergo routine evaluation, which includes bone and CT scanning. Seminal vesicle biopsies identify those patients with vesicle involvement (Figure 33-4A,B). Laparoscopy can exclude the 25% to 35%, who may harbor micrometastatic disease in the pelvic lymph nodes. Treatment is begun with 3 months of complete androgen blockade. Preimplant prostate volume is determined with an extra 10 cc added to account for the seminal vesicles. The real-time method of seed implantation where total activity is identified by nomogram and planning done in the operating room is used.43–45 The patient is brought to the OR and placed in the lithotomy position. The probe is advanced to the base of the bladder until the tips of the seminal vesicles are no longer visible. The probe is then retracted until the seminal vesicles appear under the bladder base. The seminal vesicles are contoured at 5-mm intervals, which is continued when the prostate is reached to encompass both the prostate base and seminal vesicles. The contouring is continued to the prostate apex. The physicist can then match these structures, as well as urethra and rectum, in order to perform the intraoperative planning (Figure 33-5A,B).

Chapter 33 Seminal Vesicles: Diagnosis, Staging, Surgery, and Management 559

Stage T3c prostate cancer

Laparoscopic pelvic lymph node dissection

Node negative

Node positive

3 months LHRHa plus antiandrogen

Hormonal therapy

partial Pd-103 implant to prostate and seminal vesicles Dose 100 Gy (NIST 99)

2 month break continue HT

45 Gy conformal EBRT to prostate and SV continue HT till end of radiation

Figure 33-3 Flow chart of treatment protocol for high-risk prostate cancer patients with biopsy proven seminal vesicle involvement.

Figure 33-4 A, Pretreatment biopsy: seminal vesicle with lamina propria extensively infiltrated with prostatic adenocarcinoma (Gleason’s pattern 4 + 4, total score 8). The seminal vesicle epithelium shows mild nuclear pleomorphism and atypia, which is a normal degenerative finding (arrow) (H/E, 200×). B, Posttreatment biopsy: seminal vesicle that is negative for prostatic adenocarcinoma. Focally, the seminal vesicle glands contain intraluminal secretions (arrow). Endothelium in a small vessel shows nuclear atypia consistent radiation effect (arrowhead) (H/E, 200×).

Once the intraoperative planning is complete, the peripheral needles are placed. The implant is performed in two phases, with placement of the peripheral needles and sources first, followed by the interior needles and

sources. With the use of intraoperative planning software (VariSeed 7.0, Varian, Palo Alto, CA) in an interactive fashion, the plan continually evolves as each seed is placed. The Mick Applicator (Mick Radionuclear

560


Figure 33-5 A, Axial image from planning computer (VariSeed, Varian, Palo Alto, CA) demonstrating intended needle and seen positions in seminal vesicles with isodose contours superimposed. Center isodose contour represents 100% of prescription (100 Gy palladium-103). B, 3D representation of completed implant showing the prescription dose cloud covering the prostate and proximal seminal vesicles.

Chapter 33 Seminal Vesicles: Diagnosis, Staging, Surgery, and Management 561

Figure 33-6 A, Postimplant CT image of seminal vesicle seed implant with bladder above rectum below. The 80% and 100% isodose contours encompass the vesicles with very little dose distributed to bladder or rectum. B, Coverage of SV at base of prostate.

Instruments, Mount Vernon, NY) permits each seed to be placed individually, maximizing the ability to conform the radiation dose cloud to the prostate and seminal vesicles (see Figure 33-5B). Postimplant dosimetry is performed 1 month after the implant is used in part to confirm prostate and seminal

vesicle doses and to aid in the external beam planning (Figure 33-6A,B). Two months postimplant 45 Gy of conformal external beam is given, limited to the prostate and seminal vesicles with a margin of 1.5 cm. The hormonal therapy is continued till the end of the external beam (total length of time 9 months). Routine prostate

562


100

100

0

Survival Function Censored 0

3

5

8

Years

Figure 33-7 Kaplan-Meier estimates of PSA freedom from failure defined as being free from 3 consecutive PSA rises above a nadir (ASTRO). Of the 32 patients treated, 8 have failed. The 7-year freedom from failure is 74%. The median PSA for these 24 is 10,000

Chapter 34 Testis Tumors: Diagnosis and Staging 573

Table 34-2 Staging Classification (Stage Groups) Stage grouping Stage 0

pTis

N0

M0

S0

Stage I

pT1-4

N0

M0

SX

Stage IA

pT1

N0

M0

S0

Stage IB

pT2-4

N0

M0

S0

Stage IS

Any pT/Tx

N0

M0

S1-3

Stage II

Any pT/Tx

N1-3

M0

SX

Stage IIA

Any pT/Tx

N1

M0

S0-1

Stage IIB

Any pT/Tx

N2

M0

S0-1

Stage IIC

Any pT/Tx

N3

M0

S0-1

Stage III

Any pT/Tx

Any N

M1

SX

Stage IIIA

Any pT/Tx

Any N

M1a

S0-1

Stage IIIB

Any pT/Tx

N1-3

M0

S2

Stage IIIB

Any pT/Tx

Any N

M1a

S2

Stage IIIC

Any pT/Tx

N1-3

M0

S3

Stage IIIC

Any pT/Tx

Any N

M1a

S3

Stage IIIC

Any pT/Tx

Any N

M1b

Any S

Table 34-3 International Germ Cell Consensus Classification Nonseminoma

Seminoma

Good prognosis Testis/retroperitoneal primary

Any primary site

And No nonpulmonary visceral metastasis


And Good markers

And Nomal AFP, any HCG, any LDH

AFP < 1000 ng/ml and HCG < 5000 IU/l (1000 ng/ml) and LDH < 1.5 upper limit of normal 5-year PFS 89%

5-year PFS 82%

5-year survival 92%

5-year survival 86% Continued

574

Part VI Testis

Table 34-3—cont’d Nonseminoma

Seminoma

Intermediate prognosis Testis/retroperitoneal primary

Any primary site


And Nonpulmonary visceral metastasis

And Intermediate markers

And Nomal AFP, any HCG, any LDH

AFP > 1000 ng/ml and 5000 IU/l and 1.5 × N and 10,000 ng/ml or HCG > 50,000 IU/l or LDH > 10 × upper limit of normal 5-year PFS 41% 5-year survival 48%

REFERENCES 1. Richie JP: Detection and treatment of testicular cancer. CA Cancer J Clin 1993; 43:151–175. 2. Richie JP: Advances in the diagnosis and treatment of testicular cancer. Cancer Invest 1993; 11(6):670–675. 3. McCaffrey JA, Bajorin DF, Motzer RJ, et al: Risk assessment for metastatic testis cancer. Urol Clin NA 1998; 25(3):389–395. 4. Bosl GJ, Goldman A, Lange PH, et al: Impact of delay in diagnosis on clinical stage of testicular cancer. Lancet 1981; 2:970–973. 5. Nikzas D, Champion AE, Fox M: Germ cell tumours of testis: prognostic factors and results. Eur Urol 18:242–247. 6. Richie JP, Steele GS: Neoplasms of the testis. In Walsh PC, Retik AB, Vaughan ED, Wein A (eds) Campbell’s Urology, 8th edition. Philadelphia, PA, WB Saunders, 2002.

7. Kennedy BJ, Schmidt JD Winchester DP, et al: National survey of patterns of care for testis cancer. Cancer 1987; 60:1921–1930. 8. Bokemeyer C, Hartmann JT, Fossa SD, et al: Extragonadal germ cell tumors: relation to testicular neoplasia and management options. APMIS 2003; 111:49–63. 9. Small EJ, Torti FM: Testes. In Abeloff MD, Armitage JO, Lichter AS, Niederhuber JE (eds) Abeloff Clinical Oncology, 2nd edition. Philadelphia, PA, Churchill Livingston, 2000. 10. Klein EA: Tumor markers in testis cancer. Urol Clin North Am 1993; 20:67–73. 11. Javadpour N: Significance of elevated serum alphafetoproteins (AFP) in seminoma. Cancer 1980; 45:2166. 12. Richie JP: Neoplasms of the testis. In Walsh PC, Retik AB, Stamey TA, Vaughan ED (eds). Campbell’s Urology, 6th edition. Philadelphia, PA, WB Saunders, 1992.

Chapter 34 Testis Tumors: Diagnosis and Staging 575 13. Bloomer JR, Waldmann TA, McIntire KR, et al: Serum alpha-fetoprotein levels in patients with nonneoplastic liver disease. Gastroenterology 1973; 65:530. 14. Bower M, Rustin GJS: Serum tumor markers and their role in monitoring germ cell cancers of the testis. In Vogelzang NJ, Scardino PT, Shipley WU, Coffey DS (eds): Comprehensive Textbook of Genitourinary Oncology, 2nd edition. Philadelphia, PA, Lippincott Williams and Wilkins, 1999. 15. Boyle LE, Samuels ML: Serum LDH activity and isoenzyme patterns in nonseminomatous germinal (NSG) testis tumors. Proc Am Soc Clin Oncol 1977; 18:278. 16. Mencel PJ, Motzer RJ, Mazumdar M, et al: Advanced seminoma; treatment results, survival, and prognostic factor in 142 patients. J Clin Oncol 1994; 12:120–126. 17. Stoter G, Bosl GJ, Droz JP, et al: Prognostic factors in metastatic germ cell tumors. Porg Clin Biol Res 1990; 357:313–319. 18. National Comprehensive Cancer Network Practice Guidelines in Oncology, Vol 1, Testicular Cancer. Rockledge, PA, 2003. 19. Laguna MP, Pizzocaro G, Klepp O, et al: EAU guidelines on Testicular Cancer. Eur Urol 2001; 40:102–110. 20. Albrecht W, Bonner E, Jeschke K, et al: PLAP as a marker for germ cell tumors. In Jones NG, Appleyard I, Harnden P, Joffe JK (eds): Germ Cell Tumours IV. London, John Libbey & Co, 1998. 21. Koshida K, Nishino A, Yamamoto H, et al: The role of alkaline phosphatase isoenzymes as a tumor marker for testicular germ cell tumors. J Urol 1991; 146:57. 22. Lange PH, Millan JL, Stigbrand T, et al: Placental alkaline phosphatase as a tumor marker for seminoma. Cancer Res 1982; 42:3244. 23. Muensch HA, Maslow WC, Azama F, et al: Placental-like alkaline phosphatase. Reevaluation of the tumor marker with exclusion of smokers. Cancer 1986; 58:1689. 24. Nielsen OS, Muntro AJ, Duncan W, et al: Is placental alkaline phosphatase (PLAP) a useful marker for seminoma? Euro J Cancer 1990; 26(10):1049–1054. 25. Gross AJ, Dieckmann KP: Neuron-specific enolase: a serum marker in malignant germ-cell tumors? Euro Urol 1993; 24(2):277–278. 26. Benson CB: The role of ultrasound in diagnosis and staging of testicular cancer. Semin Urol 1988; 6(3):189–202. 27. Richie JP, Birnholz J, Garnick MB: Ultrasonography as a diagnostic adjunct for the evaluation of masses in the scrotum. Surg Gyn Obs 1982; 154:695–698. 28. Schwerk WB, Schwerk WN, Rodeck G: Testicular tumors: prospective analysis of real-time US patterns and abdominal staging. Radiology 1987; 164:369–374. 29. Marth D, Scheidegger J, Studer UE: Ultrasonography of testicular tumors. Urol Int 1990; 45(4):237–240. 30. Oyen R, Verellen S, Drochmans A, et al: Value of MRI in the diagnosis and staging of testicular tumors. JBR BTR 1993; 76:84–89. 31. Boden G, Gibb R: Radiotherapy and testicular neoplasms. Lancet 1951; 2:1195. 32. Maier JG, Sulak MH: Radiation therapy in malignant testis tumors. Cancer 1973; 32:1217–1226.

33. Doornbos JF, Hussey DH, Johnson DE: Radiotherapy for pure seminoma of the testis. Radiology 1975; 116:401–404. 34. Ball D, Barrett A, Peckham MJ: The management of metastatic seminoma testis. Cancer 1982; 50:2289–2294. 35. Crawford ED, Smith RB, DeKernion JB: Treatment of advanced seminoma with preradiation chemotherapy. J Urol 1983; 129:752–756. 36. Fleming ID, Cooper JS, Henson DE, et al. (eds): Testis. In American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 5th edition. Philadelphia, PA, Lippincott-Raven, 1997. 37. Donohue JP, Zachary JM, Maynard BR: Distribution of nodal metastasis in nonseminomatous testis cancer. J Urol 1982; 128:315–320. 38. Hilton S, Herr HW, Teitcher JB, et al: CT detection of retroperitoneal lymph node metastasis in patients with clinical stage I testicular nonseminomatous germ cell cancer: assessment of size and distribution criteria. AJR 1997; 169(2):521–525. 39. Stomper PC, Fung CY, Socincki MA, et al: Detection of retroperitoneal metastasis in early stage nonseminomatous testicular cancer: analysis of different CT criteria. AJR 1987; 149:1187–1190. 40. Leibovitch I, Foster RS, Kopecky KK, et al: Improved accuracy of computerized tomography based clinical staging in low stage nonseminomatous germ cell cancer using size criteria of retroperitoneal lymph nodes. J Urol 1995; 154:1759–1763. 41. Ellis JH, Bies JR, Kopecky KK, et al: Comparison of NMR and CT imaging in the evaluation of metastatic retroperitoneal lymphadenopathy from testicular carcinoma. J Comput Assist Tomogr 1984; 8(4):709–719. 42. Hogeboom WR, Hoekstra HJ, Mooyaart EL, et al: Magnetic resonance imaging of retroperitoneal lymph node metastases of nonseminomatous germ cell tumours of the testis. J Surg Oncol 1993; 19:429–437. 43. Bussar-Maatz R, Weissbach L: Retroperitoneal lymph node staging of testicular tumours. BJU 1993; 72:234–240. 44. Casellino RA: Lymphography. In Pollack HM, McClennan BL (eds): Pollack Clinical Urography, 2nd edition. Philadelphia, PA, WB Saunders, 2000. 45. Wishnow KI, Johnson DE, Tenney D: Are lymphangiograms necessary before placing patients with nonseminomatous testicular tumors on surveillance? J Urol 1989; 141:1133–1135. 46. Cremerius U, Wildberger JE Borchers H, et al: Does positron emission tomography using 18-fluoro-2deoxyglucose improve clinical staging of testicular cancer? Results of a study of 50 patients. Urology 1999; 54:900–904. 47. Hain SF, O’Doherty MJ, Timothy AR, et al: Fluorodeoxyglucose PET in the initial staging of germ cell tumours. Eur J Nucl Med 2000; 27(5):590–594. 48. Donohue JP, Thornhill JA, Foster RS: Retroperitoneal lymphadenectomy for clinical stage A testis cancer (1965–1989): modifications of technique and impact on ejaculation. J Urol 1993; 149:237–243.

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49. Klepp O, Olsson AM, Henrikson H, et al: Prognostic factors in clinical stage I nonseminomatous germ cell tumors of the testis: multivariate analysis of a prospective multicenter study. Swedish-Norwegian testicular cancer group. J Clin Oncol 1990; 8:509–518. 50. Albers P, Siener R, Kliesch S, et al: Risk factors for relapse in clinical stage I nonseminomatous testicular germ cell tumors: results of the German testicular cancer study group trial. J Clin Oncol 2003; 21:1505–1512. 51. Hermans BP, Sweeney CJ, Foster RS, et al: Risk of systemic metastases in clinical stage I nonseminomatous germ cell testis tumor managed by retroperitoneal lymph node dissection. J Urol 2000; 163:1721–1724. 52. Janetschek G, Hobisch A, Peschel R, et al: Laparoscopic retroperitoneal lymph node dissection. Urology 2000; 55:136–140. 53. Nelson JB, Chen RN, Bishoff JT, et al: Laparoscopic retroperitoneal lymph node dissection for clinical stage I nonseminomatous germ cell testicular tumors. Urology 1999; 54:1064–1067.

54. Richie JP, Kantoff PW: Is adjuvant chemotherapy necessary for patients with stage B1 testicular cancer? J Clin Oncol 1991; 9:1393–1396. 55. See WA, Hoxie L: Chest staging in testis cancer patients: imaging modality selection based upon risk assessment as determined by abdominal computerized tomography scan results. J Urol 1993; 150:874–878. 56. Hoskin P, Dilly S, Easton D, et al: Prognostic factors in stage I nonseminomatous germ cell testicular tumors managed by orchiectomy and surveillance: implications for adjuvant chemotherapy. J Clin Oncol 1986; 4:1031–1036. 57. The International Germ Cell Collaborative Group: International germ cell consensus classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 1997; 15(2):594–603. 58. Davis BE, Herr HW, Fair WR, et al: The management of patients with nonseminomatous germ-cell tumors of the testis with serologic disease only after orchiectomy. J Urol 1994; 152:111–114.

C H A P T E R

35 Seminoma: Management and Prognosis Michael A. S. Jewett, MD, FRCSC, FACS, Rishikesh Pandya, MCh, DNB, MS, and Padraig Warde, MB, BCh, BAO

Testicular cancer is uncommon and accounts for only 1% to 2% of all cancers in North America, but it is the most common solid malignancy in men 20 to 35 years of age.1 The vast majority (98%) are primary germ cell tumors (GCTs). Of GCTs, approximately 60% are seminomas and most usually present as an asymptomatic testicular mass.1,2 The identification of prognostic factors in patients with both early and advanced disease has helped to refine management strategies for these patients. The management of patients with testicular tumors is significantly affected by histology and disease extent. Treatment results with seminoma have been good for many years because of the relatively low metastatic rate and high radiosensitivity. More recent advances in chemotherapy (CT) have improved the cure rate to >95% overall. The postorchidectomy management of the stage I group seminoma patients is focused on reducing the side effects of therapy. Treatment options include surveillance, adjuvant radiation therapy (RT), retroperitoneal lymphadenectomy, and adjuvant CT. Adjuvant retroperitoneal RT remains the treatment of choice in most centers. The success of surveillance in stage I nonseminomatous germ cell testis tumors, the establishment of curative CT for advanced disease, and the improvements in computed tomography for staging have led to reexamination of the standard treatment approach in some centers. Also, while the acute morbidity of the relatively low-dose RT used in this setting is minimal, there are reports of impaired spermatogenesis, increased rates of gastrointestinal symptoms and peptic ulceration on long-term follow-up, and increasing concern regarding the possible induction of second malignancies by RT. However, the low relapse rates following radiation, the

lack of apparent serious morbidity with adjuvant RT, the lack of long-term follow-up in surveillance studies, and the increased cost of surveillance have all dissuaded most clinicians from abandoning the traditional treatment approach.3 Stage II group patients with small bulk retroperitoneal lymphadenopathy have a high probability of long-term disease control with RT.4 Stage II group patients with large masses and stage III group patients are managed by CT. EPIDEMIOLOGY The age distribution of testicular cancer is similar in all Caucasian populations. There is a small peak in early childhood around 2 years of age, with rates then remaining low until 15 years of age.5 There is a second peak in young adults around 25 to 40 years of age and the rate then declines with a small peak again between 65 and 75 years of age. Testicular cancers occurring in childhood and in the young adult years are usually GCTs, while those occurring after age 65 are principally nongerm cell malignancies, mainly lymphomas. Nonseminomatous tumors are more common in childhood and in the 15-to-30 age group, while seminomas are seen more frequently in slightly older (25 to 45 years) patients. In 2003, it is estimated that there will be approximately 7500 new cases and probably 300 deaths due to testicular cancer in the U.S.6 The current incidence of testicular cancer in the white U.S. population is 6:100000 males per year and in Canada it is 4:100000.7,8 The cumulative lifetime risk of developing a GCT is 0.2%.5 The incidence of testicular tumors is rising but the reasons are not well understood. The incidence rate has doubled in the past 30 years, and

577

578

Part VI Testis

while most patients present with early-stage curable disease, the continued rising incidence of these tumors presents a challenge. Weir et al.2 reported that the incidence of testicular GCT (TGCT) has risen in Ontario by 60% between 1964 and 1996. Seminomas have increased by 72% and nonseminomas by 45%. From SEER data, the overall incidence of TGCT rose over 44% from 3.35 to 4.84 per 100,000 men between 1973 to 1978 and 1994 to 1998. Among white men, the incidence rose 52% from 3.69 in 1973 to 1978 to 5.62 per 100,000 men in 1994 to 1998. Among black men, the overall incidence of TGCT rose 25% from 0.83 in 1973 to 1978 to 1.04 per 100,000 men in 1994 to 1998.1. The incidence in England and Wales was 5.4 in 1997 compared with 2.9 per 100,000 person-years in 1971.9 Similar increases in incidence have been reported in other populations with European ancestry, including Australia, New Zealand, and Europe itself.10 Geographically, the highest incidence of testicular cancers is seen in Denmark (8.4 per 100,000 men per year) and Switzerland (8.8 per 100,000 per year).5 It is known that the incidence is lower in nonwhites compared to whites. Low incidence rates are seen in other ethnic groups, such as Americans of Chinese and Japanese descent. However, a high incidence of testicular cancer is seen in some nonwhite populations, such as the Maoris in New Zealand and Native Americans. ETIOLOGY Cryptorchidism affects 0.7% of men and is the only condition that has been definitely associated with an increased risk of testicular cancer.7,11 The mechanisms are unknown. Pure seminoma is the most common tumor histology observed in cryptorchid testes.11 Impalpable cryptorchid testes may be detected with 91% and 95% accuracy by ultrasound and CT, respectively. The pattern of nodal metastasis may be different from that of scrotal primary tumors with a much higher incidence of pelvic nodal involvement.12 There is ongoing research to define the genetics of susceptibility to testicular cancer. An international consortium has been established to collect pedigrees of patients and their families who are thought to have increased susceptibility. A gene on the X chromosome (Xp27) has been identified. Patients with a family history of testis cancer, undescended testes, and bilateral testicular cancers are being studied to identify further susceptibility genes.13 There may be a relation between estrogenic exposure in utero and testicular cancer, and there is evidence that environmental pollutants with estrogenic or antiandrogenic activity result in hormonal disruption and are responsible for the steadily increasing incidence of testicular cancer.14,15 The increased incidence of germ cell cancers among men with testicular atrophy, testicular dysgenesis, cryptorchidism, and infertility suggests a common etiologic

relation between germ cell cancers and these genital abnormalities. SYMPTOMS The commonest mode of presentation is a painless swelling of the testis but a few patients complain of pain or heaviness in the affected side. A hard, nontender testis mass that cannot be transilluminated is diagnostic of a testicular cancer until proven otherwise. Occasionally, presentation with loss of libido or infertility leads to detection of a testicular mass. Acute presentations with symptoms resembling torsion, hematospermia, varicocele, or thrombosis of the pampiniform plexus are rare. Nipple tenderness or breast swelling is noted in approximately 5% of patients. Back pain as a result of metastatic lesion is a very rare presentation. Any history of cryptorchidism, orchiopexy, or any other inguinal or scrotal surgeries should be elicited, as these may be relevant to etiology or pattern of metastasis. When RT is being considered, the presence of inflammatory bowel disease (IBD), previous abdominal or pelvic surgeries, or any other intraabdominal diseases should be ruled out. PRIMARY SURGERY AND STAGING Radical inguinal orchiectomy is usually the initial treatment that is both diagnostic of the tumor type and therapeutic. It is curative in approximately 75% of patients with clinical stage I disease. An intraoperative excisional biopsy of the testicular mass for frozen-section evaluation after delivery of the testis from the scrotum may prevent unnecessary orchiectomy in the small proportion of patients who are ultimately found to have benign testicular masses, but it is not routinely performed if the mass is large or clinically malignant in appearance. Measurement of the serum tumor markers alphafetoprotein (AFP), the beta subunit of human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH) play an important role in the diagnosis, treatment, and establishment of prognosis. A detectable AFP is an indication of nonseminomatous elements, which mandates treatment as a nonseminoma. Up to 40% of patients with pure seminomas have low but detectable levels of (β−hCG) and >200 ng/ml of (β−hCG) suggests metastatic disease or nonseminomatous elements.16 LDH is a useful marker in cases of advanced seminoma and therapy can be monitored by serial measurements.17,18 Placental alkaline phosphatase is nonspecific and has not generally been found useful in the management of seminoma.18 The half-lives of AFP and β-hCG are 5 days and 24 hours, respectively. The tumor markers are measured serially, immediately before or at the time of radical

Chapter 35 Seminoma: Management and Prognosis 579

orchidectomy. If elevated, measurements should be repeated until the level(s) normalize or plateau (the later indicates residual metastatic disease). Staging investigations should include a chest x-ray and a CT scan of the abdomen and pelvis. Patients with retroperitoneal lymphadenopathy should also have a CT scan of the chest and a bone scan. Clinical staging of testis tumors is now generally done according to the 2002 UICC TNM staging system (see staging chart as Table 35-1). Seminoma is clinically confined to the testis at diagnosis (T1–4, N0, M0, or stage I group) in approximately 75% of men. The disease is characterized by an orderly, predictable spread pattern from the testis to paraaortic lymph nodes at or below the renal hilar and then to distant sites, including mediastinal and supraclavicular lymph nodes, lung, and bone. Approximately 20% of patients have involvement of regional lymph nodes at presentation (any T, N1-3, M0, or stage II group), most commonly paraaortic nodes. Distant metastases are evident at diagnosis (any T, Any N, M1, or stage III group) in only 5% of patients. Nonstandard surgical approaches (scrotal violations), including scrotal orchiectomy, open testicular biopsy, and fine needle aspiration, have historically been condemned as potentially complicating further treatment and compromising patient prognosis.19 Capelouto et al.20 showed that although statistically significant differences were found in the local recurrence rate among the scrotal violation and inguinal group studies, the overall local recurrence rates were small (2.9% versus 0.4%, respectively) and did not occur in stage I group seminoma patients. There were no statistical differences in distant recurrences or survival rates in all groups analyzed. Patients with scrotal violation who did not receive prophylactic local therapy fared as well as those who did. Patients with stage I disease and scrotal violation should not necessarily be disqualified from surveillance protocols or subjected to adjuvant local therapy.

Classical seminoma is usually seen in the fourth decade of life. The typical histologic picture is sheets of relatively large cells with clear cytoplasm and densely staining nuclei with 10% to 15% of them showing syncytiotrophoblastic elements and 20% showing lymphocytic infiltration. β-hCG levels are proportionate to the extent of syncytiotrophoblastic cells. Anaplastic seminoma also occurs in the fourth decade. This histologic subtype may indicate a poorer prognosis but this is not supported by the results with surveillance.27 Increased mitotic activity, microinvasion, nuclear pleomorphism, and cellular anaplasia are its typical features. β-hCG levels are elevated in 36%, 25% present with higher stage disease, and almost half of these patients have extragonadal extension of the primary tumor. Spermatocytic seminoma is a histologic variant that occurs in the elderly, around the sixth decade. They are large multinodular fleshy gelatinous and hemorrhagic tumors. Under the microscope they have solid sheets of cells interrupted by pseudoglandular patterns. Nests of cells in edematous stroma with occasional lymphocytic infiltrates can be seen. Spermatocytic seminomas do not metastasize, so radical orchiectomy is an adequate treatment. Warde et al.28 showed that on univariate analysis, tumor size (relapse-free rate or RFR: = 4 cm 87% versus >4 cm 76%; p = 0.003), rete testis invasion (RFR: 86% when absent versus 77% when present, p = 0.003), and the presence of SVI (small vessel invasion) (RFR: 86% when absent versus 77% when present, p = 0.038) were predictive of relapse. 28 On multivariate analysis, tumor size (= 4 cm) and invasion of the rete testis remained important predictors for relapse. Thus, the size of the primary tumor and rete testis invasion are important prognostic factors for relapse in patients with stage I seminoma when managed with surveillance. PATTERNS OF SPREAD

PATHOLOGY Testicular Intraepithelial Neoplasia Testicular intraepithelial neoplasia (TIN), previously referred to as carcinoma-in-situ (CIS), is the precursor to all TGCTs except spermatocytic seminoma.21 Furthermore, virtually all cases of TIN in postpubertal men will progress to invasive cancer if given sufficient time.22 The incidence of TIN in the contralateral testis of men with a unilateral GST is approximately 5%, which approximates the incidence of second contralateral testicular tumors.23–26 There are three histologic subtypes of seminoma: classical (70% to 85%), anaplastic (10% to 30%), and spermatocytic (2% to 12%).

The N staging of the testicular tumor depends on the number and size of involved retroperitoneal lymph nodes. Spread is primarily lymphatic and is predictable. Surgical mapping studies by Donohue et al.,29 Weissbach and Boedefeld,30 and other workers have defined the patterns of metastasis in terms of its landing sites or stations. For right-sided tumors, the first station is the interaortocaval nodes, then the precaval and preaortic; for leftsided, first station is paraaortic and preaortic and then the interaortocaval nodes. The presence of more caudal metastatic nodes is generally seen in high volume disease or with aberrant lymphatic drainage. Contralateral spread is more common from right-sided tumors than left, especially in high volume disease.

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Part VI Testis

Table 35-1 Staging (UICC 2002) DEFINITIONS Pathologic

Primary Tumor (T)(1)

■

pTX Primary tumor cannot be assessed (if no radical orchiectomy has been performed, TX is used)

■

pT0 No evidence of primary tumor (e.g., histologic scar in testis)

■

pTis Intratubular germ cell neoplasia (carcinoma in situ)

■

PT1 Tumor limited to the testis and epididymis without vascular/ lymphatic invasion; tumor may invade into the tunica albuginea but not the tunica vaginalis

■

pT2 Tumor limited to the testis and epididymis with vascular/ lymphatic invasion, or tumor extending through the tunica albuginea with involvement of the tunica vaginalis

■

PT3 Tumor invades the spermatic cord with or without vascular/lymphatic invasion

■

pT4 Tumor invades the scrotum with or without vascular/lymphatic invasion

Clinical ■

Pathologic

Notes 1. Except for pTis and pT4, extent of primary tumor is classified as radical orchiectomy. TX may be used for other categories in the absence of radical mechiactomy.

Primary Tumor (T) Tumor stage is generally determined after orchiectomy at which time a pathologic stage is assigned. Regional Lymph Nodes (N)

Clinical Regional Lymph Nodes (N) ■ NX Regional lymph nodes cannot be assessed

■

pNX Regional lymph nodes cannot be assessed

■

pN0 No regional lymph node metastasis

■

N0 No regional lymph node metastasis

■

pN1 Metastasis with a lymph node mass 2 cm or less in greatest dimension and less than or equal to 5 nodes positive, none more than 2 cm in greatest dimension

■

N1 Metastasis with a lymph node mass 2 cm or less in greatest dimension; or multiple lymph nodes, none more than 2 cm in greatest dimension

■

pN2 Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or more than 5 nodes positive, none more than 5 cm; or evidence of extranodal extension of tumor

■

■

pN3 Metastasis with a lymph node mass more than 5 cm in greatest dimension

N2 Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, any one mass greater than 2 cm but not more than 5 cm in greatest dimension

■

N3 Metastasis with a lymph node mass more than 5 cm in greatest dimension

Clinical

Pathologic

Distant Metastasis (M)

■

■

MX Distant metastasis cannot be assessed

■

■

M0 No distant metastasis

■

■

M1 Distant metastasis

■

■

M1a Non-regional nodal or pulmonary metastasis

■

■

M1b Distant metastasis other than to non-regional lymph nodes and lungs Biopsy of metastatic site performed ■ Y ■ N Source of pathologic metastatic specimen_____


Table 35-1 Staging—cont’d Serum Tumor Murder (S) (N indicates the upper limit of normal for the LDH assay) ■

■

SX Marker studies not available or not performed

■

■

S0 Marker study levels within normal limits

■

■

S1 LDH < 1.5 × N AND hCG (mIu/ml) < 5000 AND AFP (ng/ml) < 1000

■

S2 LDH 1.5–10 × N OR

■

hCG (mIu/ml) 5000–50,000 OR AFP (ng/ml) 1000–10,000 ■

S3 LDH > 10 × N OR

■

hCG (mIu/ml) > 50,000 OR AFP (ng/ml) > 10,000 Clinical

Pathologic

Stage Grouping

■

■

0

pTis

N0

M0

S0

■

■

I

pT1-4

N0

M0

SX

■

■

IA

pT1

N0

M0

S0

■

■

IB

pT2

N0

M0

S0

pT3

N0

M0

S0

pT4

N0

M0

S0

■

■

IS

Any pT/Tx

N0

M0

S1–3

■

■

II

Any pT/Tx

N1–3

M0

SX

■

■

IIA

Any pT/Tx

N1

M0

S0

Any pT/Tx

N1

M0

S1

Any pT/Tx

N2

M0

S0

Any pT/Tx

N2

M0

S1

Any pT/Tx

N3

M0

S0

Any pT/Tx

N3

M0

S0

■

■

■

■

IIB

IIC

■

■

III

Any pT/Tx

Any N

M1

SX

■

■

IIIA

Any pT/Tx

Any N

M1a

S0

Any pT/Tx

Any N

M1a

S1

Any pT/Tx

N1–3

M0

S2

Any pT/Tx

Any N

M1a

S2

■

■

IIIB

Notes Additional Descriptiors Lymphatic Vessel Invasion (L) LX Lymphatic vessel invasion cannot be asscesed L0 No lymphatic vessel invasion L1 Lymphatic vessel invasion Venous Invasion (V) VX Venous invasion cannot be assumed V0 No venous invasion V1 Microscoic venous invasion V2 Macroscopic venous invasion

Continued

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Part VI Testis

Table 35-1 Staging—cont’d ■

■

IIIC

Any pT/Tx

N1-3

M0

S3

Any pT/Tx

Any N

M1a

S3

Any pT/Tx

Any N

M1b

Any S

Residual Tumor (R) ■ RX Presence of residual tumor cannot be assessed ■ R0 No residual tumor ■ R1 Microscopic residual tumor ■ R2 Macroscopic residual tumor Additional Descriptors For identification of special cases of TNM or pTNM classifications, the “m” suffix and “y,” “r,” and “a” prefixes are used. Although they do not affect the stage grouping, they indicate cases needing separate analysis. ■

m suffix indicates the presence of multiple primary tumors in a single site and is recorded in parentheses: pT(m)NM.

■

y prefix indicates those cases in which classification is performed during or following initial multimodality therapy. The cTNM or pTNM category is identified by a “y” prefix. The ycTNM or ypTNM categories the extent of tumor actually present at the time of that examination. The “y” categorization is not an estimate of tumor prior to multimodality therapy.

■

r prefix indicates a recurrent tumor when staged after a disease-free interval, and is identified by the “r” prefix rTNM.

■

a prefix designates the stage determined at autopsy: aTNM.

Indicate on diagram primary tumor and regional nodes involved.

Prognostic Indicators (if applicable)

Involvement of inguinal, pelvic, and iliac lymph nodes is uncommon except in cases of (i) prior pelvic or abdominal surgery where the normal lymphatic drainage may be disturbed, (ii) seminomas arising in a cryptorchid testis, (iii) congenital anomalies of the genitourinary tract, (iv) bulky paraaortic lymphadenopathy, and (v) possibly postscrotal orchiectomy with incision of the tunica albuginea and with tumor invasion of tunica vaginalis or the lower third of the epididymis.31–33

PREVENTION AND EARLY DETECTION The identification of TIN as a precursor of TGCT has raised the possibility that the development of invasive testicular cancer can be prevented by treating TIN. The incidence of TIN in the general population is low at 0.7%; however, the diagnosis should be considered in high-risk patients, including those with a history of cryptorchidism, presumed extragonadal GCT, androgen


insensitivity syndrome, with intersex syndromes or gonadal dysgenesis, and in patients with contralateral GCTs.34,35 It has been suggested that men with a unilateral tumor should undergo biopsy of the contralateral testis, preferably at the time of ipsilateral orchiectomy with the aim of identifying and treating TIN before progression to invasive disease.36 Those with a small, soft contralateral testis and severe oligospermia or aspermia are at a higher risk that appears to justify biopsy if treatment is going to be recommended. Men with a normal testicular biopsy can be reassured that their risk of a contralateral tumor is 6 cm) were associated with

relapse.48 Among 57 patients who had no adverse prognostic factors (age > 34, tumor size < 6 cm, and no lymphvascular invasion), tumor relapse was 6% at 5 years. In the DATECA study, primary tumor size was the only risk factor. Risk of relapse at 4 years was 6%, 18%, and 36% among patients with tumors 6 cm, respectively.46 In a series published by the group at Royal Marsden, only the presence of lymph vascular space involvement was associated with relapse (9% versus 17%).52

Table 35-2 Prognostic Factors for Relapse in Stage I Seminoma Patients on Surveillance Series Horwich, 1992, n = 103

von der Masse, 1993, n = 261

Relapse (%) 18

20

Factor

Strata

SVI*

No

10

Yes

20

Size

Histology

Necrosis

Rete testis

Warde, 1997, n = 201

15

Size

Age

SVI

18

Size

Worde et al. 1999, n = 638 Rete testis

SVI

*SVI, Small vessel invasion by tumor.

6 cm

36

Spermatocytic

0

Classical

16

Anaplastic

33

No

14

Yes

23

No

14

Yes

23

6 cm

33

34

21

No

14

Yes

31

4 cm

24

No

14

Yes

24

No

14

Yes

23


Effective surveillance for seminoma implies efficacious therapy for patients who relapse. In the DATECA and PMH series, most patients were treated with retroperitoneal RT. Second relapse post-RT was 19% in the PMH series and 11% in the DATECA series. Although this relapse rate is higher than de novo treated patients, it is important to recognize that this represents a subset of patients who have already failed surveillance. Overall failure for the entire cohort is similar to upfront RT, and almost 100% of patients are cured regardless of choice of therapy postorchiectomy. An additional concern about surveillance is the ability to detect retroperitoneal disease at a small volume (3 cm in diameter and those 3 cm, to determine if they will decrease in size. The natural history of residual masses in seminoma is not well defined. It may be one of gradual shrinkage unless nonseminomatous elements or a second primary are present. OTHER ISSUES AND MANAGEMENT OF UNUSUAL CASES Patients With High hCG β-hCG > 200 ng/ml are suggestive of metastatic disease and/or there may be nonseminomatous elements as the cause.16 Thus, the higher levels of β-hCG normally should arouse a suspicion for nonseminomatous tumors. Weissbach and Busser-Maatz108 (in a large prospective study of seminomas) found 31% of patients with β-hCG secreting tumors were more likely to have metastases in retroperitoneal lymph nodes. In seminoma, β-hCG is an indicator of tumor burden rather than a sign of tumor aggressiveness. A high hCG with negative imaging

590

Part VI Testis

studies is suggestive of retroperitoneal or distant occult metastatic disease. Bilateral Tumors The reported incidence of bilateral synchronous or metachronous testicular germ cell tumors is 0.5% to 7%. Approximately 5% are bilateral.25,26,109 Several studies have reported an increasing incidence possibly due to increased overall survival and earlier age of onset.109,110 Frequent examination of the remaining testis after treatment of a unilateral tumor, including self-examination by patients, is important to detect a second GCT early when small and confined to the testis. Bilateral inguinal orchiectomy has been the standard management in this situation. However, patients then require life-long androgen replacement therapy, which may be associated with sexual dysfunction, mood swings, and a general impairment of quality of life. Partial orchidectomy with preservation of some normal testicular tissue and androgen production has been proposed as an alternative to orchiectomy.111–113 Heidenreich and coworkers reported 52 metachronous and 17 synchronous bilateral testicular germ cell tumor patients who underwent an organ-sparing approach. As expected, approximately 60% had seminoma, 20% embryonal carcinoma, 15% mature teratoma, and 8% mixed GCT. The mean tumor diameter was 15 mm. Eighty-two percent of patients had associated TIN and the residual testis was treated with 18 Gy of local radiation. On mean follow-up of 91 months (3 to 191 months) 98.6% patients had no evidence of disease and only 1 had died of disease. There was no local relapse in 46 patients who received local radiation. Testosterone levels were normal in 85% of patients, and clinical hypogonadism occurred in about 10%. For tumors of 20 mm and less, tumor enucleation may be a reasonable alternative to bilateral orchiectomy. Horseshoe or Ectopic Kidney Horseshoe kidney occurs in approximately 1 in 400 of the general population. There is an association between renal fusion abnormalities and cryptorchidism, which in turn is associated with an increased incidence of testicular neoplasms.114 There are two main problems in the management of GCTs associated with horseshoe or pelvic kidney. The first is related to the technical problem of delivery of RT in patients with seminoma. In a number of cases of horseshoe kidney, a large part of the renal parenchyma lies within the standard radiation volume and directly overlies the regional lymph nodes. The delivery of a standard radiation dose would be associated with an unacceptable risk of radiation nephritis. The second problem is related to the possible abnormalities in lymphatic drainage of the testis and therefore the possi-

bility of relapse when the standard radiation fields are used. Unusual patterns of relapse have been observed in patients managed by surveillance, confirming concerns regarding abnormal lymphatic pathways.115 For these reasons, postorchiectomy surveillance in stage I and chemotherapy in stage II have usually been recommended. Retroperitoneal lymphadenectomy is another option for patients unwilling to follow the surveillance program. This approach has been reported to be both safe and effective in selected cases where it was performed although surgeons must be aware of the potential for anomalous vasculature.116,117 Inflammatory Bowel Disease Preexisting morbid conditions like IBD have to be taken into consideration when RT is planned. Radiation leads to increased gastrointestinal bleeding, peptic ulceration, and long-term incidence of stenosis. SEMINOMA IN PATIENTS WITH IMMUNOSUPPRESSION AND HUMAN IMMUNODEFICIENCY VIRUS INFECTION Testicular neoplasms appear to be 20 to 50 times more prevalent among patients on immunosuppression compared to the general population and in patients who are seropositive for human immunodeficiency virus (HIV).118,119 The interpretation of staging investigations for seminoma can be difficult in the later patients because of the benign lymphadenopathy that is frequently associated with HIV infection. A compilation of the reported experience with testicular tumors in HIVpositive patients showed a higher than expected frequency of stage II disease (58% versus 20%).119 This may be attributable at least in part to the false assignment of patients with HIV to stage II because of benign paraaortic lymphadenopathy. However, it is also possible that seminoma may have a more aggressive clinical course in HIV-positive patients. The majority of patients described in the literature have received standard treatment. RT and chemotherapy appear to be well tolerated except in patients with very advanced immunosuppression.119 Most patients are cured. Overall survival is usually determined by the severity of immunosuppression and the complications of the acquired immunodeficiency syndrome (AIDS) rather than by seminoma.119,120 Following renal transplant there are cases reported of seminomas.49,121,122 In such patients stages I and II have usually been treated with postoperative RT, but the concerns regarding potential damage to the transplanted kidney may dictate surveillance. Short-term follow-up of these patients does not suggest a higher risk of relapse, but the available data are limited.


THE NONCOMPLIANT PATIENT As the cure rate for patients with stages I and II seminomas approaches 100%, problems with patient compliance with treatment or follow-up recommendations may affect the outcome more than choice of therapy. Every large cancer center has experience with patients refusing conventional therapy or failing to attend for follow-up with eventual death due to disease. Although Hao et al.49 reported that compliance with clinical evaluations in patients with nonseminomas was 61.5% in year 1 and 35.5% in year 2, compliance with CT was only 25% and 11.8% in years 1 and 2, respectively. The compliance with this surveillance program was poor but this study was too small to demonstrate whether poor compliance adversely affects overall survival; other studies show no relation to survival. Patient education regarding the diagnosis, available treatment options and outcome in testis tumors, and need for regular evaluation should be given high priority. MANAGEMENT OF SEMINOMA IN CRYPTORCHID TESTES The management of seminoma presenting in cryptorchid testis depends on the location of the primary tumor and the extent of the disease. The awareness of orchiopexy early in childhood appears to have led to a significant drop in the incidence of patients presenting with tumors in uncorrected cryptorchids. Giving similar doses of radiation and adjusting the size of the paraaortic and pelvic radiation fields to cover the known extent of disease can achieve comparable survival.123 EXTRAGONADAL GERM CELL TUMORS Extragonadal germ cell tumors (EGCTs) have a similar histology to testicular GCTs but are found in other parts of the body, in the absence of a testicular mass. They account for 1% to 5% of all GCTs and, like testicular GCTs, tend to occur in young men, although the median age of presentation is 5 to 10 years older than with testicular GCTs.124 Ten percent of adult EGCTs occur in women, usually as ovarian dysgerminomas. In infants, EGCTs are more common than testicular primary tumors (usually sacrococcygeal teratomas).125,126 An increased incidence of EGCTs is seen with Klinefelter’s syndrome.126 Overall, patients with extragonadal GCTs (especially NSGCTs) have a worse prognosis than patients with testicular primaries. In a recent review of published results of chemotherapy for mediastinal tumors, 28 of 37 (76%) patients with seminomatous histology were disease free in comparison to 90 of 204 patients (44%) with nonseminomatous tumors.127 The use of aggressive regimens for patients with nonseminomatous tumors has been recom-

mended, and a 5-year survival of 73% has been reported with the use of cisplatin + vincristine + methotrexate + bleomycin + actinomycin D + cyclophosphamide +etoposide (POMB/ACE) chemotherapy.128 SUMMARY Testicular seminoma is highly curable with currently available treatments. There is good evidence that patients with stage I disease can be managed equally well after radical orchiectomy with either adjuvant RT or surveillance. Current areas of investigation in stage I patients include optimization of the RT treatment technique to minimize toxicity and the use of 1 or 2 cycles of single-agent carboplatin instead of RT or surveillance. Patients with small bulk stage II disease are treated effectively with RT. Patients with bulky stage II or stage III disease should receive 4 cycles of etoposide and cisplatin (EP) or equivalent chemotherapy. Overall, more than 95% of patients with seminoma are cured with this strategy. The current challenge for clinicians is to maintain high cure rates while minimizing toxicity and individualizing therapy to the specific social, emotional, and economic circumstances of each patient. It is important to continue to study the long-term consequences of current treatment strategies, particularly with respect to serious late side effects that might ultimately compromise the longevity of patients with seminoma diagnosed and treated decades earlier. The treatment objectives not only include long-term survival but should include a near normal quality of life. It is important that modifications in surgery, radiation, and chemotherapy, as well as advanced care to improve the quality of life in terms of sexual function, fertility, and problems of hormone replacement be integrated into current management strategies as they become available, and that the doctrine established as a result of years of successful treatment not present an insurmountable barrier to changes that may enhance the therapeutic ratio and improve overall patient outcome. REFERENCES 1. McGlynn KA, et al: Trends in the incidence of testicular germ cell tumors in the United States. Cancer 2003; 97(1):63–70. 2. Weir HK, Marrett LD, Moravan V: Trends in the incidence of testicular germ cell cancer in Ontario by histologic subgroup, 1964–1996. CMAJ 1999; 160(2):201–205. 3. Warde P, Jewett MA: Surveillance for stage I testicular seminoma: is it a good option? Urol Clin North Am 1998; 25(3):425–433. 4. Milosevic MF, Gospodarowicz M, Warde P: Management of testicular seminoma. Semin Surg Oncol 1999; 17(4):240–249.

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5. Parkin DM, Muir CS: Cancer Incidence in Five Continents. Comparability and quality of data. IARC Sci Publ 1992; 120:45–173. 6. Parker SL, et al: Cancer statistics, 1997. CA Cancer J Clin 1997; 47(1):5–27. 7. Brown N: Cryptorchidism—a significant risk factor for testicular cancer. Br J Gen Pract 1991; 41(348):305. 8. Prener A, Engholm G, Jensen OM: Genital anomalies and risk for testicular cancer in Danish men. Epidemiology 1996; 7(1):14–19. 9. Power DA, et al: Trends in testicular carcinoma in England and Wales, 1971–1999. BJU Int 2001; 87(4):361–365. 10. Huyghe E, Matsuda T, Thonneau P: Increasing incidence of testicular cancer worldwide: a review. J Urol 2003; 170(1):5–11. 11. Abratt RP, Reddi VB, Sarembock LA: Testicular cancer and cryptorchidism. Br J Urol 1992; 70(6):656–659. 12. Klein FA, et al: Inguinal lymph node metastases from germ cell testicular tumors. J Urol 1984; 131(3): 497–500. 13. Rapley EA, et al: Localisation of susceptibility genes for familial testicular germ cell tumour. APMIS 2003; 111(1):128–133 [Discussion 33-5]. 14. Swerdlow AJ, et al: Risks of breast and testicular cancers in young adult twins in England and Wales: evidence on prenatal and genetic aetiology. Lancet 1997; 350(9093):1723–1728. 15. Klotz LH: Why is the rate of testicular cancer increasing? CMAJ 1999; 160(2):213–214. 16. Ruther U, et al: Role of human chorionic gonadotropin in patients with pure seminoma. Eur Urol 1994; 26(2):129–133. 17. Edler von Eyben F, et al: Serum lactate dehydrogenase isoenzyme. 1. An early indicator of relapse in patients with testicular germ cell tumors. Acta Oncol 1995; 34(7):925–929. 18. Nielsen OS, et al: Is placental alkaline phosphatase (PLAP) a useful marker for seminoma? Eur J Cancer 1990; 26(10):1049–1054. 19. Herr HW, Sheinfeld J: Is biopsy of the contralateral testis necessary in patients with germ cell tumors? J Urol 1997; 158(4):1331–1334. 20. Capelouto CC, et al: A review of scrotal violation in testicular cancer: Is adjuvant local therapy necessary? J Urol 1995; 153(3 Pt 2):981–985. 21. Skakkebaek NE, et al: Carcinoma-in-situ of the testis: possible origin from gonocytes and precursor of all types of germ cell tumours except spermatocytoma. Int J Androl 1987; 10(1):19–28. 22. Giwercman A, von der Maase H, Skakkebaek NE: Epidemiological and clinical aspects of carcinoma in situ of the testis. Eur Urol 1993; 23(1):104–110 [Discussion 111-4]. 23. Dieckmann KP, Loy V: Prevalence of contralateral testicular intraepithelial neoplasia in patients with testicular germ cell neoplasms. J Clin Oncol 1996; 14(12):3126–3132. 24. Dieckmann KP, Classen J, Loy V: Diagnosis and management of testicular intraepithelial neoplasia

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36. 37.

38.

39.

40.

41.

(carcinoma in situ)—surgical aspects. APMIS 2003; 111(1):64–68 [Discussion 68-9]. Wanderas EH, Fossa SD, Tretli S: Risk of a second germ cell cancer after treatment of a primary germ cell cancer in 2201 Norwegian male patients. Eur J Cancer 1997; 33(2):244–252. Osterlind A, et al: Risk of bilateral testicular germ cell cancer in Denmark: 1960–1984. J Natl Cancer Inst 1991; 83(19):1391–1395. Warde P, et al: Stage I testicular seminoma: results of adjuvant irradiation and surveillance. J Clin Oncol 1995; 13(9):2255–2262. Warde P, et al: Prognostic factors for relapse in stage I seminoma managed by surveillance: a pooled analysis. J Clin Oncol 2002; 20(22):4448–4452. Donohue JP, Zachary JM, Maynard BR: Distribution of nodal metastases in nonseminomatous testis cancer. J Urol 1982; 128(2):315–320. Weissbach L, Boedefeld EA, FTTTS Group: Localization of solitary and multiple metastases in stage II nonseminomatous testis tumor as basis for a modified staging lymph node dissection in stage I. J Urol 1987; 138:77–82. Gauwitz MD, Zagars GK: Treatment of seminoma arising in cryptorchid testes. Int J Radiat Oncol Biol Phys 1992; 24(1):153–159. Li YX, et al: Seminoma arising in corrected and uncorrected inguinal cryptorchidism: treatment and prognosis in 66 patients. Int J Radiat Oncol Biol Phys 1997; 38(2):343–350. Mason MD, et al: Inguinal and iliac lymph node involvement in germ cell tumours of the testis: implications for radiological investigation and for therapy. Clin Oncol (R Coll Radiol) 1991; 3(3):147–150. Giwercman A, et al: Evidence for increasing incidence of abnormalities of the human testis: a review. Environ Health Perspect 1993; 101(Suppl 2):65–71. Giwercman A, et al: Current concepts of radiation treatment of carcinoma in situ of the testis. World J Urol 1994; 12(3):125–130. Rorth M, et al: Carcinoma in situ in the testis. Scand J Urol Nephrol Suppl 2000; 205:166–186. Petersen PM, et al: Endocrine function in patients treated for carcinoma in situ in the testis with irradiation. APMIS 2003; 111(1):93–98 [Discussion 98-9]. Freeman A, Rowbotham C, Parkinson MC: The prevalence of testicular microlithiasis in an asymptomatic population of men 18 to 35 years old. J Urol 2003; 169(4):1474. Holm M, et al: The prevalence of testicular microlithiasis in an asymptomatic population of men 18 to 35 years old. J Urol 2002; 168(3):1108 [author reply 1108-9]. Peterson AC, et al: The prevalence of testicular microlithiasis in an asymptomatic population of men 18 to 35 years old. J Urol 2001; 166(6):2061–2064. Steele GS, et al: The National Cancer Data Base report on patterns of care for testicular carcinoma, 1985–1996. Cancer 1999; 86(10):2171–2183.

Chapter 35 Seminoma: Management and Prognosis 593 42. Fossa SD, et al: Optimal planning target volume for stage I testicular seminoma: a medical research council randomized trial. Medical Research Council Testicular Tumor Working Group. J Clin Oncol 1999; 17(4):1146. 43. Travis LB, et al: Treatment-associated leukemia following testicular cancer. J Natl Cancer Inst 2000; 92(14):1165–1171. 44. Travis LB, et al: Risk of second malignant neoplasms among long-term survivors of testicular cancer. J Natl Cancer Inst 1997; 89(19):1429–1439. 45. Fiveash J, Sandler HM, Controversies in the management of stage I seminoma. Oncology (Huntingt) 1998; 12(8):1203–1212 [Discussion 1212-21]. 46. von der Maase H, et al: Surveillance following orchidectomy for stage I seminoma of the testis. Eur J Cancer 1993; 29A(14):1931–1934. 47. Michael H, et al: The pathology of late recurrence of testicular germ cell tumors. Am J Surg Pathol 2000; 24(2):257–273. 48. Warde P, et al: Prognostic factors for relapse in stage I testicular seminoma treated with surveillance. J Urol 1997; 157(5):1705–1709 [Discussion 1709-10]. 49. Hao D, et al: Compliance of clinical stage I nonseminomatous germ cell tumor patients with surveillance. J Urol 1998; 160(3 Pt 1):768–771. 50. Sharda NN, Kinsella TJ, Ritter MA: Adjuvant radiation versus observation: a cost analysis of alternate management schemes in early-stage testicular seminoma. J Clin Oncol 1996; 14(11):2933–2939. 51. Warde P, et al: Long term outcome and cost in the management of stage I testicular seminoma. Can J Urol 2000; 7(2):967–972 [Discussion 973]. 52. Horwich A, et al: Surveillance following orchidectomy for stage I testicular seminoma. Br J Cancer 1992; 65(5):775–778. 53. Fossa SD, Aass N, Kaalhus O: Radiotherapy for testicular seminoma stage I: treatment results and long-term post-irradiation morbidity in 365 patients. Int J Radiat Oncol Biol Phys 1989; 16(2):383–388. 54. Dosmann MA, Zagars GK: Post-orchiectomy radiotherapy for stages I and II testicular seminoma. Int J Radiat Oncol Biol Phys 1993; 26(3):381–390. 55. Hamilton C, et al: Radiotherapy for stage I seminoma testis: results of treatment and complications. Radiother Oncol 1986; 6(2):115–120. 56. Hamilton C, et al: Radiotherapy for stage I seminoma testis: results of treatment and complications. Radiother Oncol 1986; 6(2):115. 57. Centola GM, et al: Effect of low-dose testicular irradiation on sperm count and fertility in patients with testicular seminoma. J Androl 1994; 15(6): 608–613. 58. Joos H, et al: Endocrine profiles after radiotherapy in stage I seminoma: impact of two different radiation treatment modalities. Radiother Oncol 1997; 43(2):159–162. 59. Fraass BA, et al: Peripheral dose to the testes: the design and clinical use of a practical and effective gonadal shield. Int J Radiat Oncol Biol Phys 1985; 11(3):609–615.

60. Lester SG, Morphis JG II, Hornback NB: Testicular seminoma: analysis of treatment results and failures. Int J Radiat Oncol Biol Phys 1986; 12(3): 353–358. 61. Dosoretz DE, et al: Megavoltage irradiation for pure testicular seminoma: results and patterns of failure. Cancer 1981; 48(10):2184–2190. 62. Sultanem K, et al: Para-aortic irradiation only appears to be adequate treatment for patients with stage I seminoma of the testis. Int J Radiat Oncol Biol Phys 1998; 40(2):455–459. 63. Kiricuta IC, Sauer J, Bohndorf W: Omission of the pelvic irradiation in stage I testicular seminoma: a study of postorchiectomy paraaortic radiotherapy. Int J Radiat Oncol Biol Phys 1996; 35(2):293–298. 64. Read G, Johnston RJ: Short duration radiotherapy in stage I seminoma of the testis: preliminary results of a prospective study. Clin Oncol (R Coll Radiol) 1993; 5(6):364–366. 65. Thomas GM: Alternative management options to radiation therapy for stage I and IIA testicular seminoma. Int J Radiat Oncol Biol Phys 1994; 28(2):547–548. 66. Donohue JP, et al: Primary retroperitoneal lymph node dissection in clinical stage A non-seminomatous germ cell testis cancer. Review of the Indiana University experience 1965–1989. Br J Urol 1993; 71(3): 326–335. 67. Schmidberger H, et al: Radiotherapy in stages IIA and IIB testicular seminoma with reduced portals: a prospective multicenter study. Int J Radiat Oncol Biol Phys 1997; 39(2):321–326. 68. Dieckmann KP, et al: Adjuvant carboplatin treatment for seminoma clinical stage I. J Cancer Res Clin Oncol 1996; 122(1):63–66. 69. Aparicio J, et al: Multicenter study evaluating a dual policy of postorchiectomy surveillance and selective adjuvant single-agent carboplatin for patients with clinical stage I seminoma. Ann Oncol 2003; 14(6):867–872. 70. Reiter WJ, et al: Twelve-year experience with two courses of adjuvant single-agent carboplatin therapy for clinical stage I seminoma. J Clin Oncol 2001; 19(1): 101–104. 71. Steiner H, et al: Long-term experience with carboplatin monotherapy for clinical stage I seminoma: a retrospective single-center study. Urology 2002; 60(2): 324–328. 72. Dieckmann K-P, et al: Adjuvant carboplatin treatment for seminoma clinical stage I. J Cancer Res Clin Oncol 1996; 122:63–66. 73. Tsatalpas P, et al: Diagnostic value of 18F-FDG positron emission tomography for detection and treatment control of malignant germ cell tumors. Urol Int 2002; 68(3):157–163. 74. Hultenschmidt B, et al: Results of radiotherapy for 230 patients with stage I-II seminomas. Strahlenther Onkol 1996; 172(4):186–192. 75. Vallis KA, et al: Radiotherapy for stages I and II testicular seminoma: results and morbidity in 238 patients. Br J Radiol 1995; 68(808):400–405.

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76. Warde P, et al: Management of stage II seminoma. J Clin Oncol 1998; 16(1):290–294. 77. Warszawski N, Schmucking M: Relapses in early-stage testicular seminoma: radiation therapy versus retroperitoneal lymphadenectomy. Scand J Urol Nephrol 1997; 31(4): 355–359. 78. Hanks GE, Peters T, Owen J: Seminoma of the testis: long-term beneficial and deleterious results of radiation. Int J Radiat Oncol Biol Phys 1992; 24(5):913–919. 79. Lederman GS, et al: Cardiac disease after mediastinal irradiation for seminoma. Cancer 1987; 60(4):772–776. 80. Loehrer PJ Sr, et al: Chemotherapy of metastatic seminoma: the Southeastern Cancer Study Group experience. J Clin Oncol 1987; 5(8):1212–1220. 81. Fossa SD, et al: The treatment of advanced metastatic seminoma: experience in 55 cases. J Clin Oncol 1987; 5(7):1071–1077. 82. Herr HW, et al: Surgery for a post-chemotherapy residual mass in seminoma. J Urol 1997; 157(3):860–862. 83. International Germ Cell Cancer Collaborative Group: International germ cell consensus classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 1997; 15(2):594–603. 84. Porcaro AB, et al: Management of testicular seminoma advanced disease. Report on 14 cases and review of the literature. Arch Ital Urol Androl 2002; 74(2):81–85. 85. Gholam D, et al: Advanced seminoma—treatment results and prognostic factors for survival after first-line, cisplatin-based chemotherapy and for patients with recurrent disease: a single-institution experience in 145 patients. Cancer 2003; 98(4):745–752. 86. Stanton GF, et al: VAB-6 as initial treatment of patients with advanced seminoma. J Clin Oncol 1985; 3(3):336–339. 87. Williams MP, Husband JE, Heron CW: Intrathoracic manifestations of metastatic testicular seminoma: a comparison of chest radiographic and CT findings. Am J Roentgenol 1987; 149(3):473–475. 88. Mencel PJ, et al: Advanced seminoma: treatment results, survival, and prognostic factors in 142 patients. J Clin Oncol 1994; 12(1):120–126. 89. Miller KD, et al: Salvage chemotherapy with vinblastine, ifosfamide, and cisplatin in recurrent seminoma. J Clin Oncol 1997; 15(4):1427–1431. 90. Toner GC, et al: The management of testicular cancer in Victoria, 1988–1993. Urology Study Committee of the Victorian Co-operative Oncology Group. Med J Aust 2001; 174(7):328–331. 91. Mackey JR, Venner P: Seminoma with isolated central nervous system relapse, and salvage with craniospinal irradiation. Urology 1998; 51(6):1043–1045. 92. Bokemeyer C, et al: Treatment of brain metastases in patients with testicular cancer. J Clin Oncol 1997; 15(4):1449–1454. 93. Senturia YD, Peckham CS, Peckham MJ: Children fathered by men treated for testicular cancer. Lancet 1985; 2(8458):766–769. 94. Petersen PM, Skakkebaek NE, Giwercman A: Gonadal function in men with testicular cancer: biological and

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clinical aspects. APMIS 1998; 106(1):24–34 [Discussion 34-6]. Moller H, et al: Incidence of second primary cancer following testicular cancer. Eur J Cancer 1993; 29A(5): 672–676. van Leeuwen FE, et al: Second cancer risk following testicular cancer: a follow-up study of 1909 patients. J Clin Oncol 1993; 11(3):415–424. Travis LB, Curtis RE, Hankey BF: Second malignancies after testicular cancer. J Clin Oncol 1995; 13(2):533–534. Ruther U, et al: Second malignancies following pure seminoma. Oncology 2000; 58(1):75–82. Caffo O, et al: Quality of life after radiotherapy for early-stage testicular seminoma. Radiother Oncol 2001; 59(1):13–20. Tinkler SD, Howard GC, Kerr GR: Sexual morbidity following radiotherapy for germ cell tumours of the testis. Radiother Oncol 1992; 25(3):207–212. Brennemann W, et al: Pretreatment follicle-stimulating hormone: a prognostic serum marker of spermatogenesis status in patients treated for germ cell cancer. J Urol 1998; 159(6):1942–1946. Hallak J, et al: Investigation of fertilizing capacity of cryopreserved spermatozoa from patients with cancer. J Urol 1998; 159(4):1217–1220. Rosenlund B, et al: In-vitro fertilization and intracytoplasmic sperm injection in the treatment of infertility after testicular cancer. Hum Reprod 1998; 13(2):414–418. Ravi R, et al: The management of residual masses after chemotherapy in metastatic seminoma. BJU Int 1999; 83(6): 649–653. Flechon A, et al: Management of post-chemotherapy residual masses in advanced seminoma. J Urol 2002; 168(5):1975–1979. Duchesne GM, et al: Radiotherapy after chemotherapy for metastatic seminoma—a diminishing role. MRC Testicular Tumour Working Party. Eur J Cancer 1997; 33(6):829–835. Ogan K, et al: Laparoscopic versus open retroperitoneal lymph node dissection: a cost analysis. J Urol 2002; 168(5):1945–1949 [Discussion 1949]. Weissbach L, Bussar-Maatz R: hCG-positive seminoma. Eur Urol 1993; 23(Suppl 2):29–32. Patel SR, Richardson RL, Kvols L: Synchronous and metachronous bilateral testicular tumors. Mayo Clinic experience. Cancer 1990; 65(1):1–4. Coogan CL, et al: Bilateral testicular tumors: management and outcome in 21 patients. Cancer 1998; 83(3):547–552. Heidenreich A, Weissbach L, Holt W, et al: Organ sparing surgery for malignant germ cell tumor of the testis. J Urol 2001; 166(6):2161–2165. Richie JP: Organ sparing surgery for malignancy germ cell tumor of the testis. J Oncl 2003; 21(1):87. Li, FP, Fraumeni JF: Testicular cancers in children: epidemiologic characteristics. J Natl Cancer Inst 1972; 48(6):1575–1581. Elyan SA, Reed DH, Ostrowski MJ, et al: Problems in the management of testicular seminoma associated with a


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horseshoe kidney. Clin Oncol (R Coll Radiol) 1990; 2(3):163–167. Key DW, Moyad R, Grossman HB: Seminoma associated with crossed fused renal ectopia. J Urol 1990; 143(5):1015–1016. Sogani PC, Whitmore WF Jr: Retroperitoneal lymphadenectomy for germ cell tumor of testis in association with horseshoe kidney. Urology 1981; 18(5):446–452. Lyter DW, Bryant J, Thackeray R, et al: Incidence of human immunodeficiency virus-related and nonrelated malignancies in a large cohort of homosexual men. J Clin Oncol 1995; 13(10):2540–2546. Leibovitch I, Baniel J, Rowland RA, et al: Malignant testicular neoplasms in immunosuppressed patients. J Urol 1996; 155(6):1938–1942. Timmerman JM, Northfelt DW, Small EJ: Malignant germ cell tumors in men infected with the human immunodeficiency virus: natural history and results of therapy. J Clin Oncol 1995; 13(6):1391–1397. Dieckmann KP, Due W, Offermann G: Testicular seminoma in an immunosuppressed renal transplant recipient. Br J Urol 1989; 63(5):549–550. Villalona-Calero MA, Ducker T, Holasek M, et al: Management of testicular seminoma following organ transplantation. Med Pediatr Oncol 1992; 20(4):338–340.

123. Sham JS, Choy P, Chan KW et al: Seminoma of normally-descended and cryptorchid testis. Eur J Surg Oncol 1990; 16(1):33–36. 124. Shirdasani RA: Extragonadal germ-cell tumours. In Scher H, Raghavan D, Leibel S, Lange P (eds): Principles and Practice of Genitourinary Oncology, p 751. Philadelphia, Lippincott-Raven Publishers, 1997. 125. Mann JR, Pearson D, Barrett A, et al: Results of the United Kingdom Children’s Cancer Study Group’s malignant germ cell tumor studies. Cancer 1989; 63(9):1657–1667. 126. Nichols CR, Heereina NA, Palma C, et al: Klinefelter’s syndrome associated with mediastinal germ cell neoplasms. J Clin Oncol 1987; 5(8):1290–1294. 127. Droz JP, Horwich A: Extragonadal germ cell tumours. In Vogelzang NJ, Scardino P (eds): Comprehensive Textbook of Genitourinary Oncology. Baltimore, Williams & Wilkins, 1995. 128. Bower M, Brock C, Holden L, et al: POMB/ACE chemotherapy for mediastinal germ cell tumours. Eur J Cancer 1997; 33(6):838–842. 129. Worde P, Specht L, von der Masse H, et al: Prognostic factors for relapse in Stage I seminoma managed by surveillance (abstract). J Urol 1999; 161:158.

C H A P T E R

36 Nonseminomatous Germ Cell Testis Tumors: Management and Prognosis Randall G. Rowland, MD, PhD

The survival rates for patients with testis cancer have improved dramatically over the last 30 years. This has been especially true for nonseminomatous germ cell testis tumors (NSGCTT). There are several factors involved in this improvement in survival: improved diagnostic tools, such as serum markers; better imaging studies; improved surgical techniques; effective chemotherapeutic agents; multimodal therapy when appropriate; and increased public awareness. The high rate of cure of NSGCTT has allowed us to concentrate on reducing the morbidity and mortality of the treatments, while maintaining the high rate of efficacy. Fertility can even be preserved in the majority of patients using modified templates and nerve-sparing techniques during radical retroperitoneal lymph node dissection (RPLND). This chapter will focus on the diagnoses, staging, treatments, and outcomes of NSGCTT. DIAGNOSIS Germ cell testis tumors (GCTT) are the most common solid tumors in males from the age of 20 to 35 years.1 GCTTs have been reported in patients from infants to age 89 years. NSGCTTs account for approximately 60% of all GCTTs.2 Any mass in the testicle has to be considered a potential GCTT until proven otherwise. GCTTs must also be considered as a possibility in patients with scrotal pain and/or swelling, the presence of a hydrocele, or a hematocele after relatively minor scrotal trauma. Production of human chorionic gonadotropin (HCG) by some tumors causes patients to present with gynecomastia or breast tenderness. Metastases of GCTT have made some patients present with hemoptysis from pul-

596

monary lesion or back pain from large retroperitoneal adenopathy. Physical examination of the testicle still plays a major role in the evaluation of the patient. It is important to differentiate a mass in the testicle versus the epididymis or cord structures. Scrotal ultrasound is perhaps the best and most readily available imaging study for suspected GCTTs. Ultrasound scans facilitate the location of scrotal masses, as well as giving us information on the homogeneity or heterogeneity of the mass. Scrotal ultrasounds may give some insight regarding the cell type(s) in a mass. Pure seminomas tend to be very homogeneous masses (Figure 36-1), while mixed GCTTs may have a heterogeneous echo pattern (Figure 36-2). The finding of cystic structures in a mass suggests the presence of teratoma (Figure 36-3). Serum markers are also helpful in making the diagnosis of testis cancer. Overall approximately 70% of patients with testis cancer will have elevated alpha-fetoprotein (AFP) and/or HCG levels in their blood. The clinical test for HCG is a radioimmunoassay that measures the beta chain of the HCG and is designated B-HCG. Yolk sac cell tumors produce AFP with rare exception. HCG is made by syncytio-trophoblasts, which are present in all cases of choriocarcinoma and in about 10% of cases of pure seminoma. Lactate dehydrogenase (LDH) is sometimes used as a measure of tumor bulk; however, the author does not find this text useful in clinical practice. Placental alkaline phosphatase (PLAP) is present in up to 84% of patients with seminoma. PLAP is falsely elevated in a high percentage of smokers, which could negate the value of the marker.3

Chapter 36 Nonseminomatous Germ Cell Tests Tumors: Management and Prognosis 597

Figure 36-1 Sagittal ultrasound of testis with a central mass, which was a seminoma. Note the homogeneity of the mass.

RADICAL ORCHIECTOMY VERSUS PARTIAL ORCHIECTOMY The standard approach for making the definitive diagnosis of testicular cancer has been the radical orchiectomy performed by removing the testicle using an inguinal approach. This approach helps prevent crosscontamination of the testicular lymphatics to the inguinal lymphatics. The vas deferens and the gonadal vessels are ligated and divided at the level of the internal inguinal ring. An organ-sparing approach has been advocated by some authors.4,5 In this approach, the testicle is still delivered through an inguinal incision, except the mass in the testicle is excised. The testis is reconstructed and returned to the scrotum. This technique is a benefit in patients with a solitary testis or an intratesticular lesion that is questionable with respect to its being a testicular tumor. The down-side of a local excision is the potential for leaving a finger of a lesion or a satellite lesion behind.

Transscrotal needle biopsy of testicular masses is discouraged for two reasons. First, there can easily be a sampling error that would not give a true representation of the pathology present. Second, there is a possibility for cross-contamination for the testicle lymphatics with the scrotal/inguinal lymphatics.

PATHOLOGY Histologic study of the orchiectomy specimen should include documenting the cell type(s) present in the tumor and the T stage of the tumor. Extensive sampling of the testis should be performed to allow a careful and thorough determination of the cell types that are present. T stage can be accurately assessed by careful observation and extensive histologic sampling. Tumors can be intratubular (CIS) or invasive. The cell types of germ cell tumors that occur are shown in Table 36-1. Approximately 40% of patients present with pure

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Figure 36-2 Sagittal ultrasound of testis with a mass, which was a mixed germ cell tumor. Note the more heterogeneous character of the mass.

seminoma and 60% present with nonseminomatous cell elements either as a pure cell type or more commonly as mixed cell type tumors.2 The determination of cell types present in a testicular tumor is very important in terms of treatment. Pure seminomas, including spermatocytic seminomas, are treated with a different approach than tumors with nonseminomatous elements. Table 36-2 shows the American Joint Commission on Cancer’s (AJCC) definitions of the pathologic T stages of testicular tumors.6 CLINICAL STAGING Once the histologic diagnosis of testicular cancer is documented, the patient should have clinical staging performed to allow the formulation of a treatment plan to best fit the patient’s needs. Clinical staging involves assessment of the patient using tumor markers before and after orchiectomy, radiologic imaging studies of the chest, abdomen and pelvis, and physical examination to document any adenopathy or abdominal masses. Care should also be

taken to evaluate the contralateral testis since bilateral synchronous or metachronous testicular tumors do occur. Serum Markers AFP and HCG should be rechecked after orchiectomy in all patients, but especially in those patients with elevated serum markers prior to orchiectomy. If the tumor was localized in the testis only, orchiectomy should cause the markers to return to normal. If tumor remains, the markers may not return to normal. When following the serum marker level, the time after orchiectomy and the serum half-life of each marker must be considered. The serum half-life of AFP is approximately 5 days and that of HCG is about 1 day. Markers that either fall at a lower than expected rate or rising are indicative of persistent disease. When LDH is used as a marker, it is usually considered in terms of its percentage or number of times the normal value. LDH has a half-life of approximately 3 days.


Figure 36-3 Sagittal ultrasound of testis with two adjacent masses. Note the hypoechoic areas, which correspond to cystic areas of teratoma.

Table 36-1 Germ Cell Testicular Tumors

Table 36-2 Pathologic Stage of The Primary Tumor (T)

Precursor lesions

Intratubular germ cell neoplasia (CIS)

pTX

Primary tumor cannot be assessed

Tumors of one histologic type

Seminoma Spermatocytic seminoma Embryonal carcinoma Yolk sac tumor (endodermal sinus tumor) Choriocarcinoma Teratoma Mature Immature With malignant component(s) Monodermal variants Carcinoid tumor Primitive neuroectodermal tumor

pT0

No evidence of primary tumor (e.g., histologic scar in testis)

pTis

Intratubular germ cell neoplasia (carcinoma in situ)

PT1

Tumor limited to the testis and epididymis without vascular/lymphatic invasion; tumor may invade into the tunica albuginea but not the tunica vaginalis

pT2

Tumor limited to the testis and epididymis with vascular/lymphatic invasion, or tumor extending through the tunica albuginea with involvement of the tunica vaginalis

PT3

Tumor invades the spermatic cord with or without vascular/lymphatic invasion

pT4

Tumor invades the scrotum with or without vascular/lymphatic invasion

Tumors of more Mixed germ cell tumors than one (specifically individual types) histologic type

These T stages are based on the pathologic findings from orchiectomy specimens.

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Imaging Studies

Physical Examination

The goal of imaging studies is to detect any nodal or visceral tumor involvement. Based on the known patterns of spread of testicular tumors by lymphatics and rarely by vasculature, the studies need to cover the chest, both pulmonary parenchyma and the mediastinum, the abdomen, again the viscera and the retroperitoneal lymph nodes, and the pelvis. The chest was initially evaluated by standard chest x-rays and whole lung tomograms. With the advent of computed axial tomography (CT) and subsequent improvement in CT techniques, CT scans have become the most frequent modality for doing initial clinical staging of the chest. Chest involvement more frequently occurs as peripheral pulmonary nodules in cases of low volume metastases and with the addition of mediastinal adenopathy in more advanced cases. It is important to examine the lung fields using both soft tissue settings and bone window settings. This allows parenchymal lesions to be evaluated for the presence of calcification, which leads to a finding of pulmonary granuloma rather than metastasis. Figures 36-4 and 36-5 show CT scans of a patient with metastatic pulmonary lesions. Notice that the lesions visible in Figure 36-4 do not appear in Figure 36-5, which indicates a lack of calcification. The abdomen and retroperitoneum were originally evaluated by intravenous pyelograms (IVPs) to look for evidence of displacement of the kidneys or ureters by retroperitoneal masses. The CT scan made it possible to much more accurately evaluate the abdominal viscera and retroperitoneum. There has been some debate related to the size threshold of retroperitoneal lymph nodes that is considered abnormal and likely to represent metastases. Many authors have picked a 1-cm threshold in evaluating retroperitoneal lymph nodes. Using this criterion, the sensitivity has been reported at approximately 70%. The specificity has been approximately 94%.7 Liebovitch and his associates at Indiana reported setting their size threshold at 3 mm for lymph nodes that are in the areas most likely to have nodal metastases and kept the 1-cm threshold for any other adenopathy. This increased the sensitivity to 91% but decreased the specificity to 52%.8 Using CT techniques, the sensitivity will most likely not rise about 75% because approximately 25% of patients who have normal imaging studies and still undergo surgical staging will have microscopic or small volume macroscopic retroperitoneal metastases.9 Figure 36-6 shows typical CT findings in a patient with low volume retroperitoneal lymphadenopathy, while Figure 36-7 shows higher volume retroperitoneal disease. MRI scan and PET scan have been tried in evaluation of patients with testicular cancer.7,10 As of this time, neither of these techniques offer significant advantages over CT scans in terms of initial staging of patients.

Patients should be carefully examined for adenopathy (inguinal, axillary, or cervical). The physician needs to check for neck, abdominal, or scrotal masses. The contralateral testis should be examined with great care for any possible intratesticular masses. Scrotal ultrasound is again very helpful in evaluating the contralateral testis. Clinical Stage Designations Assigning a clinical stage requires consideration of the pathologic T stage (see Table 36-2), the clinical N stage (Table 36-3), the clinical M stage (Table 36-4), and the S stage (Table 36-5).6 The T stage is based on the pathologic findings from the orchiectomy specimen. The clinical regional node stage (N) is based on imaging studies of the abdomen and pelvis. The distant metastases stage (M) is assigned based on evidence from imaging studies as well. The serum marker stage (S) is determined by the preorchiectomy marker determinations for the initial clinical staging.6 The pT, N, M, and S data are used to assign the patient to a clinical stage group as shown in Table 36-6. These clinical stage groups are used as a basis for treatment recommendations and outcomes analysis. TOOLS OF TREATMENT The various treatment modalities for testis cancer, including observation, are presented in the following prior to specific treatment recommendation for the clinical stage groups. Observation In patients with a low risk for nodal or metastatic disease, observation may be appropriate. The criteria for observing patients who present with localized testicular cancer are shown in Table 36-7. Primary tumor stage and cell types present along with the cell type proportions are used along with imaging study findings and marker levels to determine eligibility for observation. Table 36-8 presents the tests and examinations recommended for use in patients who will have observation as their primary treatment modality. The frequency recommended for tests and examinations decreases with time since the risk of recurrence diminishes with time. Primary Retroperitoneal Lymph Node Dissection: Surgical Staging and Treatment RPLND techniques have undergone significant evolution over the last 40 years. In the 1960s the concept of


Figure 36-4 Chest x-ray of a patient who presented with hemoptysis from metastatic testicular cancer.

“more is better” prevailed and the limits of RPLND were extended. Figure 36-8 illustrates the limits of dissection that were established.11 The dissection was performed in an en bloc style from the diaphragm to the level of the bifurcation of the common iliac arteries and laterally from ureter to ureter. The ipsilateral gonadal vessels were removed completely. Although this dissection was performed safely with low morbidity and mortality rates, virtually all patients lost their ability to have ejaculatory

fluid emission secondary to the removal of the postganglionic sympathetic nerve fibers that traversed the field of dissection. In the 1980s efforts were made to preserve emission in patients first by modifying the templates of dissection based on the knowledge of the distribution of positive lymph nodes in patients with low volume metastatic disease.12,13 Figures 36-9 and 36-10 show the limits of dissection generally adopted for low-stage (stage I or stages IIA and IIB)

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Figure 36-5 CT scan of chest of patient with metastases to the lungs (arrows) from a primary testicular cancer.

disease with right- and left-sided primary tumors, respectively. The dissections within the limited templates were still performed with the en bloc technique. This offered preservation of the contralateral sympathetic systems. The success rates at preserving emission were greater on rightsided dissection than on the left-sided dissection. Later in the 1980s and early 1990s a prospective nerve-sparing technique was developed and adopted using the modified templates. A better understanding of the anatomy of the lumbar sympathetic nerves allowed this technique to be applied very successfully in terms of preservation and maintenance of the efficacy of the dissection as measured by continued low tumor relapse rates.14,15 Figure 36-11 shows a diagram of the lumbar sympathetics and the postganglionic branches as would be seen in a right-sided modified template dissection. The postganglionic fibers are best identified as they emerge under the medial edge of the vena cava in the interaortocaval zone. Figure 36-12 shows the typical arrangements of the left lumbar sympathetic fibers as they travel anteriorly and caudally onto the aorta. These

nerves are best identified by dissecting along the posterior body wall from lateral to medial until the lumbar sympathetic chain is identified. The use of these prospective nerve-sparing techniques has resulted in preservation of emission in almost all patients.16 A laparoscopic approach to RPLND (LRPLND) for low-stage disease was first performed in 1992 by two European groups.17,18 These series reported favorable initial results for conversion to open procedures, 1/34 and 2/125, respectively.17,18 After the learning curve had been overcome, the mean operating times were 248 minutes in Rossweiler’s series, 219 minutes for clinical stage I patients in Jauetschek’s series for clinical stage I patients, and 226 minutes for clinical stage IIB patients. In both series together there was only one retroperitoneal recurrence. Ogan et al.19 compared the cost of LRPLND versus open RPLND. Open RPLND was less costly at $7162 than LRPLND at $7804 for operative costs. LRPLND showed a cost advantage for hospital stay costs. If an LRPLND patient’s surgery took under 5 hours and his


Figure 36-6 Abdominal CT scan of a patient with a prominent small interaortocaval lymph node consistent with metastatic testicular cancer.

hospital stay was less than 2.2 days, the overall cost of LRPLND was less than open surgery. With the increase in the number of surgeons performing laparoscopic surgery, more patients will have the opportunity to be treated laparoscopically. It should be noted, however, that LRPLND is an advanced laparoscopic procedure that should only be performed by advanced laparoscopists. The AJCC has defined classifications for pathologic nodal status that are valuable for planning the treatment for patients and assessing results of these treatments. Table 36-9 shows these definitions. Postchemotherapy RPLND Generally, patients with bulky retroperitoneal disease (stage IIc) or disseminated disease (stages IIIA to IIIC) are treated initially with systemic chemotherapy. Surgical resection is usually used in those patients who do not achieve a complete response to chemotherapy to resect

any residual disease apparent on physical examination or imaging studies. Once gross nodal involvement occurs, retrograde lymphatic flow can occur with the subsequent spread of tumor to nodes that would not ordinarily be involved. As a result the limits of dissection are usually those of the full bilateral template (see Figure 36-8). Depending on the location of nodal involvement noted on imaging studies, the nervesparing technique may be used in zones where no obvious nodal involvement has occurred. When a contralateral zone can be dissected with a nerve-sparing technique, up to 89% of the patients can have preservation of emission.20 Laparoscopic postchemotherapy RPLND (LPCRPLND) has been reported by Palese et al.21 Five of 7 patients had successful completion of laparoscopic procedures. Two required conversion to open surgery. There were 3 cases with major complications and 1 with minor complications. The authors concluded that LPCRPLND should be attempted only in selected patients with small volume radical masses.

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Figure 36-7 Abdominal CT scan of a patient with bulky retroperitoneal metastases (stage IIC), which compresses the vena cava.

Table 36-3 Clinical Regional Node Stage (N) NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis with a lymph node mass 2 cm or less in greatest dimension; or multiple lymph nodes, none more than 2 cm in greatest dimension

N2

N3

Table 36-4 Distant Metastases (M) MX

Distant metastasis cannot be assessed

Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, any one mass greater than 2 cm but not more than 5 cm in greatest dimension

M0

No distant metastasis

M1

Distant metastasis

M1a

Nonregional nodal or pulmonary metastasis

Metastasis with a lymph node mass more than 5 cm in greatest dimension

M1b

Distant metastasis other than to nonregional lymph nodes and lungs

These nodal stages are based on imaging studies.

Evidence of metastases is based on imaging studies.


Table 36-5 Serum Marker Status (S)

Table 36-7 Criteria for Primary Observation

SX

Marker studies not available or not performed

Primary tumor: pT1

S0

Marker study levels within normal limits

S1

LDH < 1.5 × N* AND hCG (mIU/ml) < 5000 AND AFP (ng/ml) < 1000

AFP, B-hCG: normal or return to normal after or orchiectomy

S2

S3

Embryonal carcinoma component ≤ 40% No teratomatous elements

LDH 1.5 – 10 × N OR hCG (mIU/ml) 5000–50,000 OR AFP (ng/ml) 1000-10,000

No choriocarcinoma No nodal or metastatic masses by imaging studies (N0, M0)

LDH > 10 × N OR HCG (mIU/ml) > 50,000 OR AFP (ng/ml) > 10,000

*N indicates the upper limit of normal for the LDH assay.

Chemotherapy Primary Short Course or Adjuvant Chemotherapy for Low-Stage Disease (Stages I, IIA and IIB)

Table 36-6 Clinical Stage Groups Stage 0

pTis

N0

M0

S0

Stage 1

PT1–4

N0

M0

SX

Stage IA

pT1

N0

M0

S0

Stage IB

pT2 pT3 pT4

N0 N0 N0

M0 M0 M0

S0 S0 S0

Stage IS

Any pT/Tx

N0

M0

S1–3

Stage II

Any pT/Tx

N1–3

M0

SX

Stage IIA

Any pT/Tx Any pT/Tx

N1 N1

M0 M0

S0 S1

Stage IIB

Any pT/Tx Any pT/Tx

N2 N2

M0 M0

S0 S1

Stage IIC

Any pT/Tx Any pT/Tx

N3 N3

M0 M0

S0 S1

Stage III

Any pT/Tx

Any N

M1

SX

Stage IIIA

Any pT/Tx Any pT/Tx

Any N Any N

M1a M1a

S0 S1

Stage IIIB

Any pT/Tx Any pT/Tx

N1–3 Any N

M0 M1a

S2 S2

Stage IIIC

Any pT/Tx Any pT/Tx

N1–3 Any N

M0 M1a

S3 S3

Any N

M1b

Any S

Any pT/Tx

Primary chemotherapy has been a treatment option for patients with clinical stages I, IIA, or IIIB. Since 1985, two cycles of bleomycin, etoposide, and cisplatin (BEP) have been the standard therapy in this setting.22-24 Schefer et al.25 reported a trial of a single course of BEP for high-risk stage I NSGCTT. In the adjuvant setting, the Indiana group has reported on 86 patients receiving 2 courses of BEP after RPLND for pN1 disease or pN2 disease.22 Kondagunta and Motzer26 published the Memorial Sloan-Kettering Cancer Center experience using cisplatin and etoposide (EP) as adjuvant treatment for pN2 patients. Primary Chemotherapy for High-Stage Disease The addition of cisplatin to Velban and bleomycin (PVB) revolutionized the treatment of metastatic testicular cancer in 1974.27 The standard treatment of metastatic testicular cancer changed to cisplatin, etoposide, and bleomycin (BEP) in 1984 after a randomized trial showed that the BEP treatment was more effective and had a lower rate of toxicity.28 The next area to be studied was trying to reduce the intensity of chemotherapy to reduce toxicity while maintaining efficacy. In order to be able to do this effectively, a system for stratification of the risk level of patients with high-stage tumors was needed. Several attempts were made to define the risk categories. Starting in 1991 an international group, the International Germ Cell Cancer Cooperative Group (IGCCCG), was started. In 1997 this group published its validated definitions of good prognosis, intermediate prognosis, and poor prognosis groups.29 The definitions of the groups for NSGCTs are shown in Table 36-10. These groups are often equated to minimal risk, moderate risk, and high risk for the patients. Treatment choices are frequently made on the basis of

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Figure 36-8 Drawing of the margins of dissection for a full bilateral RPLND. The hatched areas represent the right and left suprahilar zones, which are removed en bloc with the interaortocaval zone and left periaortic zone, respectively.

minimal-to-moderate risk categories versus high-risk categories. Second-Line or Salvage Chemotherapy For patients who did not achieve a complete response with primary chemotherapy and still had positive markers, salvage or second-line chemotherapy was tried. EP was tried starting in 1978 at Indiana for salvage treatment.30 From

1984 to 1989, vinblastine, ifosfamide, and cisplatin were used at Indiana for second-line therapy.31 Motzer et al.32 reported the use of 4 courses of paclitaxel, ifosfamide, and cisplatin (TIP) for second-line chemotherapy.32 Hinton et al.33 have reported a phase II Eastern Cooperative Oncology Group (ECOG) trial of paclitaxel and gemcitabine in refractory germ cell tumors. High-dose chemotherapy with antologous bone marrow transplantation was tried at Indiana University


Figure 36-9 Modified template for an en bloc or prospective nerve-sparing RPLND for a patient with a right-sided tumor.

between 1986 and 1989. Broun et al.34 reported the use of high-dose carboplatin and etoposide with bone marrow transplant rescue.34 A more recent report using the same approach was made from the University of Michigan by Ayash et al.35 The use of paclitaxel in salvage regimens along with cisplatin and/or ifosfamide has been reported by Kollmannsberger et al.36 from Germany.36 Another new approach for salvage therapy was reported by Rick et al.37 from Berlin. They used 3 cycles of TIP followed by 1 cycle of high-dose carbo-

platin, etoposide, and thiotepa (CET).37 The patients had rescue with antologous stem-cell transplantation. There are several additional trials still in progress. TREATMENT BY STAGE This section will present treatment alternatives by clinical stage. The tools of treatment and general follow-up routines have been presented in the previous section. When results are available from several series and are

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Figure 36-10 Modified template for an en bloc or prospective nerve-spring RPLND for a patient with a left-sided tumor.

similar, the percentages after various treatments or periods of observation will be given on the treatment option algorithms shown in Figures 36-13 to 36-15. Clinical Stage I For patients with clinical stage IA, there are three possible choices: observation, primary RPLND, or short course primary chemotherapy (see Figure 36-13). The criteria for observation are given in Table 36-7. The suggested followup testing for observation is shown in Table 36-8. Overall

approximately 70% of patients observed for clinical stage IA disease will remain disease free. Approximately 30% will relapse over a 4-year period. Most relapses will occur within the first year and nearly 90% within 2 years. Patients on observation who relapse are treated based on their stage at relapse. Those who relapse with stage IIA disease or stage IIB disease are treated as shown in Figure 36-14, while those with stage IIC disease or stage III disease are treated as shown in Figure 36-15. Stage IA patients may also be treated by RPLND (modified template-nerve-sparing technique if fertility is


Figure 36-11 A view of the interaortocaval zone with the patient’s head to the right. Note the right-sided postganglionic sympathetic nerve branches emerge from under the vena cava obliquely in a caudal-anterior direction onto the anterior surface of the aorta. The branches usually are located just cephalad to the lumber (suture around one).

Figure 36-12 A view of the right and left lumbar sympathetic trunks and the postganglionic branches with the patient’s head to the right. Branches from each side join at the hypogastric plexus around the origin of the inferior mesenteric artery. Branches from the hypogastric plexus cross the area of the bifurcation of the aorta and travel caudally to the pelvic plexus.

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Table 36-8 Primary Observation Schema Year 1

Year 2

Years 3–4

Years = 5

Serum markers

Monthly

Bimonthly

Biannually

Annually

Chest x-ray

Monthly

Bimonthly

Biannually

Annually

CT scans (chest, abdomen, and pelvis)

Quarterly

Semiannually

Annually

—

Physical examination

Bimonthly

Every 4 months

Biannually

Annually

Table 36-9 Pathologic Nodal Stage (PN) pNX

Regional lymph nodes cannot be assessed

pN0


pN1

Metastasis with a lymph node mass 2 cm or less in greatest dimension and less than or equal to 5 nodes positive, none more than 2 cm in greatest dimension

pN2

Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or more than 5 nodes positive, none more than 5 cm; or evidence of extranodal extension of tumor

pN3

Metastasis with a lymph node mass more than 5 cm in greatest dimension

Nodal status is determined from RPLND specimens.

Table 36-10 IGCCCG NSGCT Definitions Good prognosis Testis/retroperitoneal primary and No nonpulmonary visceral metastases and AFP < 1000 ng/ml and HCG < 5000 IU/1 and LDH < 1.5 × N* Intermediate prognosis

Testis/retroperitoneal primary and No nonpulmonary visceral metastases and AFP = 1000 and = 10,000 ng/ml and/or HCG = 5000 and = 50,000 IU/1 and/or LDH = 1.5 × N and = 10 × N

Poor prognosis Mediastinal primary or Nonpulmonary visceral metastases or AFP = 10,000 ng/ml and/or HCG = 50,000 IU/1 and/or LDH = 10 × N *N = upper limit of normal.

an issue) or primary short course chemotherapy. RPLND has been performed more in the United States, while chemotherapy has been used more frequently in Europe. For clinical stage IB patients, RPLND has been the more prevalent treatment and chemotherapy has been used less frequently in the U.S. In clinical stage IB, patients who have T4 disease, a hemiscrotectomy is also usually performed if it was not already completed as part of the radical orchiectomy. RPLNDs in clinical stages IA and IB patients yield negative lymph nodes in approximately 70% of the patients, while the remaining 30% have positive lymph nodes (pN1 or pN2) despite negative markers and imaging studies. Patients with clinical stage is used to be treated routinely with RPLND. Davis et al.38 recommended the use of primary chemotherapy instead of RPLND because of the high relapse rate after RPLND. In the last several years, the Indiana group has recommended primary chemotherapy in these patients.39 Primary chemotherapy for stages IA, IB, or S has low relapse and death rates (1% to 2% and 5 years) was available for 16 patients; 9 patients were alive with no evidence of disease, 4 were alive with recurrent disease and 3 were dead with the cause of death attributed to recurrent SCT. The following pathologic features were correlated with a malignant course: tumor diameter greater than 5 cm, necrosis, moderate to severe nuclear atypia, vascular invasion, and >5 mitoses per 10 high power fields. Only 1 of 9 benign cases exhibited more than 1 of these features; 5 of 7 of the malignant cases exhibited 3 or more. Sclerosing sertoli cell tumor. SSCT is a recently

described entity. Zukerberg et al.30 described 10 patients aged 18 to 80 years (median 30) with SSCT. The tumors generally presented as a painless mass, with one arising in a cryptorchid testis and another in a testis that had undergone orchiopexy. All tumors were unilateral and ranged from 0.4 to 4.0 cm in diameter. Eight of 10 tumors were l.5 cm or less. The tumors were well demarcated, hard, and yellow-white to tan. Microscopically 9 of 10 tumors were discrete. The 10th tumor invaded the rete testis, epididymis, and blood vessels. The tumors contained simple and anastomosing tubules, large cellular

aggregates, and cords of epithelial cells. The cells were medium sized with rounded vesicular to dark nuclei. The epithelial elements proliferated in a dense hyaline stroma within which were entrapped nonneoplastic seminiferous tubules lined by immature Sertoli cells. No patient showed evidence of malignant behavior, including the 80-year old man with histologic evidence of invasion. Several cases have been reported subsequent to the report by Zukerberg et al.31 bringing the total number of cases reported to 12. Large cell calcifying sertoli cell tumor. Proppe and

Scully,32 in 1980 characterized unusual and distinctive tumors of the testis in 10 patients as LCCSCTs. Since then, at least 35 additional LCCSCTs have been reported.33–35 Age at presentation ranges from 5 to 48 years with the majority less than age 20. As of 1995, only 2 reported cases were deemed malignant.36 There have been subsequent reports of malignant cases.37 The tumor has been associated with a variety of somatic syndromes, including Carney’s syndrome (cardiac myxomas, spotty skin pigmentation, endocrine abnormalities, and schwannomas), Peutz-Jeghers syndrome (gastrointestinal polyposis and mucocutaneous pigmentation), adrenal cortical hyperplasia, primary pigmented adrenal cortical disease, LCTs of the testis, acromegaly, pituitary gigantism, Cushing’s syndrome, acidophilic adenoma of the pituitary gland, gynecomastia, isosexual precocity, and AIS.33,34,38 A recent review of Carney’s syndrome identified 26 reported cases of testicular tumors in patients with Carney’s syndrome, most of proven LCCSCT

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pathology.39 The neoplasms may involve the entire testis but in general are 4 cm or less in maximum dimension. They are frequently multifocal, bilateral in approximately 40%, and are well circumscribed. On cross-section the masses are yellow-tan sometimes with calcific foci. Microscopically, the tumor grows both within seminiferous tubules and within the interstitium. Within tubules the neoplastic cells are large with abundant pink cytoplasm and expand the tubules. Some tubules have a markedly thickened tunica propria, which extends into tubular lumens as eosinophilic spherules. The interstitial tumor is composed of cords, nests, and trabeculae. The tumor cells range from 12 to 25 μm in diameter and have ground glass or finely granular cytoplasm. Transitions between intratubular and interstitial growth may be seen. Calcific rounded nodules, plaques, and masses may be present as intratubular and extratubular aggregates. Of the first 35 reported cases of LCCSCT, metastasis was observed in 2 cases.35 However, in 1997, Kratzer et al.35 reported 6 malignant and 6 benign LCCSCTs. Malignant tumors were more likely to be unilateral (all 8 cases to date), solitary, occurred in older patients (mean age 39 versus 17 for benign cases), and occurred in the absence of a genetic syndrome. Pathologic features that were more frequently identified in the malignant cases included the following: size >4 cm, extratesticular growth, necrosis, high-grade cytologic atypia, vascular space invasion, and more than 3 mitoses per 10 high power fields. All malignant cases exhibited at least 2 of these features; all benign cases exhibited none of these features. Sertoli cell adenoma associated with androgen insensitivity syndrome. AIS is caused by defective or absent

cellular androgen receptors. As a result, patients with complete AIS are phenotypic females with a shallow vagina and absent Wolffian duct derivatives. The patients have 46 XY karyotypes, and bilateral intraabdominal testes that frequently contain nodular masses comprised of multiple tubules lined almost exclusively by Sertoli cells (Figure 37-10). Hamartomas contain small tubules lined by immature Sertoli cells and may have hyperplastic Leydig cells and ovarian type stroma. Young and Scully40 and Rutgers and Scully41 distinguish between hamartomas and pure SCA, which is comprised exclusively of tubules lined by Sertoli cells (Figure 37-11). Although the SCA may be a monomorphic manifestation of a hamartoma, some SCAs achieve sizes up to 25 cm in diameter. SCAs and hamartomas are completely benign. Rarely, other types of sex cord-stromal tumors have been reported in AIS, including a few malignant tumors.42 While the SCAs and hamartomas are benign, it is well to remember that these masses are occurring in cryptorchid testes, and malignant germ cell tumors, principally malignant intratubular germ cell neoplasia and seminomas may develop concomitantly. Approximately 30% of

Figure 37-10 Sertoli cell adenoma of right testis in patient with AIS. The patient was a 17-year-old virilized phenotypic female. In the right orchiectomy specimen is a firm 1.6-cm nonencapsulated tan nodule. The white firm areas at the bottom of the photographs of the testes are smooth muscle masses at the medial portion of the testes and are of probable müllerian duct origin.

patients with complete AIS will develop malignant germ cell tumors by age 50.40 Evaluation and Management Most SCTs are not suspected preoperatively and are diagnosed only at the time of orchiectomy performed for a testicular mass. In the context of a known associated syndrome, the presence of the LCCSCT variant may be suspected preoperatively by the presence of testicular calcifications on scrotal ultrasound, but this finding is not specific to LCCSCT. When suspected, a testis-sparing surgical approach as described for LCT may be considered remembering that rare LCCSCTs may be malignant and that some may be multifocal. Histologically, benign tumors require no further therapy, although long-term follow-up may be indicated, as the occurrence of metastatic disease has been reported as long as 15 years after initial diagnosis. For metastatic lesions, involvement of the retroperitoneal nodes is frequent and there are several case reports of long-term complete remission following retroperitoneal lymphadenectomy. Experience with chemotherapy for malignant SCTs is limited and the response rate is undefined. There are reported cases of complete responses to multiagent chemotherapy.43 Granulosa Cell Tumors Clinical Presentation Two forms of granulosa cell tumors have been described in males, adult and juvenile. Nineteen cases of adult granulosa cell tumor (AGCT) of the testis have been reported in the literature, although additional sex cord-

Chapter 37 Nongerm Cell Tumors of the Testis 625

Figure 37-11 Sertoli cell adenoma. Same patient as in Figure 37-10. The SCA is on the right and is comprised of discrete uniform tubules lined by Sertoli cells. The larger tubules on the left are of the nonadenomatous testis and are separated by prominent Leydig cells (H&E × 31.2).

stromal tumors with granulosa cell differentiation have been reported.44–46 The majority have presented as scrotal masses with testicular enlargement ranging from 2 months to 15 years in the described cases. The patient with a mass of 15 years duration had delayed testicular descent and 2 other patients had been cryptorchid. Five tumors have had associated estrogenic clinical manifestations (gynecomastia). Four of these patients had lymph node or visceral metastases and 2 patients died of their disease. One patient developed metastases 121 months after diagnosis and died of disease 13 months later. Juvenile granulosa cell tumors (JGCT) rarely arise in infants over 6 months old and in all probability arise in utero. A total of 48 cases have been reported.47 Fifty percent of cases were diagnosed in newborns and 90% by 6 months of age (mean 1 month, range 0 to 11 months). They have been associated with 45XO/46XY and 45XO/46XY iso(Yq) karyotypes and numerous other forms of mosaicism.48 The tumors are generally found in descended testes although they have been discovered in undescended and torsed testes. The tumor is not associated with isosexual precocity. The testis harboring this tumor is usually enlarged, solid, and/or cystic (Figure 37-12). Pathologic Characteristics The reported AGCTs ranged in size from 4 microscopic lobules to 13 cm and were well circumscribed.44 They have been described as brownish, white, yellow, and pink

Figure 37-12 Juvenile granulosa cell tumor. One-month-old boy with left testicular mass. The testis measured 3 × 2.5 × 1.5 cm. The surface was smooth and red-tan. On cut sections, there was a variegated red to yellow lobulated parenchyma with cystic areas up to 5 mm in diameter. (Photograph and case courtesy of California Tumor Tissue Registry.)

and either solid or cystic. Two patients with metastases had hemorrhagic or friable and necrotic foci in their tumors. Their microscopic appearance has resembled that of ovarian granulosa cell tumor with solid, cystic, insular, gyriform, and trabecular patterns. Individual granulosa cells have been described as fairly uniform with scanty cytoplasm, indistinct cell borders, and longitudi-

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nal nuclear grooves in elongate cells. Jimenez-Quintero et al.44 recorded up to 26 mitotic figures in 50 high power microscopic fields. Tumor cells have been described as positive for vimentin and negative for keratin or epithelial membrane antigen. JGCT are grossly multicystic and contain follicular structures of varying size lined by one to multiple layers of cells and contain pale eosinophilic or basophilic intraluminal material (Figures 37-12 and 37-13). The stroma is fibrous and may contain groups of cells that resemble theca cells and granulosa cells, which do not resemble the cells of AGCT. Lawrence et al.48 found only a few grooved cells in a minority of tumors. In the JGCTs the granulosa cells have round to oval nuclei and pale to eosinophilic cytoplasm. Tumor granulosa cells stain positively for vimentin and some cells stain positively for keratin and S100 protein with immunoperoxidase stains.49 The cells that resemble theca cells have been demonstrated to stain positively for muscle-specific actin, vimentin, and focally for desmin with immunoperoxidase stains. Mitoses may be numerous. Tumor cells may be present in relationship to seminiferous tubules and have even been described within a seminiferous tubule. The differential diagnosis of JGCT of the testis consists of those tumors developing in the neonatal period. Probably most congenital testicular tumors and those discovered in the first 4 months of life are JGCTs rather than yolk sac tumors. Yolk sac tumors may be solid and/or cystic and may have macrocystic or microcystic areas. However, definitive areas diagnostic for yolk sac tumor, including Schiller-Duval bodies and immunoperoxidase staining for AFP, are absent in JGCT. Levels of serum

AFP are normally elevated in the neonate relative to adult values, so serum AFP levels are of no value in the diagnosis of this tumor. Evaluation and Management The diagnosis of AGCT is not usually established until the time of orchiectomy and surgical excision may be curative. There is insufficient experience with malignant forms of this tumor to comment on therapy. JGCT can be suspected on the basis of patient age and karyotype. They are invariably benign and are cured by excision. Although follow-up in many cases is still limited, none of the 48 reported cases have been associated with recurrence.47 MIXED SEX CORD/GONADAL STROMAL TUMORS AND INCOMPLETELY DIFFERENTIATED TUMORS Tumors of mixed histology occasionally occur and may consist of some areas with recognizable elements mixed with incompletely differentiated cells resembling ovarian stroma (Figure 37-14). A recently described transgenic mouse model suggests that at least some of these neoplasms may arise from tumors, that begin as SCTs.50 Like pure forms, tumors of mixed histology and incompletely differentiated tumors present as an isolated testicular mass usually without endocrinologic signs or symptoms and are diagnosed at the time of orchiectomy (Figure 37-15). Most are biologically benign but some metastatic tumors have been described.51,52 Treatment is by inguinal orchiectomy. Retroperitoneal lymph node dissection may

Figure 37-13 Juvenile granulosa cell tumor. Same patient as in Figure 37-2. Multiple small cysts and areas of solid polyhedral to rounded cells comprise the tumor. Elsewhere, larger follicles were present (H&E × 31.2).


Figure 37-14 Incompletely differentiated gonadal stromal tumor. Testicular mass in 46-yearold. Interlacing fascicles of basophilic spindled cells with large uniform nuclei resemble cells of ovarian stroma (H&E × 62.2).

Figure 37-15 Incompletely differentiated gonadal stromal tumor; 2.2-cm tan nonencapsulated, subcapsular tan firm mass. Same patient as in Figure 37-14.

have value in some cases with metastasis.53 Good responses to platinum-based chemotherapy have been described for metastatic disease.54 Miscellaneous Tumors Epidermoid Cysts Epidermoid cysts are benign lesions, which typically present as a painless testicular mass and are frequently noted incidentally on physical examination. They occur

Figure 37-16 Epidermoid cyst. Eighteen-year-old with 3month history of nontender mass of left testis. The testis contains a well-circumscribed 2-cm cyst with a 1-mm thick gray wall filled with yellow-white friable cheesy material.

slightly more commonly on the right side and rarely are much larger than 2 to 3 cm. Grossly they appear as a usually solitary cyst containing laminated keratinous material (Figure 37-16). Histologically they are composed of a squamous lining and filled with keratin.55 Treatment has historically been by orchiectomy, but there are several reports in the literature describing a characteristic appearance of this lesion on ultrasound, which may allow diagnosis preoperatively.56 The ultrasonographic appearance of a markedly heterogeneous intratesticular

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mass with or without alternating hypoechoic and hyperechoic layers surrounded by a hypoechoic or echogenic rim and absence of blood flow on color Doppler sonography suggest the diagnosis of a testicular epidermoid cyst. Although these criteria are not diagnostic, they may strengthen the indication for excisional biopsy. In such cases, inguinal exploration and excisional biopsy seem reasonable, especially in children or patients with a solitary testicle or bilateral lesions.57,58 Epidermoid cysts have rarely been reported in a patient with Klinefelter’s syndrome, and we have seen another such patient (Figure 37-17).59 Rete Testis Carcinoma Clinical presentation. Orozco and Murphy60 reported

one case and reviewed 43 cases of rete testis carcinoma (RTC) that have been recorded in the literature through 1992. The patients have ranged in age from 17 to 91 years of age with a mean of 50 years. The clinical onset may or may not be associated with pain. Testicular enlargement averaged about 2 years in duration but had been present for 5 years in four instances. Serum tumor markers were not elevated. All patients were treated by orchiectomy and some were also treated with radiotherapy, chemotherapy, and retroperitoneal lymphadenectomy. Of the reviewed patients, 33% died of RTC, 75% within a year of diagnosis. Twenty patients were alive at the time of the report, 80% free of disease at a maximum 2-year follow-up.

Pathologic characteristics. RTCs are poorly circum-

scribed gray nodules at the hilus of the testis. Most tumors are single, but multiple masses have been reported. Reported tumors have ranged in size from 1 to 15 cm. Histologically, RTCs are adenocarcinomas. The predominant growth pattern is papillary with solid, spindled, and cystic areas less common (Figures 37-18 and 37-19). Tumor cells are columnar to cuboidal with acidophilic to amphophilic cytoplasm. Nuclei are enlarged, pleomorphic and round to oval with coarsely granular chromatin and sometimes prominent nucleoli. Mitoses may be frequent. The tumors stain negative for mucin, occasionally positive for CEA, and positive for vimentin, epithelial membrane antigen, and keratin with immunoperoxidase stains. Immunoperoxidase stains are negative for AFP, hCG, and PSA. The diagnosis of RTC should be made in cases where the tumor is present in the hilus of the testis, where there is a transition from histologically normal rete testis to RTC, where primary testicular tumors of germ cell and nongerm cell origin and mesothelioma can be excluded, and where extratesticular origin can be reasonably excluded on a histologic and clinical basis. The histologic distinction between an RTC and adenoma or hyperplasia of the rete testis should not be difficult. Evaluation and management. RTCs are usually found

incidentally by palpation or at the time of orchiectomy for a testicular mass. They may be suspected on preoperative examination or ultrasound by a hilar location

Figure 37-17 Epidermoid cyst. Sixteen-year-old with cystic testicular mass. The cyst is lined by flattened squamous epithelium. Laminated keratin is present in the left upper corner. Mostly flattened seminiferous tubules lined by Sertoli cells are present beneath the cyst. Leydig cells are prominent. The patient was subsequently found to have Klinefelter’s syndrome (H&E × 31.2).


Figure 37-18 RTC. Forty-seven-year-old with recurrent hydrocele and firm nontender mass at the superior pole of the right testis. Orchiectomy specimen contained numerous irregular firm 1- to 4-cm nodules with involvement of epididymis. Papillary and solid neoplasm involves the rete testis, surrounding and projecting into rete testis lumens (H&E × 31.2).

Figure 37-19 RTC. Same case as in Figure 37-18. Glandular spaces are lined by epithelial cells with round to oval, pleomorphic, enlarged nuclei with prominent nucleoli. Glands are infiltrating connective tissue (H&E × 62.2).

or involvement of the epididymis. Initial therapy is orchiectomy followed by a staging evaluation for distant disease.61 One long-term complete remission has been reported following retroperitoneal lymphadenectomy for micrometastatic disease. Chemotherapy for disseminated disease has generally been unsuccessful.61

Malignant Mesothelioma of the Tunica Vaginalis Clinical presentation. Malignant mesothelioma (MM)

is a rare lesion. The literature consists of 81 cases with the largest series reported by Jones et al. in 1995.62,63 The age range is 7 to 80 years with a mean of 53.5 years.

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Two-thirds of patients were over 50 years at the time of diagnosis. Most patients presented with a benign appearing hydrocele with or without an inguinal or scrotal mass. Of those patients who were asked about asbestos exposure, 41% had some degree of occupational exposure. The large majority of patients had a hydrocele sac studded with papillary excrescences from several millimeters to several centimeters (Figure 37-20). In some cases, a mass involved the spermatic cord, other paratesticular structures, or rarely, the testis proper. MM that extended beyond the confines of the hydrocele invaded local structures, including spermatic cord, epididymis, testis, and penile, scrotal and lower abdominal wall skin. Jones’ series includes follow-up on 52 patients (6 months to 15 years, mean 2.8 years). Twenty-five patients developed distant metastases. The principle sites of metastasis were retroperitoneal and inguinal lymph nodes, other lymph nodes and lung. Retroperitoneal and inguinal lymph node involvement was present at the time of diagnosis in 9 and 4 cases, respectively. Of the 52 patients with follow-up data, 44% died of disease, 17% were alive with disease, and 38% had no evidence of disease. The latter figure should be considered with caution since late recurrence of well-differentiated epithelial MM has been observed. Forty-six percent of patients who presented with tumor confined to the hydrocele sac were free of disease at 2 years compared with 5.3% of patients who presented with local invasion of the spermatic cord, skin, testis, or with distant metastasis. In a review of 74 cases of MM of the tunica vaginalis, Plas et al.64 found a median survival time of 23 months.

Pathologic characteristics. Seventy-five percent of the

tumors described by Jones et al.62 were epithelial and 25% were biphasic. Epithelial tumors grew in a tubular and/or papillary growth pattern (Figure 37-21). Cellular anaplasia was variable with some tumors comprised of bland cells without mitotic activity growing in a papillary pattern on fibrous stalks with others containing large eosinophilic cells with hyperchromatic irregular nuclei, prominent nucleoli, and frequent mitoses growing in an infiltrating tubular pattern. Tumor stroma was usually dense. Psammoma bodies were occasionally present. The majority of tumors, even the best differentiated, showed some degree of stromal invasion. MMs with a biphasic pattern had a sarcomatous component with spindled cells of variable differentiation, sometimes containing numerous mitotic figures. MM must be distinguished from a number of benign and malignant lesions. Mesothelial cell hyperplasia, although prominent in a hernia sac, is rarely present in a hydrocele and does not contain the fibrous stalks characteristic of the papillary MM. Adenomatoid tumor is a benign tumor derived from mesothelial cells but has a characteristic gland-like architecture and cytology that distinguishes it from MM. It is far more difficult to distinguish MM from metastatic adenocarcinoma, RTC, and serous borderline tumors of müllerian origin (ovarian surface epithelial type) that resemble ovarian tumors of borderline malignancy, which may involve the testis or paratesticular tissue.65 Borderline serous tumors generally have broad papillae with stratified epithelial cells having a more columnar appearance, some of which are

Figure 37-20 Papillary mesothelioma. Fifty-three-year-old man with recurrent left hydrocele. The tunica vaginalis is studded with yellow-tan excrescences from 0.2 to 1.0 cm in maximum dimension.


Figure 37-21 Papillary mesothelioma. Same case as in Figure 37-20. The tumor is multifocal and comprised of a complex papillary growth lined by a single layer of mesothelial cells with oval, prominently nucleolated nuclei growing on fibrous stalks. The patient is free of MM 5 years after orchiectomy (H&E × 3 1.2).

ciliated. Immunohistochemical stains may be useful in distinguishing between these two tumors since serous tumors are frequently positive for Leu-M1, B72.3, CEA, and CA125, whereas MMs are negative for these antigens.65 MMs are usually positive for CK 5/6 and calretinin. RTC may be associated with a hydrocele and focally may have a histologic resemblance to MM, but if the criteria of diagnosis enumerated earlier are adhered to, there should be no problem distinguishing the two entities. Electron microscopy may also help distinguish the entities since mesothelial cells have long thin, bushy microvilli, and epithelial cells of rete testis origin do not. As in the pleura and peritoneum, there may rarely be a problem distinguishing MM from metastatic adenocarcinoma. The same immunohistochemical stains used to distinguish müllerian papillary serous tumors are useful in distinguishing metastatic adenocarcinomas from MM. Adenocarcinomas, that may be of gastrointestinal origin should stain positively for Leu-Ml, B72.3, and CEA and may contain intracytoplasmic mucin. Evaluation and management. MM is usually not sus-

pected preoperatively; 97.3% are encountered incidentally during hydrocelectomy.64 When the initial presentation is a scrotal mass, inguinal orchiectomy should be performed with en bloc excision of involved adjacent structures. If the tumor is incidentally discovered during a transscrotal procedure, frozen section should be performed and inguinal orchiectomy completed at the same sitting or soon thereafter after consul-

tation with the patient. Orchiectomy is associated with a lower local recurrence rate compared with hydrocelectomy (11% versus 36%, respectively) although no difference in overall survival has been demonstrated.64 A metastatic evaluation is appropriate but there is little experience in the literature to address the issues of surveillance, adjuvant chemotherapy, or prophylactic retroperitoneal or inguinal lymphadenectomy. Metastatic Tumors Symptomatic metastatic nonhematologic tumors of the testis occur only rarely. Price and Mostofi66 identified only 38 metastatic carcinomas involving the testis suitable for study at a time when the AFIP had 1600 primary testicular tumors. Four of the patients had bilateral tumors. Only 6 tumors were clinically symptomatic, generally due to testicular enlargement. The majority of tumors in their report were discovered at autopsy. Of the 38 tumors, 14 were from the lung and 12 were from the prostate gland. Tiltman67 found metastases in 6 of 248 autopsies in males with metastatic carcinoma. Testicular metastases occurred in 2 of 12 cases of prostate carcinoma, 2 of 9 cases of malignant melanoma, 1 of 4 cases of malignant pleural mesothelioma, and 1 of 89 cases of carcinoma of the lung. Haupt et al.68 reviewed the literature through 1982 and found the most common tumors metastasizing to the testes were (in descending order) carcinomas of the prostate and lung, malignant melanoma, and carcinomas of the kidney, stomach, and

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pancreas. These findings emphasize the relative rarity of metastases to the testis and the fact that in most patients testicular involvement will be discovered incidentally despite a known history of cancer. Only 24 cases of testicular enlargement as the primary manifestation of a tumor metastasis have been reported. These included primary tumors of the prostate, kidney, and GI tract, some of which were initially thought to represent primary testicular tumors even after histologic examination. Grossly metastatic tumors are generally multinodular (Figure 37-22). Microscopically, the tumor grows in the interstitium and may be within endothelial-lined spaces. The morphology of the tumor may be characteristic of the primary tumor (Figure 37-23). Treatment for tumors metastatic to the testis is directed at the underlying malignancy. Carcinoid Tumors Carcinoid tumor (CT) involving the testis and testicular adnexa represents a special problem inasmuch as both primary and metastatic tumors may have similar morphology. The nests of tumor grow in an insular pattern with groups of uniform centrally nucleated cells having fine nuclear chromatin and granular eosinophilic cytoplasm (Figure 37-24). The majority of CTs stain positively with argentaffin and argyrophil stains and for chromogranin, neuron-specific enolase, and other polypeptides with immunoperoxidase stains. ZavalaPompa et al.69 indicated that 9 of 62 testicular CTs

Figure 37-22 Metastatic undifferentiated carcinoma, small cell type, of lung. Seventy-six-year-old man with left testicular mass and previous history of undifferentiated small cell carcinoma of lung. Metastatic confluent nodules of neoplasm are present in the lower left portion of the testis.

reported through 1992 were metastatic. The largest of the metastatic CTs on which data were recorded was 2.5 cm, and 3 patients had symptoms of the carcinoid syndrome. Most patients with metastatic CTs died within a year although one patient survived for 12 years. Factors that favor a metastatic origin for a CT are bilaterality, involvement of peritesticular structures, absence of a teratomatous component, and the presence of carcinoid syndrome symptomatology. Most primary testicular carcinoids are cured with inguinal orchiectomy. However,

Figure 37-23 Metastatic prostatic adenocarcinoma. Fifty-eight-year-old man with bilateral orchiectomy for prostate cancer. One testis contained a firm tan irregular mass. Solid aggregates of tumor and neoplastic glands expand the interstitium adjacent to a seminiferous tubule (H&E × 31.2).


Figure 37-24 Carcinoid tumor. Forty-two-year-old male with enlarged right testis and epididymis containing a 3.5-cm yellow to red, firm to fibrous mass. The tumor is comprised of solid nests and cysts growing in an insular pattern. Tumor cells contain uniform, centrally nucleated cells with fine nuclear chromatin and granular eosinophilic cytoplasm (H&E × 3 1.2). (Case courtesy of California Tumor Tissue Registry.)

all patients should have a metastatic evaluation and retroperitoneal lymphadenectomy should be considered in those tumors associated with teratoma. Other Miscellaneous Tumors A variety of other uncommon and usually benign lesions may mimic more aggressive testicular tumors. Simple cysts have been described in 17 patients of all ages and ranging in size from 1 to several centimeters in diameter but are probably more common.70 Histologically, they are lined by flat or cuboidal epithelium and have a benign appearance. Cysts may be suspected preoperatively by a smooth-walled, anechoic appearance on ultrasound. Adenomatoid tumors are benign mesenchymal proliferations that usually arise from the epididymis but may also arise from the tunica albuginea and may infiltrate testicular parenchyma. Two reports of true intratesticular adenomatoid tumors have been published.71,72 These tumors present as painless enlargement and are firm or hard to palpation (Figures 37-25 and 37-26). Fibromas and fibrous pseudotumors of the testicular tunics presenting as hard painful or incidentally discovered masses have also been reported. Granulomatous orchitis and malakoplakia are benign inflammatory conditions usually diagnosed following orchiectomy. They have characteristic histologic appearances, which are pathognomonic. All of these lesions are cured by orchiectomy or simple excision and are important mostly to be differentiated from

malignant testicular tumors and, in the case of malakoplakia and granulomatous orchitis, from ML.

Hematologic Tumors Malignant Lymphoma Clinical presentation. While MLs comprise only a

small percentage of testicular tumors, they account for more than 50% of testicular tumors in men over age 65. About 80% of testicular MLs occur in men over age 50. The neoplasm generally presents as a unilateral, painless,

Figure 37-25 Adenomatoid tumor of epididymis. The epididymal specimen consists of a discrete white uniform rubbery 0.9-cm nodule in a 44-year-old man.

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Figure 37-26 Adenomatoid tumor of epididymis. Same patient as in Figure 37-25. Glandlike structures lined by flattened cells infiltrate collagenous tissue. Numerous intraluminal and intracytoplasmic vacuoles of varying size are present, creating a spider-web appearance in some areas (H&E × 31.2).

intrascrotal mass. About 5% of men present with bilateral synchronous involvement, and approximately 20% with a unilateral presentation will develop lymphomatous involvement of the opposite testis. Bilateral disease may occur in the absence of any other systemic disease.73 Generally, the diagnosis of ML is first made at the time of orchiectomy. Only a small percentage of patients have a history of antecedent lymphoma. Of 127 men with ML of the testis, Gowing74 reported only 8 with antecedent ML and 13 with active lymphoma elsewhere at the time of orchiectomy.

in the working formulation, 10 immunoblastic, 6 small noncleaved, and 6 were NOS. Of those tumors that were immunophenotype 33 were of B-cell lineage, one was of T lineage, and 5 were of indeterminate lineage. Irrespective of cell type, the pattern of infiltration is similar. Tumor cells proliferate in the interstitium separating seminiferous tubules, infiltrating the tunica propria and blood vessel walls, eventually obliterating many tubules and vessels (Figure 37-27). Sections may contain no recognizable testicular parenchyma. Tumor cells may extend into the rete testis, epididymis, tunica albuginea, or peritesticular soft tissue.

Pathologic characteristics. The neoplasm mainly

involves the testis but often extends into the epididymis or spermatic cord. The testis is enlarged, sometimes massively, and on cut section is partially or extensively replaced by an ill-defined tan-grey mass. The tumor merges imperceptibly with testicular parenchyma. Tumor consistency is more rubbery than hard, and necrosis may be present. The large majority of testicular lymphomas are diffuse non-Hodgkin’s type. Gowing74 indicated that 41% of the British Testicular Tumor Panel cases were poorly differentiated lymphocytic lymphomas and 59% were large cell lymphomas (undifferentiated “stem cell reticulum cell type”). They had no cases of Hodgkin’s disease among their 127 cases. Virtually all types of ML other than Hodgkin’s disease occur in the testis. Ferry et al.75 in 1994 reported 64 ML, which presented primarily in the testis. Of these, 53 were diffuse large cell lymphoma of which 27 were of noncleaved type

Evaluation and management. The prognosis of men

with ML of the testis has been poor. Gowing74 indicated 62% of their patients died of disseminated ML. Only 12 of 124 patients (10%) survived 5 years after orchiectomy. In a more recent study, Ferry et al.75 found 20 of 55 patients (36%) to be free of disease a median of 49 months after orchiectomy, 6 (11%) were alive with disease and 29 (53%) died of ML. With careful staging of ML it is apparent that prognosis is related to the stage of the disease at the time of orchiectomy. Turner et al.76 reported 60% disease-free survival in stage I ML contrasted with a 17% disease-free survival for stages II, III, and IV. Turner et al.’s cases were classified according to the Rappaport system and the working classification of non-Hodgkin’s lymphomas. In the latter classification, the large cell noncleaved, large cell cleaved, and diffuse mixed lymphomas were designated intermediate grade


Figure 37-27 ML, diffuse large cell type. A 225-g 9.5 cm in maximum dimension testis was subtotally replaced by a dark tan, focally hemorrhagic, focally necrotic, ill-defined mass. An extensive cellular infiltrate greatly expands the interstitium and compresses seminiferous tubules. The individual cells contain large, variably shaped, prominently nucleolated nuclei with sparse cytoplasm (H&E × 62.2).

lymphomas, and immunoblastic lymphoma, Burkitt’s lymphoma and diffuse undifferentiated lymphomas were designated as high-grade lymphomas. Eight of 17 men with intermediate grade ML were alive and well with an average follow-up of 24 months. There were no survivors among 6 men in the high-grade group whose average survival was 13 months. Thus, grade appears to be another prognostic variable. Stage I disease, unilateral right-sided ML, and microscopic sclerosis were also associated with an improved prognosis in Ferry et al.’s study.75 In 2001, Lagrange et al.77 reviewed their experience with 84 cases of primary testicular lymphoma. The median age at presentation was 67 (range 17 to 85). Forty-two patients presented with stage I disease, 19 with stage II, and 23 with stage III/IV. Using the REAL classification, 75% of the patients exhibited diffuse large Bcell histology. Treatment was generally multimodal and involved orchiectomy and chemotherapy ± radiation. A complete response was obtained in 72.6% of patients (100%, 68%, and 33% for stages I, II, and III/IV, respectively). However, median survival was 32 months (52, 32, and 12 months for stages I, II, and III/IV, respectively). Zucca et al.,78 in 2003, examined their experience with 373 patients with primary testicular diffuse large B-cell lymphoma. The median age at diagnosis was 66 years. Anthracycline-based chemotherapy was used in 68%, prophylactic intrathecal chemotherapy in 18%, and prophylactic scrotal radiotherapy in 36%. Median survival

was 4.8 years, but the survival curves showed no clear evidence of a substantial portion of cured patients. There was a 52% relapse rate at a median follow-up of 7.6 years. Relapses occurred in the CNS in 15% of the patients, occasionally as late as 10 years postorchiectomy. The authors identified a continuous risk of contralateral testicular recurrence in those patients not receiving scrotal radiotherapy. On multivariate analysis, lack of Bsymptoms, use of anthracyclines, and scrotal radiotherapy were associated with longer survival. Evidence is accumulating that primary testicular lymphoma in children has a very different natural history.79–81 Most lymphomas involving the testicle are secondary lesions in patients with diffuse extrascrotal lymphoma. Only 10 cases of primary testicular lymphoma in children have been reported. All have shared similar histology (follicular large cell lymphoma) and, despite the aggressive histologic appearance, a good prognosis. Most patients have been treated with orchiectomy and multiagent chemotherapy. The 10 reported cases include children ranging in age from 3 to 11 years. None of the tumors has demonstrated the presence of bcl-2 protein. The size of the tumors ranged from 2 to 4 cm. All 10 patients are reported to be free of disease with follow-up ranging from 7 to 59 months. It is clear that some cases of ML originate in the testis. Although rare survivals have been reported following orchiectomy alone, this is certainly insufficient therapy since the large majority of men ultimately develop extratesticular

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ML. Extratesticular involvement tends to occur in several areas, including Waldeyer’s ring and the central nervous system. Turner et al.’s76 series also suggests that MLs at these sites may have been present at the time of orchiectomy. Ferry et al.’s75 data indicate that MLs that relapsed in the testis tended to be extranodal, and that ML presenting in the testis tended to have lymphoma in extranodal sites, notably bone, CNS, skin, orbit, paranasal sinuses, stomach, nose, thyroid, and larynx.75 Treatment should be based on stage and histologic type of lymphoma. Plasmacytoma Plasma cell neoplasms involving the testis are rare and have the same implications as ML. The tumors are bilateral and sequential in about 20% of men. Tumors generally manifest as painless enlargement and are part of a systemic process sometimes identified prior to orchiectomy. Tumors may be associated with hydroceles and, on at least two occasions, the diagnosis was made on the basis of cytologic analysis of hydrocele fluid.82 All patients with sufficient follow-up reviewed by Levin and Mostofi83 and all 7 in the literature until that time succumbed to systemic disease. The mean age at the time of diagnosis was 55 years with only 8 patients under 50 and the youngest aged 26. There have been 42 reported cases of testicular plasmacytoma, only 10 of which had no documented systemic myeloma.82,84,85 The gross and microscopic appearances of plasmacytoma are similar to those of ML, the only difference being the cell type, which is a neoplastic plasma cell of variable morphology (Figure 37-28). Leukemia Leukemic involvement of the testis is common. In an autopsy study, Givler86 found 63% of 140 males with

Figure 37-28 Plasmacytoma. Massive enlargement and complete replacement of testicular parenchyma by a lobulated gray-yellow 11-cm mass in a 42-year-old man.

acute leukemia (AL) and 22% of 76 males with chronic leukemia (CL) had testicular involvement. All varieties of AL were represented. It is recognized that children with acute lymphoblastic leukemia (ALL) in bone marrow remission may have recurrence first demonstrated in the testis. In Givler’s study, 8 children with ALL developed testicular masses while receiving chemotherapy. Five of the children were in hematologic remission and the testicular masses were either the sole evidence of leukemia or associated with other extramedullary leukemic masses. Hematologic relapse followed in all cases. In 5 of 8 cases, testicular involvement was bilateral. In cases of ALL following completion of chemotherapy, biopsy of the testes to rule out occult leukemic involvement is part of some current protocols. Neither palpation nor radiographic studies, such as ultrasound or MRI, are sufficiently sensitive to the presence of leukemic infiltrates to obviate the need for biopsy. Buchanan et al.87 reported that one-third of patients with overt testicular recurrence of ALL treated with an intense protocol exhibited prolonged second remissions with the potential for cure. Only a small percentage of patients will develop testicular recurrence following a negative biopsy. The interstitial pattern of testicular involvement in ALL is similar to that of ML. Occasionally ALL involvement of the testis produces a massive enlargement (Figure 37-29). Tumors of Generalized Stroma Tumors of generalized stroma (blood vessels, smooth muscle, and other supporting stroma), also known as mesenchymal tumors, rarely occur in the testis. Petersen70 reported a total of 26 such tumors described in the literature, most of which (62%) were malignant. The histologies of the benign tumors included 5 hemangiomas, 3 hemangioendotheliomas, 1 leiomyoma, and 1

Figure 37-29 Acute lymphocytic leukemia. Massive replacement of right testis by a cream-colored, focally hemorrhagic, ill-defined mass in a 10-year-old with an 8-year history of treated ALL.


myxoid neurofibroma. The malignancies included 14 rhabdomyosarcomas, 1 osteosarcoma, and 1 leiomyosarcoma. The microscopic appearance of these tumors is similar to those that occur at more typical sites. Most of these patients presented with testicular enlargement and underwent inguinal orchiectomy with the diagnosis of a mesenchymal tumor made only after surgical excision of the testis. Benign tumors found in this manner do not require further evaluation or treatment. Rhabdomyosarcomas of the testis proper occur less frequently than in paratesticular locations but should be similarly treated with retroperitoneal lymphadenectomy, chemotherapy, and radiation, depending on stage. Testis Tumors in Acquired Immunodeficiency Syndrome Patients infected with HIV or with full-blown AIDS appear to be at a 20- to 50-times higher risk of developing primary or secondary testis tumors.88 Testis tumors are the third most common HIV-associated/AIDS-associated malignancy.88 The first 2 cases of germ cell tumors of the testis in AIDS patients were reported in 1985.89 Wilson et al.89 reported 5 of 3015 HIV positive men presenting with testicular tumors over a 5-year period, an incidence of 0.2%, more than 50 times the incidence of testis tumors in the general population. There have been additional cases of testis tumors described in the AIDS population in the urologic literature, including seminoma and mixed nonseminomatous germ cell tumors, Kaposi’s sarcoma, MLs, and plasmacytomas.90 Some of these cases presented with testicular swelling as the initial and primary manifestation of HIV infection,91 and some of these patients presented with symptoms of acute prostatitis or epididymo-orchitis and were initially treated with antibiotics before returning with complaints of progressive testicular enlargement. Reported cases were ultimately managed by inguinal orchiectomy and additional therapy based on tumor histology and status of the patient’s immune system. These reports highlight the need for a high index of suspicion for testicular tumors in men at risk for HIV who present with testicular enlargement. Testicular and Paratesticular Tumors of Ovarian Surface Epithelial Type Prior to 1995, 17 cases had been reported of testicular and paratesticular tumors of ovarian surface epithelial type, when Jones et al. reported an additional 5 cases of paratesticular serous carcinoma.92,93 These occurred in an age range of 11 to 68 years with a median of 47 years in Young et al.’s series of testicular and paratesticular tumors and in a range of 16 to 42 years with a mean of 31 years in Jones et al.’s series of paratesticular serous carcinoma. The majority of tumors of ovarian surface epithe-

lial origin are paratesticular, but at least 7 principally involved testicular parenchyma. Other areas of involvement included the tunica vaginalis and the testicularepididymal groove at the upper pole of the testis. The majority of cases have been of serous borderline type, but serous papillary carcinoma, mucinous cystadenoma, and cystadenocarcinoma, endometrioid adenoacanthoma, clear cell carcinoma, and Brenner tumors have been reported.92,93 These tumors may be derived from müllerian duct remnants, the tunica vaginalis, or both. Most borderline serous tumors behave in a benign fashion if completely excised, but the clear cell adenocarcinoma and two cases of papillary serous carcinoma behaved in a malignant fashion, one causing metastasis and death and another having extensive abdominal recurrence.93 A third patient without demonstrable recurrence has persistent elevation of serum CA125.93 It is important to recognize the müllerian nature of these neoplasms and to accurately distinguish between borderline and frankly malignant variants. The differential diagnosis of müllerian surface epithelial tumors includes germ cell tumors, rete testis adenocarcinoma, mesothelioma of the tunica vaginalis, and metastatic adenocarcinoma. Germ cell tumors, because they are the most frequent tumor in this region, must be considered in the differential diagnosis, but only teratomas with mucinous glandular differentiation or transitional cell foci might remotely be considered in the differential diagnosis of mucinous or Brenner variants of müllerian tumors. As described earlier, rete testis adenocarcinomas have a combination of diagnostic features that must be recognized for a correct diagnosis. Paratesticular and tunica vaginalis MM may closely resemble paratesticular and tunica vaginalis borderline serous müllerian tumors. MMs are about three times more frequent. Müllerian tumors stain positively for keratin and frequently for CEA, B72.3, BER-EP4, EMA, Leu-M1, S-100 protein, and PLAP, whereas MMs stain positively for cytokeratins, including CK 5/6 and calretinin.65 Although borderline serous tumors and epithelial MMs may have papillary configurations, borderline serous tumors generally have stratified nuclei and may be ciliated, whereas MMs are lined by a single cell layer. Metastatic carcinomas to the testis, tunica vaginalis and paratesticular tissues are rare but should be considered in the differential diagnosis.

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19. Palazzo JP, Petersen RO, Young RH, Scully RE: Deoxyribonucleic acid flow cytometry of testicular Leydig cell tumors. J Urol 1994; 152:415–417. 20. McCluggage WG, Shanks JH, Arthur K, Banerjee SS: Cellular proliferation and nuclear ploidy assessments augment established prognostic factors in predicting malignancy in testicular Leydig cell tumours. Histopathology 1998; 33(4):361–368. 21. Ulbright TM, Srigley JR, Hatzianastassiou DK, Young RH: Leydig cell tumors of the testis with unusual features: adipose differentiation, calcification with ossification, and spindle-shaped tumor cells. Am J Surg Pathol 2002; 26(11):1424–1433. 22. Kirkland RT, Kirkland JL, Keenan BS, et al: Bilateral testicular tumors in congenital adrenal hyperplasia. J Clin Endocrinol Metab 1977; 44:369–378. 23. Rich MA, Keating MA, Levin HS, Kay R: Tumors of the adrenogenital syndrome: an aggressive conservative approach. J Urol 1998; 160(5):1838–1841. 24. Stikkelbroeck NM, Otten BJ, Pasic A, et al: High prevalence of testicular adrenal rest tumors, impaired spermatogenesis, and Leydig cell failure in adolescent and adult males with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2001; 86(12):5721–5728. 25. Davis JM, Woodroof J, Sadasivan R, Stephens R: Case report: congenital adrenal hyperplasia and malignant Leydig cell tumor. Am J Med Sci 1995; 309:63–65. 26. Levin HS: Tumors of the testis in intersex syndromes. Urol Clin North Am 2000; 27(3):543–551. 27. Bertram KA, Bratloff B, Hodges GF, Davidson H: Treatment of malignant Leydig cell tumor. Cancer 1991; 68:2324–2329. 28. van der Hem KG, Boven E, van Hennik MB, Pinedo HM: Malignant Leydig cell tumor of the testis in complete remission on o,p′-dichlorodiphenyldichloroethane. J Urol 1992; 148(4):1256–1259. 29. Young RH, Koelliker DD, Scully RE: Sertoli cell tumors of the testis, not otherwise specified: a clinicopathologic analysis of 60 cases. Am J Surg Pathol 1998; 22(6):709–721. 30. Zukerberg LR, Young RH, Scully RE: Sclerosing Sertoli cell tumor of the testis: a report of 10 cases. Am J Surg Pathol 1991; 15:829–834. 31. Gravas S, Papadimitriou K, Kyriakidis A: Sclerosing Sertoli cell tumor of the testis—a case report and review of the literature. Scand J Urol Nephrol 1999; 33(3):197–199. 32. Proppe KH, Scully RE: Large-cell calcifying Sertoli cell tumor of the testis. Am J Clin Pathol 1980; 74:607–619. 33. Proppe KH, Dickerson GHL: Large-cell calcifying Sertoli cell tumor of the testis. Hum Pathol 1982; 13:1109–1114. 34. Tetu B, Ro JY, Ayala AG: Large cell calcifying Sertoli cell tumor of the testis: a clinicopathologic, immunohistochemical and ultrastructural study of two cases. Am J Clin Pathol 1991; 96:717–722. 35. Kratzer SS, Ulbright TM, Talerman A, et al: Large cell calcifying Sertoli cell tumor of the testis: contrasting features of six malignant and six benign tumors and a review of the literature. Am J Surg Pathol 1997; 21(11):1271–1280.

Chapter 37 Nongerm Cell Tumors of the Testis 639 36. Nogales FF, Andujar M, Zuluaga A, Garcia-Puche JL: Malignant large cell calcifying Sertoli cell tumor of the testis. J Urol 1995; 153:1935–1937. 37. Cano-Valdez AM, Chanona-Vilchis J, DominguezMalagon H: Large cell calcifying Sertoli cell tumor of the testis: a clinicopathological, immunohistochemical, and ultrastructural study of two cases. Ultrastruct Pathol 1999; 23(4):259–265. 38. Dryer L, Jacyk WK, du Plessis DJ: Bilateral large-cell calcifying Sertoli cell tumor of the testes with Peutz–Jeghers syndrome: a case report. Pediatr Dermatol 1994; 11:335–337. 39. Washecka R, Dresner MI, Honda SA: Testicular tumors in Carney’s complex. J Urol 2002; 167(3):1299–1302. 40. Young RH, Scully RE (eds): Testicular Tumors, pp 140–150. Chicago, ASCP Press, 1990. 41. Rutgers JL, Scully RE: Pathology of the testis in intersex syndromes. Semin Diagn Pathol 1987; 4:275–291. 42. Wysocka B, Serkies K, Debniak J, Jassem J, Limon J: Sertoli cell tumor in androgen insensitivity syndrome—a case report. Gynecol Oncol 1999; 75(3):480–483. 43. Athanassiou AE, Barbounis V, Dimitriadis M, Pectasidis D, Bafaloukos D: Successful chemotherapy for disseminated testicular Sertoli cell tumour. Br J Urol 1988; 61(5):456–457. 44. Jimenez-Quintero LP, Ro JY, Zavala-Pompa A, et al: Granulosa cell tumor of the adult testis: a clinicopathologic study of seven cases and a review of the literature. Hum Pathol 1993; 24:1120–1126. 45. Al-Bozom IA, El-Faqih SR, Hassan SH, El-Tiraifi AE, Talic RF: Granulosa cell tumor of the adult type: a case report and review of the literature of a very rare testicular tumor. Arch Pathol Lab Med 2000; 124(10):1525–1528. 46. Morgan DR, Brame KG: Granulosa cell tumour of the testis displaying immunoreactivity for inhibin. BJU Int 1999; 83(6):731–732. 47. Nieto N, Torres-Valdivieso MJ, Aguado P, et al: Juvenile granulosa cell tumor of the testis: case report and review of literature. Tumori 2002; 88(1):72–74. 48. Lawrence WD, Young RH, Scully RE: Juvenile granulosa cell tumor of the infantile testis. Am J Surg Pathol 1985; 9:87–94. 49. Tanaka Y, Sasaki Y, Tachibana K, et al: Testicular juvenile granulosa cell tumor in an infant with X/XY mosaicism clinically diagnosed as true hermaphroditism. Am J Surg Pathol 1994; 18:316–322. 50. Paquis-Flucklinger V, Rassoulzadegan M, Michiels J-F: Experimental Sertoli cell tumors in the mouse and their progression into a mixed germ cell-sex cord proliferation. Am J Pathol 1994; 144:454–459. 51. Lawrence WD, Young RH, Scully RE: Sex cord-stromal tumors. In Talerman A, Roth LM (eds): Pathology of the Testis and its Adnexa, Vol 7, Chap 4, Contemporary Issues in Surgical Pathology, pp 67–92. New York, Churchill Livingstone, 1986. 52. Dieckmann K-P, Loy V: Response of metastasized sex cord gonadal stromal tumor of the testis to cisplatin-based chemotherapy. J Urol 1994; 151:1024–1026. 53. Gohji K, Higuchi A, Fujii A, Kizaki T: Malignant gonadal stromal tumor. Urology 1994; 43:244–247.

54. Stewart DA, Stewart DJ, Mai KT: Active chemotherapy for metastatic stromal cell tumor of the testis. Urology l993; 42:732–734. 55. Price EB Jr: Epidermoid cysts of the testis: a clinical and pathologic analysis of 69 cases from the testicular tumor registry. J Urol 1969; 102:708–731. 56. Cho JH, Chang JC, Park BH, Lee JG, Son CH: Sonographic and MR imaging findings of testicular epidermoid cysts. AJR Am J Roentgenol 2002; 178(3):743–748. 57. Ross JH, Kay R, Elder J: Testis sparing surgery for pediatric epidermoid cysts of the testis. J Urol l993; 149:353–356. 58. Davi RC, Braslis KG, Perez JL, Soloway MS: Bilateral epidermoid cysts of the testis. Eur Urol 1996; 29(1):122–124. 59. Baniel J, Perez JM, Foster RS: Benign testicular tumor associated with Klinefelter’s syndrome. J Urol 1994; 151:157–158. 60. Orozco RE, Murphy WM: Carcinoma of the rete testis: case report and review of the literature. J Urol l993; 150:974–977. 61. Stein JP, Freeman JA, Esrig D, Chandrasoma PT, Skinner DG: papillary adenocarcinoma of the rete testis: a case report and review of the literature. Urology 1994; 44:588–594. 62. Jones MA, Young RH, Scully RE: Malignant mesothelioma of the tunica vaginalis. A clinicopathologic analysis of 11 cases with review of the literature. Am J Surg Pathol 1995; 19:815–825. 63. Iczkowski KA, Katz G, Zander DS, Clapp WL: Malignant mesothelioma of tunica vaginalis testis: a fatal case with liver metastasis. J Urol 2002; 167(2 Pt 1):645–646. 64. Plas E, Riedl CR, Pfluger H: Malignant mesothelioma of the tunica vaginalis testis: review of the literature and assessment of prognostic parameters. Cancer 1998; 83(12):2437–2446. 65. De Nictolis M, Tommasoni S, Fabris G, Prat, J: Intratesticular serous cystadenoma of borderline malignancy. A pathological, histochemical and DNA content study of a case with long-term follow-up. Virchows Archiv A Pathol Anat 1993; 423:221–225. 66. Price EB Jr, Mostofi FK: Secondary carcinoma of the testis. Cancer 1957; 10:592–595. 67. Tiltman AJ: Metastatic tumors of the testis. Histopathology 1979; 3:31–37. 68. Haupt HM, Mann RB, Trump DL, Abeloff MD: Metastatic carcinoma involving the testis. Clinical and pathologic distinction from primary testicular neoplasms. Cancer 1984; 54:709–714. 69. Zavala-Pompa A, Ro JY, el-Naggar A, et al: Primary carcinoid tumor of testis. Immunohistochemical, ultrastructural and DNA flow cytometric study of three cases with a review of the literature. Cancer 1993; 72:1726–1732. 70. Peterson RO (ed): Urologic Pathology, 2nd edition, p 451. Philadelphia, JB Lippincott, 1992. 71. Horstman WG, Sands JP, Hooper DG: Adenomatoid tumor of testicle. Urology 1992; 40(4):359–361.

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72. Samad AA, Pereiro B, Badiola A, Gallego C, Zungri E: Adenomatoid tumor of intratesticular localization. Eur Urol 1996; 30(1):127–128. 73. Hurley LJ, Burke CR, Shetty SK, et al: Bilateral primary non-Hodgkin’s lymphoma of the testis. Urology 1996; 47(4):596–598. 74. Gowing NFC: Malignant lymphoma of the testis. In Pugh RCB (ed): Pathology of the Testis, pp 334–355. Oxford, Blackwell Scientific Publications, 1976. 75. Ferry JA, Harris NL, Young RH, et al: Malignant lymphoma of the testis, epididymis and spermatic cord. A clinicopathologic study of 69 cases with immunophenotypic analysis. Am J Surg Pathol 1994; 18:376–390. 76. Turner RR, Colby TV, MacKintosh FR: Testicular lymphomas, a clinicopathologic study of 35 cases. Cancer 1981; 48:2095–2102. 77. Lagrange JL, Ramaioli A, Theodore CH, et al: Radiation Therapy Group and the Genito-Urinary Group of the French Federation of Cancer Centres. Non-Hodgkin’s lymphoma of the testis: a retrospective study of 84 patients treated in the French anticancer centres. Ann Oncol 2001; 12(9):1313–1319. 78. Zucca E, Conconi A, Mughal TI, et al: Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the international extranodal lymphoma study group. J Clin Oncol 2003; 21(1):20–27. 79. Pakzad K, MacLennan GT, Elder JS, et al: Follicular large cell lymphoma localized to the testis in children. J Urol 2002; 168(1):225–228. 80. Finn LS, Viswanatha DS, Belasco JB, et al: Primary follicular lymphoma of the testis in childhood. Cancer 1999; 85(7):1626–1635. 81. Pileri SA, Sabattini E, Rosito P, et al: Primary follicular lymphoma of the testis in childhood: an entity with peculiar clinical and molecular characteristics. J Clin Pathol 2002; 55(9):684–688.

82. Suzuki K, Shioji Y, Morita T, Tokue A: Primary testicular plasmacytoma with hydrocele of the testis. Int J Urol 2001; 8(3):139–140. 83. Levin HS, Mostofi FK: Symptomatic plasmacytoma of the testis. Cancer 1970; 25:1193–1203. 84. Reddi VR, Anne GP, Rani AV, et al: Primary plasmacytoma of testis. Report of a case. Indian J Cancer 1998; 35(4):152–155. 85. Fischer C, Terpe HJ, Weidner W, Schulz A: Primary plasmacytoma of the testis. Case report and review of the literature. Urol Int 1996; 56(4):263–265. 86. Givler RL: Testicular involvement in leukemia and lymphoma. Cancer 1969; 23:1290–1295. 87. Buchanan GR, Boyett JM, Pollock BH, et al: Improved treatment results in boys with overt testicular relapse during or shortly after initial therapy for acute lymphoblastic leukemia. A Pediatric Oncology Group Study. Cancer 1991; 68:48–55. 88. Leibovitch I, Baniel J, Rowland RG, et al: Malignant testicular neoplasms in immunosuppressed patients. J Urol 1996; 155(6):1938–1942. 89. Wilson WT, Frenkel E, Vuitch F, Sagalowsky AI: Testicular tumors in men with human immunodeficiency virus. J Urol 1992; 147:1038–1040. 90. Ramadan A, Naab T, Frederick W, Green W: Testicular plasmacytoma in a patient with the acquired immunodeficiency syndrome. Tumori 2000; 86(6):480–482. 91. Munver R, Donehower RC, Kronz JD, Polascik TJ: HIV infection presenting as an unusually large pure yolk sac tumor of the testis. J Urol 2000; 164(5):1653–1654. 92. Young RH, Scully RE: Testicular and paratesticular tumors and tumor-like lesions of ovarian common epithelial and Mullerian types. Am J Clin Pathol 1986; 86:146–152. 93. Jones MA, Young RH, Srigley JR, Scully RE: Paratesticular serous papillary carcinoma. A report of six cases. Am J Surg Pathol 1995; 19:1359–1365.

C H A P T E R

38 Radical Orchiectomy and Retroperitoneal Lymph Node Dissection Richard S. Foster, MD, Ashraf Mosharafa, MD, and Richard Bihrle, MD

RADICAL ORCHIECTOMY General Considerations Approximately 95% of primary intratesticular tumors are of germ cell origin. The other 5% of tumors consist of a variety of benign and malignant lesions. These include Leydig cell and Sertoli cell tumors, adrenal cortical rests, and other benign lesions.1 Similarly, secondary tumors of the testis may occur rarely and mainly are hematopoietic in origin. Hence, patients presenting with a tumor that is intratesticular are usually found histologically to have a germ cell tumor. Most patients present with a palpable intratesticular mass. Typically, the mass is firm and definitely different from the consistency of normal testicular tissue. If such a lesion is discovered, immediate determination of serum alpha fetoprotein and beta-HCG is necessary and the elevation of either of these markers confirms the diagnosis of a germ cell tumor. If the tumor is palpable, testicular ultrasound is not necessary and the patient may be taken immediately to radical inguinal orchiectomy. Alternatively, if there is doubt as to the diagnosis, transscrotal ultrasound is useful and the finding of an intratesticular abnormality on testicular ultrasound in a patient in the appropriate age range for germ cell tumors may confirm the diagnosis. Magnetic resonance imaging has been studied in the diagnosis of testicular tumors but is rarely needed clinically.2 Historically, radical inguinal orchiectomy meant removal of the testis and cord but sometimes also included an extension of the incision and palpation of the retroperitoneum.3 With modern imaging and staging techniques this extension of the incision to palpate the retroperitoneum is not necessary. Currently, radical

inguinal orchiectomy includes an inguinal approach to high ligation of the spermatic cord at the internal ring and the subsequent removal of the testis. It is typically performed as an outpatient procedure. The technique is relatively straightforward; an inguinal incision is made parallel to the inguinal ligament and the dissection is carried through the subcutaneous tissues to the aponeurosis of the external oblique. The external ring is identified, and the aponeurosis of the external oblique is split from the external ring to the internal ring. Cremasteric fibers are divided and the ilioinguinal nerve is identified and dissected from the cord structures. Next, the cord is dissected from the inguinal floor and circumferential control is attained at the internal ring. If the decision has been made to perform inguinal orchiectomy, the cord is divided into 2 segments with a large clamp, after which the segments are ligated with permanent sutures and/or suture ligatures. Sometimes it is necessary to dissect the peritoneum away from the medial aspect of the cord prior to performing ligation. Typically, after ligating the cord the cord stump retracts into the abdomen through the internal ring. This facilitates removal of the cord stump at subsequent retroperitoneal lymph node dissection (RPLND). After ligation of the cord the dissection is carried distally with subsequent mobilization of the testis through the upper part of the scrotum and division of the gubernacular fibers. If the testis tumor is so large that it cannot be easily delivered through the opening in the scrotum, the incision is extended on to the scrotum in order to remove the testis intact. After hemostasis is obtained the aponeurosis of the external oblique and Scarpa’s fascia are subsequently closed. Typically, the skin is closed using a running subcuticular suture.

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If the diagnosis is unclear at the time of exploration and a frozen section is necessary, the same steps are performed with the exception of early division of the cord. Typically, if a frozen section is to be obtained, a tourniquet is applied to the cord at the internal ring after which the testis is mobilized up into the incision. Drapes are placed over the incision and the frozen section is done away from the incision itself so as to not spill tumor into the incision. Subsequently, if a frozen section diagnosis confirms a germ cell tumor, the radical orchiectomy is completed. The reasoning behind an inguinal approach to a germ cell tumor of the testis is to avoid spilling tumor into the wound. Typically, germ cell tumor implants and if tumor is spilled into the inguinal area, potentially another area of lymphatic drainage (inguinal nodes) is contaminated. Historically, if a scrotal approach to a testis tumor was carried out, a subsequent recommendation was made to perform hemi-scrotectomy so as to avoid contamination of the inguinal lymphatics. With the advent of systemic chemotherapy this procedure now is rarely necessary although the inguinal approach to radical orchiectomy continues to be the standard of care and should be appropriate management for any patient presenting with a germ cell tumor of the testis.4 Approximately 1% to 2% of all patients who present with a testicular germ cell tumor will develop a subsequent tumor on the contralateral side.5 Historically, radical inguinal orchiectomy was performed for the second tumor and the patient was placed on testosterone supplementation so as to maintain libido and sexuality. It is now clear that small secondary tumors at the polar aspects of the testis can be managed by partial orchiectomy with good long-term results. Most series of partial orchiectomy have recommended postoperative radiation therapy to the testis, which prevents local recurrence and eradicates carcinoma in situ in the remaining testicular tissue.6 The benefit of this approach is that over the long term these patients are able to sustain production of androgens from the remaining Leydig cells and therefore do not need supplementation. However, the postoperative radiation therapy effectively eliminates fertility, and therefore the benefit of partial orchiectomy is to maintain adequate androgen serum levels. RETROPERITONEAL LYMPH NODE DISSECTION The germ cell tumors of the testis are not only chemosensitive but also “surgery sensitive.” Even after lymphatic metastasis has occurred, the surgical removal of involved lymph nodes may be curative from 50% to 75% of the time, dependent on the volume of metastatic disease.7,8 Most other cancers (breast, colon, lung, etc.) are not surgically curable if lymphatic metastasis occurs; germ cell testis tumors are surgically curable in the face

of lymphatic metastasis. From a urologic point of view, this is perhaps the most unique aspect of the surgical treatment of germ cell tumors. Hence, since surgery may be curative in many patients with metastatic germ cell tumor, urologic oncologists necessarily need to understand and be proficient in techniques of removal of lymph nodes in the retroperitoneum. RPLND is essentially two different operations; one operation for low-stage disease in patients who have not received chemotherapy and a completely different operation for those patients who require an RPLND for a residual mass after chemotherapy. These two techniques are discussed separately. RETROPERITONEAL LYMPH NODE DISSECTION FOR LOW-STAGE DISEASE Low-stage seminoma is not managed surgically and the discussion here relates only to low-stage nonseminoma. Clinical stage I disease is defined as no evidence of metastasis on radiologic imaging. Typically, this involves CT scanning of the abdomen and chest. Some prefer only a chest x-ray as opposed to a CT of the chest. Additionally, serum alpha fetoprotein and beta-hCG should have normalized after radical orchiectomy or alternatively should be decaying based on normal half-lives of approximately 5 days for alpha fetoprotein and 11⁄2 days for beta-hCG.9 If the patient has no evidence of metastasis on radiologic imaging but these markers are not normalizing according to half-life, the patient should be treated with chemotherapy because of the high probability of having occult systemic disease.10,11 Several alternatives for management exist in clinical stage I that in the short term yield roughly the equivalent chance for survival. These alternatives include RPLND (with nerve sparing), surveillance with chemotherapy at relapse, or primary chemotherapy. Pro and con arguments exist for each of these approaches depending on long-term side effects, psychologic issues, access to health care, etc. As opposed to surveillance, the benefits of RPLND include the immediate determination of pathologic stage, the avoidance of chemotherapy (since many of these patients are cured with surgery alone), and the elimination of the necessity of using CT scans of the abdomen in follow-up. Conversely, the follow-up period after RPLND is only 2 years, whereas patients managed on surveillance have to be followed for a longer period of time.12 Similarly, the main benefit of surveillance is that patients who have no metastasis receive no treatment and only patients documented to have metastatic disease are subject to any sort of therapy. Approximately 30% of clinical stage I patients are subsequently found to have metastatic disease.13 Generally, metastatic tumor is found in retroperitoneal lymphatics. Rarely, the retroperitoneum is normal and metastasis is

Chapter 38 Radical Orchiectomy and Retroperitioneal Lymph Node Dissection 643

hematogenous only. Hence, the high probability of retroperitoneal metastasis is the rationale for performing RPLND. Risk factors identified in the orchiectomy specimen may increase the probability of metastasis to 50%, but prediction of metastasis at a higher level than 50% is not possible.14 Therefore, clinical stage I patients will have a 50% to 70% chance of having normal lymph nodes removed. Since some patients who undergo RPLND for clinical stage I disease have no metastasis, it is important and pertinent to limit the morbidity of the procedure. Currently, RPLND for low-stage disease has an acceptably very low morbidity, which consists of about a 1% chance of developing a subsequent small bowel obstruction and a 3% to 5% chance of an abdominal incisional hernia.15 The operative procedure is approximately 2 to 2 hours in length. Transfusions are not required and the average hospitalization is about 3.3 days. Return to full physical activity occurs in three to 6 weeks depending on age of the patient and body habitus. TECHNIQUE FOR LOW-STAGE DISEASE In low-stage nonseminoma mapping studies have shown that metastatic spread is unilateral.16 Hence, for a patient presenting with a right-sided primary, the involved lymphatics are usually interaortocaval, precaval, and right paracaval (Figure 38-1). Similarly, for a left-sided primary, the involved lymphatics are typically left paraaortic and preaortic (Figure 38-2). Though historically full bilateral RPLND was performed (Figure 38-3), these mapping studies illuminated the fact that a unilateral template could be used. This was important since a unilateral template dissection preserved contralateral sympathetics important for emission and ejaculation. These so-called modified templates preserved ejaculation at the 30% to 90% level, depending on individual technique.7,8 In order to further minimize morbidity, it was necessary to improve the technique to maintain emission and ejaculation at a higher level. These modifications were termed nerve sparing since nerve-sparing RPLND involves the prospective dissection of efferent sympathetic fibers followed by removal of lymphatics based on a unilateral template (Figure 38-4).17,18 Thus, nerve-sparing RPLND preserves sympathetic nerves bilaterally whereas a template dissection preserves only contralateral nerves. The prospective dissection and preservation of efferent sympathetic fibers maintains emission and ejaculation at the 99% level. Right Nerve-Sparing RPLND A midline incision is made and a self-retaining retractor is used. A general palpation and inspection of the abdomen is performed and in the rare circumstance of

Figure 38-1 The template of dissection for a patient presenting for a right-sided primary is displayed.

discovery of higher-volume metastasis than was predicted by preoperative scans, a full bilateral dissection may be required. Currently, CT scans are high resolution and the intraoperative discovery of unsuspected high-volume metastasis is rare. After palpation and inspection an incision is made in the posterior peritoneum from the cecum to the area of the ligament of Treitz. The root of the small bowel and the right colon are reflected to the patient’s right and held in place with self-retaining retractors. The template of dissection includes the interaortocaval, precaval, and right paracaval lymph nodes. The so-called “split and roll” maneuver is employed. This is essentially a vascular isolation technique whereby lymphatic tissue is split at the 12 o’clock position over vessels and rolled laterally away from those vessels. RPLND is a vascular procedure. First, the split maneuver is performed over the left renal vein and tissue is rolled inferiorly. The anterior aspect of the aorta is identified posterior to the left renal vein and the split maneuver is carried out on the 12 o’clock position of the aorta from the crossing of the left renal vein

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Figure 38-2 The template of dissection for a left-sided primary is displayed.

distally to the origin of the inferior mesenteric artery. Tissue is rolled medially into the interaortocaval zone in order to determine whether or not a lower pole rightsided precaval renal artery is present. Attention is then turned to the vena cava. The split maneuver is performed at the 12 o’clock position on the vena cava (Figure 38-5). The origin of the right gonadal vein is identified and divided between silk ties. It is subsequently dissected to the internal ring at which point the cord stump from the radical orchiectomy is identified, mobilized from the internal ring, and the specimen is removed as right gonadal vein. The roll maneuver is then performed on the vena cava after which all lumbar veins passing posteriorly from the cava to the posterior body wall are identified and divided between silk ties (Figure 38-6). Typically, the efferent sympathetic fibers from the right sympathetic chain pass cephalad to these lumbar veins. Care must be taken to not injure the nerves in the course of dividing the veins. The nerves are then dissected away from lymphatic tissue and placed in vessel loops. Typically, the right-sided nerves coalesce in the interaor-

Figure 38-3 Full bilateral RPLND includes the removal of right paracaval, interaortocaval, left peri-aortic, and interiliac nodal packages.

tocaval area and then pass distally into the interiliac area at the bifurcation of the aorta. Attention is then turned back to the aorta at which point the split maneuver is continued along the distal aorta and right common iliac artery. The nerves have been previously dissected and therefore are avoided in the process of this split maneuver. Tissue is rolled medially into the interaortocaval area and the right-sided lumbar arteries are divided between ties. The renal artery is typically seen passing over the crus of the diaphragm and lymphatic tissue, is dissected away from it. Finally, the right ureter is dissected laterally away from lymphatic tissue after which the right paracaval and interaortocaval nodal packages are dissected from the posterior body wall (Figure 38-7). Clips are used as necessary to secure lymphatics or to gain hemostasis from the lumbars as they penetrate the posterior body wall. Cautery is also helpful in this regard. After irrigation the posterior peritoneum is closed. Closure of the abdominal incision is performed using a looped absorbable suture.


Figure 38-5 Viewed from the patient’s left side, the split maneuver on the superior portion of the aorta and the vena cava as performed for a right modified nerve-sparing RPLND is displayed.

Technique for Left-Sided Nerve-Sparing RPLND

Figure 38-4 The anatomy of retroperitoneal sympathetic nerves in relationship to the vascular structures is shown.

For a left-sided dissection, after palpation and inspection has been performed, an incision is made in the posterior peritoneum lateral to the left colon. The left colon is mobilized medially and held in place with self-retaining retractors. The first step in a left-sided dissection is to identify the efferent sympathetic fibers. Typically, these can be seen coursing anterior to the left common iliac artery and can be dissected away from lymphatic tissue and placed in vessel loops (Figure 38-8). If these fibers are not easily seen at this level an alternative approach is to mobilize the left ureter laterally and roll lymphatic tissue off the psoas muscle to expose the sympathetic chain. The efferent fibers can then be seen passing from the sympathetic chain to the interiliac area. After the nerve

Figure 38-6 Mobilization of the vena cava is performed by rolling lymphatic tissue away from the vena cava, identifying the lumbar veins and subsequently dividing them. The three lumbar veins passing to the posterior body wall are shown in the figure prior to division.

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Figure 38-7 In a completed right modified nerve-sparing RPLND all lymphatic tissue is removed in the interaortocaval and right para-caval packages. Shown in the figure are the mobilized vena cava, the sympathetic chain, and the efferent sympathetic fibers in vessel loops.

Figure 38-9 The lymphatic tissue has been rolled away from the left side of the aorta. Two lumbar arteries passing posteriorly are seen. A silk tie has been passed around one in preparation for subsequent ligation distally and division of the lumbar artery.

fibers are identified they are dissected slightly proximally. In a left-sided dissection, the lymphatics intermingle with the efferent fibers and the dissection is technically slightly more difficult because of this. The split maneuver is performed over the left renal vein and tissue is rolled inferiorly. The origin of the left gonadal vein is identified, dissected, and divided between silk ties. The left gonadal vein is then dissected to the internal ring at which point the cord stump is mobilized from the internal ring and the left gonadal vein specimen is removed.

Next, the split maneuver is performed on the aorta from the crossing of the left renal vein distally to the bifurcation of the left common iliac artery. The bifurcation of the left common iliac represents the lower boundary of the dissection. Tissue is rolled into the left paraaortic area and the left-sided lumbar arteries are identified, dissected, and divided between silk ties (Figure 38-9). Care must be taken to determine whether or not lower pole renal arteries exist and these should be preserved if possible. The ureter is dissected laterally away

Figure 38-8 In this figure the anatomy of left-sided sympathetic efferent fibers is shown. Note the confluence of the fibers anterior to the left common iliac artery. Right-sided fibers join the left-sided fibers in the inter-iliac area.


from the lymphatic tissue and this represents the lateral boundary of the dissection. Finally, lymphatic tissue is dissected off the posterior body wall as one package taking care to avoid the sympathetic chain and the efferent sympathetic fibers passing into the interiliac area. At the renal hilum lymphatic tissue is dissected away from the renal artery and clips are applied at the crus of the diaphragm. The left colon is then placed back in the anatomic position and the abdomen is closed as noted earlier with a running, looped absorbable suture. POSTOPERATIVE MANAGEMENT Historically, nasogastric tubes were used because of the suspicion of the postoperative paralytic ileus. Currently, no postoperative nasogastric decompression is necessary. Patients are given liquids the day after the procedure and subsequently are advanced to full diet. The average hospitalization for this procedure is around 3 days and return to full physical activity is three to 6 weeks. Patients are followed postoperatively with chest x-rays, physical examination, and determination of serum alpha-fetoprotein and beta-hCG. This monitoring typically is performed for 2 years. The frequency of these examinations is contingent on the pathologic stage. CT scans of the abdomen are not necessary postoperatively.

POSTCHEMOTHERAPY RETROPERITONEAL LYMPH NODE DISSECTION Indications Patients who present with high volume distant metastatic germ cell cancer are typically managed with systemic chemotherapy. After the administration of systemic chemotherapy, if serum alpha-fetoprotein and beta-hCG have normalized and no evidence of metastatic tumor remains on radiographic imaging, patients are observed. The probability of relapse in this clinical situation is low and hence observation is reasonable. Some centers advocate postchemotherapy RPLND in the absence of persistent radiographic tumor if the transverse diameter of disease in the retroperitoneum before chemotherapy was >3 cm.19 However, the practice at Indiana University is to observe patients with a complete clinical remission.20 If patients normalize serum markers and have persistent tumor on radiographic imaging in the retroperitoneum, postchemotherapy RPLND is advised (Figure 38-10). Histologically, remaining tumor consists of teratoma in 40% to 60% of cases, fibrosis and necrosis in approximately 40% of cases, and persistent germ cell cancer (or nongerm cell cancer arising in a teratoma) in 5% to 10% of cases. The surgical removal of teratoma or cancer is therapeutic and hence the rationale for RPLND in these clinical situations is solid. However, the surgical

Figure 38-10 CT scan performed after chemotherapy in a patient with normal alpha fetoprotein and beta-hCG. Pathologically the resected tumor proved to be teratoma.

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removal of necrosis confers no survival advantage on the patient and it would be desirable to select such patients preoperatively so as to avoid postchemotherapy RPLND. It is very difficult to clinically select for patients who have only necrosis and therefore RPLND is advised for any persistent mass. Exceptions to this rule include those patients with pure seminoma managed with systemic chemotherapy and some highly selected patients with no teratoma in the orchiectomy specimen who experience a dramatic response to systemic chemotherapy. However, controversy exists in the management of the postchemotherapy mass in pure seminoma patients. Some advocate resection of the mass if it is >3 cm in transverse diameter; at Indiana University these patients are observed because of the high probability of the mass containing fibrosis only.21,22 Rarely, postchemotherapy RPLND is recommended in patients who have not experienced a normalization of serum AFP or HCG. These are very highly selected patients who have failed all systemic chemotherapy but have a persistent retroperitoneal mass. Since beta-HCG and/or alpha fetoprotein are elevated, germ cell cancer remains within the mass. Postchemotherapy RPLND in this situation is termed “desperation RPLND” but is capable of curing such patients around 30% of the time.23 It is truly remarkable that in this situation of chemo refractory metastatic disease surgery remains a therapeutic option. Testis cancer is a unique and interesting disease. TECHNIQUE OF POSTCHEMOTHERAPY RPLND Generally, postchemotherapy RPLND is a full bilateral dissection, which includes the resection of tumor and lymphatics from the crus of the diaphragm to the bifurcation of the common iliac arteries, from ureter to ureter. The reasoning behind performing a full bilateral dissection is that mapping studies showed that the higher volume of metastasis, the greater the likelihood of bilateral retroperitoneal disease. It is clear, however, that highly selected patients do not require full bilateral RPLND and that the likelihood of bilateral disease in some patients is very low. Typically, these are patients who have been administered so-called good risk chemotherapy and initially presented with relatively low volume metastatic disease to the retroperitoneum. However, generally, full bilateral RPLND is recommended. The type incision is contingent on the position and size of the tumor. Depending on the individual patient, a midline, chevron, supra 11th extra pleural approach, or thoracoabdominal approach may be used. The same techniques employed in low-stage disease are used in postchemotherapy RPLND. These techniques include the split and roll technique and in highly selected patients, nerve sparing. However, in postchemotherapy RPLND

there is commonly a fibrotic and desmoplastic reaction in the retroperitoneum that makes tumor and lymphatics quite adherent to surrounding structures, such as the aorta, the vena cava, and the renal arteries and veins. Dissection along the great vessels should be in an extra adventitial plane so as to not weaken these vessels, which can lead to significant vascular problems. Surgeons who undertake postchemotherapy RPLND should be well versed in techniques of vascular control and repair, as this essentially is a vascular procedure. The “subtraction” technique was initially described by Donohue. This technique employs the prospective dissection of the vessels away from tumor followed by resection of tumor and lymphatics from the posterior body wall (Figure 38-11). Hence, after the incision is made, the retroperitoneum is exposed by incising in the posterior peritoneum from the foramen of Winslow distally around the cecum up to the area of the inferior mesenteric vein. The inferior mesenteric vein is divided and the right colon and root of the small bowel is dissected off the retroperitoneum and retracted onto the patient’s chest with a self-retaining retractor. Typically, tumor does not invade the mesentery but sometimes may invade the duodenum, which requires resection of duodenum and subsequent repair. Fortunately, invasion of the duodenum is relatively rare and typically the bowel is easily dissected onto the patient’s chest. The split maneuver is then performed on the left renal vein and tissue is rolled inferiorly. The anterior aspect of the aorta is identified and the split maneuver is performed on the aorta at the 12 o’clock position from the crossing of the left renal vein distally to the origin in the inferior mesenteric artery. For full bilateral dissection the inferior mesenteric artery is typically dissected and divided between silk

Figure 38-11 The subtraction concept involves the mobilization of great vessels away from retroperitoneal tumor and lymphatics with a subsequent resection of tumor and lymphatics from the posterior body wall. In this figure the aorta is being mobilized from tumor and lymphatics.


ties. This allows the left mesocolon to be retracted laterally. Because testis cancer is typically a disease of young men, the vascularity of the left colon is maintained through collaterals and colon ischemic has not occurred in these postchemotherapy patients. The dissection is then carried distally along the aorta and along both common iliac arteries. The split maneuver is continued and subsequently tissue is rolled medially and laterally off the aorta and the common iliac arteries. Lumbar arteries are subsequently identified and divided. Typically, three lumbar arteries exist on each side of the aorta and their position is fairly predictable. Superiorly, the left gonadal vein is divided from the left renal vein, and the left renal vein and left renal artery are dissected from lymphatics and tumorous tissue. Attention is then turned to the vena cava. A similar split maneuver at the 12 o’clock position is performed on the vena cava. The origin of the right gonadal vein is divided and subsequently tissue, tumor, and lymphatics are rolled medially and laterally from the vena cava. The lumbar veins are identified, dissected, and divided between ties. The position and size of the lumbar veins is not as predictable as arterial lumbar anatomy. Lymphatics and tumor are dissected from the right renal artery as it passes over the lower portion of the crus of the diaphragm. Similarly, the ureters are dissected laterally away from the lymphatics and tumorous tissue. The gonadal vein is removed along with the cord stump, depending on the laterality of the primary. Finally, as the vessels and ureters have been dissected away from the tumor and lymphatics, these lymphatic packages are dissected from the posterior body wall. Typically, in full bilateral RPLND there will be four packages: the right paracaval, interaortocaval, left para-aortic, and interiliac. The bowel is then placed back in anatomic position and secured in anatomic position with running absorbable sutures. The bowel is run to make sure there is no evidence of any retractor injury, after which closure of the abdomen is performed. SPECIAL CONSIDERATIONS Preoperatively, postchemotherapy RPLND patients are given informed consent indicating that intraoperative decisions may be necessary. The decision to resect adjacent organs, such as bowel or kidneys, requires intraoperative judgment.24 A decision to resect an adjacent organ depends on the amount of adherence to the tumor and also the clinical situation. For instance, the threshold for resecting an adjacent organ is much lower in desperation RPLND as opposed to straightforward RPLND performed for a patient with low volume tumor and normal markers. However, a partial removal of tumor is not therapeutic and surgeons performing RPLND should have the mind set to remove all palpable and visual tumor.

Figure 38-12 Postchemotherapy, full bilateral RPLND with bilateral nerve sparing. Such patients maintain emission and ejaculation and if recovery from chemotherapy is complete may maintain fertility.

Nerve sparing is possible in some patients who undergo postchemotherapy RPLND.25 Indeed, some of these patients may recover fertility after recovery from the effects of chemotherapy. Again, the decision to perform nerve sparing is dependent on the clinical situation and intraoperative findings (Figure 38-12). The complications of postchemotherapy RPLND are generally more significant and frequent compared to primary RPLND.26 The major source of postoperative morbidity relates to the lungs, as many of these patients have received bleomycin as a part of the chemotherapeutic regimen. Typically, an effort is made to restrict fluids perioperatively so that if bleomycininduced ARDS occurs the patient is not volume overloaded. Other complications of postchemotherapy RPLND include ileus, lymphatic or chylous ascites, and other complications associated with a major surgical procedure. Nasogastric tubes are used variably and the hospitalization is typically more lengthy compared to primary RPLND. SUMMARY Germ cell tumors of the testis are not only chemo sensitive but also surgery sensitive. For optimal care of a patient with germ cell cancer chemotherapeutic therapies and surgical techniques are complimentary. Surgeons who perform these procedures should be well versed in techniques of vascular mobilization and control. Finally, though some of these procedures may be time consuming and arduous providing, excellent long-term outcomes are possible after complete surgical removal of metastatic tumor.

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REFERENCES 1. Ulbright TM, Amin MB, Young RH: Tumors of the Testis, Adnexa, Spermatic Cord, and Scrotum. Washington, Armed Forces Institute of Pathology, 1999. 2. Thurnher S, Hricak H, Carroll PR, et al: Imaging the testis: comparison between MR staging and us. Radiology 1988; 167:633. 3. Hinman F: The operative treatment of tumors of the testicle with the report of thirty cases treated by orchiectomy. JAMA 1914; 63:2009. 4. Our scrotal violation paper. 5. Kristianslund S, Fossa SD, Kjellevold K: Bilateral malignant testicular germ cell cancer. Br J Urol 1986; 58:60. 6. Heidenreich A, Weissbach L, Holtl W, et al: Organ sparing surgery for malignant germ cell tumor of the testis. J Urol 2001; 166:2161. 7. Richie JP: Clinical stage I testicular cancer: the role of modified retroperitoneal lymphadenectomy. J Urol 1990; 144:1160. 8. Donohue JP, Thornhill JA, Foster RS, et al: Retroperitoneal lymphadenectomy for clinical stage A testis cancer (1965 to 1989): modifications of technique and impact on ejaculation. J Urol 1993; 149:237. 9. Nichols CR, Timmerman R, Foster RS, et al: Neoplasms of the testis in cancer medicine. Baltimore, Williams & Wilkins, 1997 10. Davis BE, Herr HW, Fair WR, et al: The management of the patients with nonseminomatous germ cell tumors of the testis with serologic disease only after orchiectomy. J Urol 1994; 152:111. 11. Saxman SB, Nichols CR, Foster RS, et al: The management of patients with clinical stage I nonseminomatous testicular tumors and persistently elevated serologic markers. J Urol 1996; 155:587. 12. Sharir S, Foster RS, Donohue JP, et al: What is the appropriate follow-up after treatment? Semin Urol Oncol 1996; 14:45. 13. Roeleveld TA, Horenblas S, Meinhardt W, et al: Surveillance can be the standard of cave for stage I nonseminomatous testicular tumors and even high risk patients. J Urol 2001; 166:2166.

14. Read G, Stenning SP, Cullen MH, et al: Medical research council prospective study of surveillance for stage I testicular teratoma. J Clin Oncol 1992; 10:1762. 15. Baniel J, Foster RS, Rowland RG, et al: Complications of primary retroperitoneal lymph node dissection. J Urol 1994; 152:424. 16. Donohue JP, Zachary J, Maynard B. Distribution of nodal metastases in nonseminomatous testis cancer. J Urol 1982; 128:315. 17. Jeweh MA, Kong YS, Goldberg SD, et al: Retroperitoneal lymphadenectomy for testis tumor with nerve sparing for ejaculation. J Urol 1988; 139:1220. 18. Donohue JP, Foster RS, Rowland RG, et al: Nervesparing retroperitoneal lymphadenectomy with preservation of ejaculation. J Urol 1990; 144:287. 19. Toner GC, Panicek DM, Heelan RT, et al: Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: recommendations for patient selection. J Clin Oncol 1990; 8:1683. 20. Debono DJ, Heilman DK, Einhorn LH, et al: Decision analysis for avoiding post chemotherapy surgery in patients with disseminated nonseminomatous germ cell tumors. J Clin Oncol 1997; 15:1455. 21. Motzer R, Bosl G, Heelan R, et al: Residual mass: an indication for further therapy in patients with advanced seminoma following systemic chemotherapy. J Clin Oncol 1987; 5:1064. 22. Schutlz SM, Einhorn LH, Conces DJ, et al: Management of post chemotherapy residual mass in patients with advanced seminoma: Indiana University experience. J Clin Oncol 1989; 7:1497. 23. Donohue JP, Leibovitch I, Foster RS, et al: Integration of surgery and systemic therapy: results and principles of integration. Semin Urol Oncol 1998; 16:65. 24. Our nephrectomy paper. 25. Wahle, GR, Foster RS, Bihrle R, et al: Nerve-sparing retroperitoneal lymphadenectomy after primary chemotherapy for metastatic testicular carcinoma. J Urol 1994; 152:428. 26. Baniel J, Foster RS, Rowland RG, et al: Complications of postchemotherapy retroperitoneal lymph node dissection. J Urol 1994; 152:424.

C H A P T E R

39 Retroperitoneal Tumors: Diagnosis, Staging, Surgery, Management, and Prognosis S. Bruce Malkowicz, MD, and Victor Ferlise, MD

Retroperitoneal tumors are uncommon lesions that are important to the urologist because they occur in our surgical domain and often involve urologic organs. These lesions often present as very large lesions, which have been relatively indolent. Because of their rarity (0.5% to 1.0% of adult malignancies) it is important to be aware of the systematized approach to the treatment of these tumors. Beyond the attempt to attain complete surgical resection, it is difficult to outline the optimal treatment scheme for these lesions since there are few large cohorts of patients treated in a similar fashion. Additionally, many clinical reports have a combination of extremity, as well as retroperitoneal lesions mixed together in the results. The clinical assessment of these lesions and the surgical approach to therapy is fairly well outlined and remains the foundation of treatment. Radiation therapy and chemotherapy for these lesions continue to evolve, although their overall efficacy in retroperitoneal lesions is unclear. Primary sarcomas of the genitourinary organs are even rarer than primary retroperitoneal sarcomas. When radical extirpation is possible, it is usually the appropriate option, although in some instances, such as bladder lesions, other choices do exist. The evaluation of adjuvant and salvage therapies for these lesions is limited. But overall frequently with these lesions it is required to reorganize and appropriately treat these lesions. PRIMARY RETROPERITONEAL SARCOMA Incidence and Etiology Retroperitoneal sarcomas are rare tumors that account for only 0.1% to 0.2% of all malignant tumors and approximately 10% to 20% of all soft tissue sarcomas.1

Less than one-half of all retroperitoneal tumors are retroperitoneal sarcomas. Generally, 15% to 20% of retroperitoneal tumors are benign (e.g., lipoma). The remainders comprise lymphomas or primary urologic tumors.2 Approximately 500 to 1000 new cases of retroperitoneal sarcoma are diagnosed each year. Incidence figures on specific genitourinary sarcomas are difficult to establish due to the rarity of such lesions.2,3 Retroperitoneal sarcomas arise most commonly in the 5th and 6th decade of life, but age incidence may span from the 2nd to 8th decades.3,4 There is a slight male predominance but no distinct ethnic or racial distribution. While any histologic pattern may be seen at any age, rhabdomyosarcoma generally clusters in younger patients, even excluding the pediatric population, and malignant fibrous histiocytoma is usually seen in older age groups. Generally, these lesions are not associated with other conditions and a pattern of familial transmission has not been demonstrated. However, rare patients with neurofibromatosis may develop malignant schwannomas at an anatomic site.5 There is little known of the etiology of retroperitoneal sarcomas. Radiation injury, prior trauma, and environmental exposure to agents, such as dioxin and asbestos, have been implicated.6,7 Radiation may predispose patients to the development of sarcomas. Approximately 0.1% of patients treated with radiation therapy who survive >5 years may develop a sarcoma at that site.8 To qualify as a postradiation sarcoma a lesion must meet specific established criteria.6 In these cases, the sarcoma has to develop within the radiated field and prior documentation stating that the area was normal must be established. Additionally, histologic confirmation of the diagnosis is necessary, and a latency of at least 3 years is 651

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required. There appears to be no difference in the incidence of postradiation-induced disease between those patients treated with orthovoltage and megavoltage. The most common postradiation tumor is the malignant fibrous histiocytomas (MFHs) followed by osteosarcoma and fibrosarcoma. Most of these postradiation-induced lesions appear to be of high grade and generally have poorer survival.8 Earlier epidemiologic studies reported that exposure to herbicides, such as dioxin and wood preservatives, may contribute to the development of retroperitoneal sarcomas.9 More recent data are mixed in its findings and may be affected by the particular herbicide used and the degree of dioxin contamination.10 In studies of Vietnam era soldiers exposed to Agent Orange, no significant association was found between the development of sarcomas and exposure in case control studies.11 In some industrial studies, an association was noted between dioxin exposure and the development of sarcomas if the exposure was prolonged (>1 year) and the period significant (over 20 years).12 No distinct viral or immunologic etiologies have been proposed for the development of retroperitoneal sarcomas. PATHOLOGY Retroperitoneal sarcomas arise primarily from soft tissues of fibrous and adipose origin, as well as muscle, nerve, and lymphatic tissues. These tissues are derived from primitive mesenchyme from the mesoderm with some contribution from neuroectoderm.13 Their location allows for a rather long indolent preclinical course at that time the tumor can grow to significant proportions. This growth may result in local areas of necrosis or liquefaction as the tumor outstrips its vascular supply. In classic reviews of these lesions the common tissue distribution in descending order is liposarcoma, leiomyosarcoma, and fibrosarcoma followed by other histologies.4,14–26 MFH figures much more prominently in contemporary series; however, owing to intensive pathologic interest in defining this disorder, many tumors previously described as variants of fibrosarcoma or liposarcoma have been reclassified as MFH.27,28 Therefore, fibrosarcoma has been replaced in frequency order by this condition. Although a well-developed understanding of the fundamental pathology of these lesions has not yet emerged, evaluation of the cytogenetic alterations in many sarcomas is beginning to suggest some molecular themes. Several of these tumors display specific chromosomal translocations. Although the translocations appear unique for specific tumors [t(12;16)(q13;p11) in myxoid liposarcoma] nearly all of these translocations result in the production of novel, tumor-specific, chimeric, transcription factors. These factors interact with the upstream regulatory component of a

gene and can significantly affect the expression of that gene at the messenger RNA level. The nucleic acid binding domain of the chimeric transcription factor confers target specificity within the tissue genome, while the transcription factor portion of this novel protein determines the transactivation potential and expression level of the target gene.29–31 Additionally, the development of extra abnormal chromosomes (ring chromosomes and giant rods) involving chromosome 12 can result in the amplification of certain gene products, such as MDM2 and SAS. MDM2 can be involved in p53 inactivation that can contribute to carcinogenesis32,33 Additionally, alterations in cell cycle regulating elements, such as CDK4, have been demonstrated.34 Novel these insights into sarcoma pathology may provide approaches for future therapeutic strategies directed at these lesions. Benign Lesions Lipomas Lipomas consist almost entirely of mature fat and are uncommonly found in the retroperitoneum (Table 39-1). They are probably the most common soft tissue tumor in man. Most of these lesions occur superficially but they may occur in other areas, such as the retroperitoneum. Deep lipomas within the retroperitoneum are usually not as well circumscribed as their superficial counterparts and can conform to irregular spaces in this body space.35,36 The adipocytes are normal or slightly larger in appearance and have a well-developed vascular network. There is very little in the way of nuclear irregularity. Differing levels of fibrous connective tissue can be found in these lesions. The rim of the lipocyte is reactive for S100 protein. While the majority of these masses are idiopathic in nature, they can occasionally be a manifestation of steroid lipomatosis. Pelvic lipomatosis while not a distinct tumor per se was first described in 1959 as an overgrowth of fat in the perivesical and perirectal area. It is a hyperplastic rather

Table 39-1 Benign Lesions of the Retroperitoneum Lipoma Pelvic lipomatosis Myelolipoma Leiomyoma Ganglioneuroma Hemangiopericytoma Schwannoma

Chapter 39 Retroperitoneal Tumors 653

neoplastic entity which can create a space occupying lesion. Approximately two-thirds of patients are AfricanAmerican and women are rarely affected.37 The growth is diffused rather than nodular and often it is difficult to distinguish it from normal adipose tissue. The condition may be associated with cystitis glandularis.38 The general clinical course is slowly progressive and may result in the need for urinary diversion.39 Occasionally fat necrosis in these lesions can be mistaken for sarcomatous degeneration.40 Myelolipoma This is a tumor-like growth of mature fat and bone marrow elements. Although it usually occurs in the adrenal gland, it can be seen as an isolated pelvic lesion.41,42 It is distinct from extra-medullary hematopoietic tumors which are usually multiple and generally associated with mild proliferative diseases and skeletal disorders. These generally occur in patients older than 40 years of age and are rarely >5 cm in size.43 They are usually found as incidental imaging findings. The adrenal gland can create inferior renal displacement due to radiolucent mass. Pathologically, it may display the features of a lipoma or have a darker appearance if myeloid elements predominate. Adrenal myelolipoma development may be secondary to prolonged stress and excessive stimulation with adrenocorticotropic hormones.

rate of metastasis depends on the degree of tumor differentiation, with nearly 90% of poorly differentiated tumors metastasizing.46–48 Significant advances in cytogenetics has allowed the reclassification of these lesions on a molecular basis (Table 39-2). Well-differentiated and dedifferentiated

Table 39-2 Malignant Lesions of the Retroperitoneum and Histologic Subclassifications Liposarcoma Myxoid liposarcoma Well differentiated Lipoma-like Inflammatory Sclerosing Differentiated Round cell Pleomorphic Leiomyosarcoma Malignant fibrous histiocytoma (MFH)

Leiomyoma These, generally rare lesions, are seen in a distribution that represents smooth muscle tissue in the body. They are overwhelmingly found in the female genital tract but have also been reported in the urinary bladder. There are occasional reports of these tumors in the retroperitoneum, where they can grow asymptomatically to a considerable size. Leiomyomas stain positive for desmin, which separates them from their malignant counterpart. Extension of these lesions from the uterus into the vascular system can create tumor thrombi not unlike those seen with renal lesions.44 Malignant Lesions Liposarcoma Liposarcomas are among the most common of primary retroperitoneal tumors that are often distinguished by their large dimensions and range of subtypes. These lesions are found with their peak incidence between ages 40 and 60.45 They account for 10% to 15% of sarcomas and approximately 20% of these lesions arise in the retroperitoneum. One unfortunate clinical feature of these lesions is their great tendency to recur often within the first 6 months after surgery. The principal tissue type is usually recapitulated at the time of recurrence. The

Storiform-pleomorphic Myxoid MFH MFH-giant cell type Inflammatory MFH Fibrosarcoma Rhabdomyosarcoma Embryonal Botryoid Alveolar Pleomorphic Spindle cell Malignant hemangiopericytoma Malignant peripheral nerve sheath tumors (malignant schwannoma) Synovial sarcoma Angio sarcoma

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lesions are a continuum of lesions based on the genetic abnormality of giant and ring chromosomes usually involving chromosome 12. Gene amplification, particularly MDM2 drives their pathology.49,50 Myxoid and round cell, cell lesions (poorly differentiated myxoid) are another continuum, which have fusion transcripts caused by translocations in chromosomes 16 and 12 as their principle pathologic feature. Pleomorphic liposarcomas are rare and poorly understood.51 Unlike benign lipomas, liposarcomas may bear little resemblance to classic fat filled structures. The gross lesion is usually described as having a “fish flesh” appearance, and while generally encapsulated, it can often display invasive characteristics. Besides the retroperitoneum, these lesions arise in the deep soft tissues of the proximal extremities. They generally present as very large lesions when originating from the retroperitoneum. Myxoid liposarcoma is the most common liposarcoma usually occurring in the lower extremity. It accounts for 50% of sarcomas and represents a large proportion of retroperitoneal lesions. Its peak presentation is in the fifth decade. They display a background of stellate mesenchymal cells, and a prominent capillary pattern often described as a “chicken wire” (Figure 39-1). The distinct cell is the lipoblast that is similar to the fetal adipocyte. These cells are noted by a lipid vacuole that scallops the nucleus. This creates the lipoma-like appearance of these

lesions (Figure 39-2). These lesions have as their common pathology fusion proteins as mentioned previously. Higher-grade lesions tend to demonstrate a higher number of p53 mutations.52 The round cell subtype is also referred to as a lipoblastic variant and is distinguished by sheets of round cells with lipoblastic differentiation. These lesions are considered the most aggressive part of the spectrum of myxoid lesions. Well-differentiated liposarcomas mostly resemble lipomas and are usually designated as low grade. They are a common sarcoma of later life. Subvariants include the lipoma like, inflammatory, sclerosing, and differentiated. The first 3 variants are often confused with benign processes, such as scarring or inflammation, while the differentiated subtype is often noted in long-standing retroperitoneal lesions and considered higher grade. Generally, these lesions are now considered as a group with dedifferentiated lesions since they share genetic similarities. Pleomorphic liposarcoma comprises 10% to 15% of liposarcomas and are defined as a high-grade malignant variant with very bizarre nuclei and huge lipoblasts. Leiomyosarcoma This tumor accounts for 5 mitoses per high power field) present in the specimen. Again, a continuum exists in the pathologic progression of these smooth muscle lesions; therefore, the cut point between benign, moderate and high grade may sometimes be arbitrary. There is little evidence of sarcomatous degeneration from benign leiomyomas. The characteristic pathologic finding of a leiomyosarcoma is malignant spindle cells with “cigar”-shaped nuclei. The muscle fascicles interweave. These tumors immunohistochemically stain for smooth muscle myosin, vimentin, actin, and less often for desmin. They stain negative for S-100. Ultrastructural features include bundles of thin cyto-filaments that can help distinguish leiomyosarcomas from other lesions. The rare retroperitoneal variants of these tumors are leiomyosarcomas, which originate from the great vessels.54 These occur predominantly in women. Tumors of the iliac

vessels usually present with lower extremity edema, while those of the inferior vena cava can display findings consistent with Budd-Chiari syndrome.55 Resection of these lesions is recommended when anatomically feasible. Survival, however, is usually 4 mitoses per 10 HPF have a worse prognosis.64,65

there is usually a lag time of 5 months from initial symptoms to diagnosis. The principle clinical finding is abdominal mass and abdominal pain (60% to 80%).1 Many patients also experience nausea and vomiting and weight loss (20% to 30%). Neurologic findings are noted in 30% of patients.66 Lower extremity edema is seen in 17% to 20% of patients, while urinary symptoms are surprisingly rare, seen in 3% to 5% of patients in most series. Physical examination will generally demonstrate a protuberant abdomen that may be accompanied by an appearance of extremity wasting. Peripheral or inguinal adenopathy may be present although lymphadenopathy is not usually associated with these tumors ( 5 cm in greatest diameter

T2a

Superficial tumor

T2b

Deep tumor

Regional lymph node involvement N0

No known metastasis

N1

Verified metastases to lymph nodes

Distant metastasis M0

No known distant metastasis

M1

Known distant metastasis

Stage grouping Stage 1A

Low grade, small (G1-2, T1a or b, N0, M0)

Stage 1B

Low grade, large, superficial (G1-2, T2a, N0, M0)

Stage IIA

Low grade, large, deep (G1-2, T2b, N0, M0)

Stage IIB

High grade, small (G3-4, T1b.N0, M0)

Stage IIC

High grade, large, superficial G3-4, T2a, N0, M0

Stage III

High grade, large, deep G3-4, T2b, N0, M0

Stage IV

Nodal or distant metastases Any G, any T, N1, M0 or any G, any T, any N, M1 Continued

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Table 39-3—cont’d DEFINITIONS Clinical Pathologic ■

■

Primary Tumor (T) TX Primary tumor cannot be assessed

■

■

T0

No evidence of primary tumor

■

■

T1

Tumor 5 cm or less in greatest dimension

■

■

T1a superficial tumor(1)

■

■

T1b deep tumor

■

■

T2

■

■

T2a superficial tumor(1)

■

■

T2b deep tumor

Notes 1. Superficial tumor is located exclusively above the superficial fascia without invasion of the fascia; deep tumor is located either exclusively beneath the superficial fascia, superficial to the fascia with invasion of or through the fascia, or both superficial yet beneath the fascia. Retroperitoneal, mediastinal, and pelvic sarcomas are classified as deep tumors. 2. Ewing’s sarcoma is classified as G4.

Tumor more than 5 cm in greatest dimension

Regional lymph nodes (N) ■

■

NX Regional lymph nodes cannot be assessed

■

■

N0


■

■

N1

Regional lymph node metastasis

Distant metastasis (M) ■

■

MX Distant metastasis cannot be assessed

■

■

M0

No distant metastasis

■

■

M1

Distant metastasis Biopsy of metastatic site performed

■

Y

■

N

Source of pathologic metastatic specimen __________________ Stage Grouping ■

■

■

■

I

II

T1a

N0

M0

G1-2

G1

Low

T1b

N0

M0

G1-2

G1

Low

T2a

N0

M0

G1-2

G1

Low

T2b

N0

M0

G1-2

G1

Low

T1a

N0

M0

G3-4

G2-3

High

T1b

N0

M0

G3-4

G2-3

High

T2a

N0

M0

G3-4

G2-3

High

G2-3

High

■

■

III

T2b

N0

M0

G3-4

■

■

IV

Any T

N1

M0

Any G Any G

High or low

Any T

N0

M1

Any G Any G

High or low


Table 39-3—cont’d Histologic Grade (G)

Notes

■

GX

Grade cannot be assessed

Additional Descriptors

■

G1

Well differentiated

Lymphatic vessel invasion (L)

■

G2

Moderately differentiated

■

G3

Poorly differentiated

■

G4

Poorly differentiated or undifferentiated (four-tiered systems only)(2)

LX Lymphatic vessel invasion cannot be assessed L0 No lymphatic vessel invasion L1 Lymphatic vessel invasion Venous Invasion (V) VX V0 V1 V2

Residual Tumor (R) ■

RX

Presence of residual tumor cannot be assessed

■

R0

No residual tumor

■

R1

Microscopic residual tumor

■

R2

Macroscopic residual tumor

Venous invasion cannot be assessed No venous invasion Microscopic venous invasion Macroscopic venous invasion

Table 39-4 Pooled Data on Complete Versus Partial Resection Series

No. of Patients

Resection (No. %) Complete

Mean Survival (Months)

Partial

Complete

Partial

Complete Resection 5–Yr Survival (%)

Dalton et al.19

116

63/54

25/21

72

13

54

Jacques et al.20

86

43/50

34/39.5

65

28

74

McGrath et al.18

47

18/38

18/38

120

24

70

Glenn et al.22

50

37/74

8/16

40

—

38

Karakouis et al.24

68

27/40

7/10

84

48

64

Kilkeny et al.26

63

49/78

10/16

41

9

48

Zornig et al.23

51

30/59

21/41

60

—

35

267/55.5

123/25.6

70.3

24.4

TOTAL

481

sectable. It has also been suggested that the lateral incision of the peritoneum into the deep body wall is important to explore on a level posterior to the spinous processes (see Figure 39-5). If the operator’s fingers can be bi-manually palpated, this sarcoma is considered resectable. It is imperative in the preoperative period that both the patient and the surgeon realize the potential need for en bloc resection of affected organs. This can include vascular structures, as well as the kidney, portion of the diaphragm, liver, stomach, gall bladder, spleen, pancreas, and gut. In review of several series, up to 68% of operations required resection of an adjacent organ to insure

54.7

adequate negative margins. The most frequently resected organs are listed in decreasing order in (Table 39-5). A recent review reported that 20% of patients undergoing surgery for a retroperitoneal sarcoma required nephrectomy. The majority of them (72%) underwent this during their initial resection. The usual reason for nephrectomy was total encasement of the organ, followed by dense adherence to the kidney, and less often direct invasion of the renal unit.85 While a Dacron graft can be employed to replace a portion of resected aorta, there is debate among surgeons with regard to the need for venous reconstruction. Many feel that the venous collaterals that develop secondary to vena caval compression

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Part VI Testis

Determination of resectability Operative maneuvers

1 2 IVC A o 2

Psoas major muscle Quadratus lumbarum muscle Vertebra

Spinal cord

Figure 39-5 Transabdominal approach to determine resectability of a primary retroperitoneal sarcoma. Pertinent maneuvers consist of intraabdominal assessment of visceral and vascular contents and retroperitoneal assessment of attachment to musculoskeletal and spinous structures.

Table 39-5 Organs Sacrificed During Complete Resection of Sarcoma Organ

Frequency of Resection (%)

Kidney

32–46

Colon

25

Adrenal gland

18

Pancreas

15

Spleen

10

are adequate to allow for appropriate drainage from otherwise vascularly compromised organs. When bowel viability is questionable, it should be resected if possible. Although many visceral organs can be resected, unresectability is usually denoted by sarcomatosis, nerve root involvement, pelvic sidewall involvement, malignant ascites, or the presence of distant metastasis.1,21 When defining the operative field it is often necessary to release multiple intraabdominal adhesions. This must be performed meticulously since an enterotomy and subsequent fistula formation can cause major morbidity. Tactile, as well as visual perceptions, aids in avoiding violation of the bowel. In addition, the use of sharp curved Mayo scissors rather than Metzenbaum scissors may aid in avoiding this complication. During the dissection of a large tumor mass, it is often necessary to shift the location of the dissection when one particular area becomes difficult due to concerns of a clear margin or the potential for vascular damage. A centripetal dissection allows

one to dissect those areas that are amenable to dissection, and which in turn may free up a previously more constrained area of the operative field.86 Morbidity and mortality rates for contemporary surgical series are acceptable. An operative mortality of 2% to 7% with morbidity rates of 6% to 25% is the norm. Hemorrhage, intra-abdominal abscess, and enterocutaneous fistula are the most commonly described complications. Another surgical technique is the modified thoracoabdominal approach, which has been developed and popularized by Skinner. Those familiar with the technique feel that it allows maximum exposure to the posterior retroperitoneum, which is often a difficult area to assess through a midline incision. Additionally, it provides access and control to the ipsilateral great vessels above the diaphragm. Whether a left- or right-sided procedure is performed, excellent exposure can be developed in the contralateral retroperitoneal region without difficulty. A technique described here is a summary of Skinner’s approach.87 With the thoracoabdominal approach, patient positioning is critical. The patient is not placed in a “pure flank” position, similar to that used in stone surgery. Rather, a modified flank position is employed. The contralateral leg is flexed 90 degrees, and the hip is flexed approximately 30 degrees. The ipsilateral shoulder and chest is placed 20 degrees off the horizontal with the arm brought across the chest and placed in an adjustable armrest. The pelvis is at most rotated 10 degrees off the horizontal, and this position is maintained with a role sheet. The table is fully hyperextended with the break located above the iliac crest. The patient is secured with wide adhesive tape, and the ipsilateral leg is supported on a pillow. A mid-axillary incision is carried in the mid-axillary line from the 8th, 9th, or 10th rib. The height of this incision is based on the size of the primary lesion. It extends over the rib and costochondral junction into the epigastrium and then proceeds inferiorly as a midline incision into the pelvis. The rib is resected subperiosteally and the costochondral junction is divided. The rectus muscle is divided and retracted laterally. In most instances, the peritoneum will be opened, and the bowel contents mobilized superiorly. This mobilization is based on the superior mesenteric artery pedicle. It is important that this artery be identified initially, and care is taken not to traumatize it. In many instances, the inferior mesenteric artery may have to be resected. Most care should be taken to maintain the marginal artery. In most instances, a large bowel section will be avoided, yet if there is a question of viability at the end of the case, any suspect area of bowel should be resected. Vena cava obstruction may be associated with any right-sided lesions, and if this is the case, it is usually best to resect the vena cava en bloc with removal of the tumor. Often, a right nephrectomy


may also be required. If this maneuver is performed, it is best to maintain vascular connection between the vena cava and left renal vein to decrease the possibility of acute or long-term renal insufficiency. In general, the aorta can be dissected free of large retroperitoneal tumors but rarely may require replacement with a Dacron graft. During dissection or mobilization of the great vessels, care must be taken to control the lumbar vessels with ligation and division to avoid problematic bleeding. While the distal vessels may be controlled with hemoclips, it is appropriate to ligate the lumbar vessel at its origin on its great vessel. In the case of significant bleeding, the vessel tear can be controlled with the use of a Judd or Allis clamp. While the possibility of spinal devascularization exists, it is very uncommon due to the significant collateral blood supply to the spine from the artery of the Adamkiewicz. In younger patients, the potential for ejaculatory dysfunction is significant. SURGICAL OUTCOME The classic overall survival for patients presenting with retroperitoneal sarcomas is poor. In a multiinstitutional review, the 2-, 5-, and 10-year mean survivals for patients with this disease were 56%, 34%, and 18%, respectively.21 Recent series suggest 2-year survivals of over 70% and 5-year survivals of 50% to 60% in patients without metastases.88,89 The effective surgical management of retroperitoneal tumors has been limited by their size at presentation that often results in secondary organ involvement. This has a poor impact on the ability to achieve negative surgical margins even with the resection of adjacent organs. Historically, a complete surgical resection with negative margins was achieved in 50% to 60% of patients. The more recent series demonstrate complete resection rates in the 60% to 80% range, which may be due to improvements in imaging, preoperative planning, and surgical technique. Those patients who achieve a complete resection display superior survival to those patients with incomplete resection of their tumors (see Table 39-4). This is also supported in laboratory models.90 In an analysis of microscopic margins, however, positive margins at this level of pathologic resolution had little impact on recurrence-free survival.91 On the average, the 5-year survival of patients with completely resected tumors is 54% compared to 17% for incomplete resections at 10 years, this difference is 45% to 17%. Thus, a nearly 40% survival advantage is seen at 5 to 10 years in those patients with complete surgical resection of their lesion (Figure 39-6). Tumor recurrence after complete surgical resection, however, is significant. There is a 72% chance of local recurrence at 5 years and a 90% chance of recurrence at 10 years in most series. These data imply fairly poor survival at 15 years.21

Proportion Surviving 1.0 81

0.8

54

0.6

45 0.4

34 17

0.2

8

0.0 0

2 Complete Resection

5 Years

10 Incomplete Resection

Figure 39-6 Patient survival as a function of completeness of the surgical resection. The data represent x complete resections and y incomplete resections from collected series.

Reoperative surgery for the treatment of recurrent retroperitoneal sarcoma can be of value. Over 60% of patients may be experienced a complete resection.88 In one series, 30 patients with a previous complete resection of the primary lesion experienced local tumor recurrence at a mean interval of 23 months. Sixty percent of these patients were rendered free of disease after reoperative surgery. To accomplish this, 33% of these patients required the resection of adjacent viscera. Those patients who achieved a complete resection with a second operation had a 33-month median survival compared to a 14month median survival in those patients who did not experience a second complete resection.92 The role of subtotal resection has never been clearly established, yet some data suggest that this may have some positive value compared to palliative or debulking surgery. The argument for the possible value of incomplete resection has been made the management of liposarcomas. In a series of 55 patients, 75% received symptom relief from their surgery and partial resection compared with biopsy or exploration alone had a significant impact on increased survival (26 months versus 4 months).93 In another report, 22 patients with complete resection of tumor displayed a similar median survival to 15 patients with subtotal resection (median survival >120 months) compared to those only having a partial palliative resection or exploration (12 to 20 months).94 An aggressive surgical approach in cases where near complete resection can be obtained has also been advocated by others.24 There is no set protocol for the postoperative monitoring of patients with primary retroperitoneal sarcoma, but recommendations can be made given the rapidity of recurrence, the advantage of reresection, and the lethality of this condition. It would be appropriate to perform an abdominal CT scan, chest x-ray, and biochemistry profile with complete blood count (CBC) every 6 months. A

664

Part VI Testis

Proportion Surviving 1.0 83 0.8

74

0.6 54

42

0.4 24

0.2

11

0.0 0

2 G 2,3 Tumors

5 Years

10 G 1 Tumors

Figure 39-7 Patients’ survival as a function of tumor grade in cases of primary retroperitoneal sarcoma. The data represent 50 low-grade and 80 high-grade tumors from collected series.

series. It is associated with a lower rate of local recurrences and fewer GI complications, yet peripheral neuropathies are more frequent, and it is difficult to demonstrate a survival advantage with its use.100–104 Combined modality therapy with external beam and radiation with surgery and IORT (15 Gy) is being explored. It appears that such intensive regimens are tolerable up to 50.4 Gy of EBRT.105 Additionally, the use of brachytherapy postoperatively in primary or recurrent disease has been explored using different techniques up to 32 Gy.106,107 These techniques are feasible yet significant side effects can be encountered when they are applied to the upper abdomen. Newer radiation delivery techniques, such as intensity modulated radiation therapy (IMRT), are being explored for the treatment of these lesions.108,109 CHEMOTHERAPY

lengthening of this follow-up interval should be considered only after 5 years. Data support the concept that close follow-up allows for early detection less bulky recurrences that allow for more successful salvage surgery.95 The effect of tumor grade on patient survival cannot be underestimated. Low-grade lesions display a 50% survival advantage over intermediate- and high-grade lesions at 5 years (74% to 24%) and a 30% survival at 10 years (42% to 11%) (Figure 39-7). This is demonstrated even in the face of total surgical resection. While aggressive surgical resection of retroperitoneal sarcoma serves as the foundation of therapy for this condition, the high local recurrence rate and eventual mortality from this disease has prompted the exploration of adjuvant therapeutic modalities.

Multimodal therapy for extremity sarcoma has provided an inference for the role of chemotherapy in retroperitoneal lesions. The majority of large-scale chemotherapy trials, however, comprise patients with extremity disease, so these findings may not be directly applicable. Overall, the argument for adjuvant therapy seems reasonable since the potential for distant recurrence is significant with retroperitoneal lesions. The data in this regard have been somewhat contradictory, yet a metaanalysis of these studies suggests a slight advantage for the use of adjuvant doxorubicin therapy to decrease the risk of death and recurrence in patients with high-grade extremity lesions.99 Such therapy is associated with toxicity, however, and has not gained considerable acceptance for retroperitoneal lesions.110

RADIATION THERAPY

Metastatic Disease

The role of radiation therapy in the treatment of soft tissue sarcomas has been established by the advances in extremity lesions. Unfortunately, the radiosensitivity of adjacent soft visceral organs in the retroperitoneum has limited the direct transfer of such techniques to lesions in this region.96,97 While extremity tumors are treated in the dose range of 60 to 64 Gy, most series of retroperitoneal lesions are treated in the 40- to 55-Gy range. In general, one sees a decrease in local recurrences compared to historic controls at the cost of increased gastrointestinal complications (nausea, vomiting, and enteritis). It is difficult to demonstrate a significant improvement in survival, and on multivariable analysis the completeness of the surgical resection and the grade of the tumor have the most significant bearing on outcomes.98–100 Intraoperative radiation therapy (IORT) has been employed as a surgical adjuvant in several small

Approximately 20% of patients with soft tissue retroperitoneal sarcoma will present with metastatic disease. Those patients who recur after treatment for localized disease generally do so by 60 months.111,112 Those patients who recur demonstrate disease at multiple sites (47%) or display a local recurrence (30%). Isolated pulmonary lesions occur in approximately 20% of patients. Three-year survival in patients undergoing complete excision of lung-only lesions is 38%.113 Doxorubicin is the foundation for chemotherapy in advanced sarcoma.114,115 The general response rate is 20% to 25%, but sustained complete responses are uncommon. Other classic agents demonstrating activity include dacarbazine, ifosfamide, methotrexate, and cyclophosphamide. In several phase III studies, however, combination treatments were not superior to singleagent doxorubicin.116–118 Other phase III studies have not demonstrated superior response, yet they do show


significant increased toxicity (myelosuppression and cardiac) with the addition of other agents.119 Another combination regimen of mesna, adriamycin (doxorubicin), ifosfamide, and dacarbazine (MAID) has been successful in neoadjuvant programs for extremity sarcomas compared to historic controls, yet less data are available with regard to other soft tissue sites.120,121 In general, salvage therapy for patients has been associated with poor responses and little in the way of quality of life advantages.121 More recently, gemcitabine has been investigated as an initial agent in advanced disease and for salvage therapy. As a single agent the results have been disappointing with response rates below 5% in either setting.122–124 The combination of gemcitabine and docetaxel in patients with unresectable leiomyosarcoma, however, demonstrated a 10% complete response and an overall response of 53%. It was felt to be a tolerable and active combination in treated and untreated patients.125 Disseminated intraperitoneal spread of disease is very difficult to treat. A novel approach is the application of photodynamic therapy.126 In a preliminary report, patients underwent surgical debulking and were treated with photofrin and laser light. Of initial 11 patients, 5 demonstrated no evidence of disease over a range of 2 to 17 months. The advancement of such technologies and the implementation of small molecule therapy may provide improved outcomes for such patients in the future.

Table 39-6 Common Genitourinary Sarcomas in Decreasing Order of Frequency Renal Leiomyosarcoma Liposarcoma Malignant fibrous histiocytoma Hemangiopericytoma Rhabdomyosarcoma Osteogenic sarcoma Bladder Leiomyosarcoma Rhabdomyosarcoma Osteogenic sarcoma Liposarcoma Malignant fibrous histiocytoma Fibrosarcoma Prostate Leiomyosarcoma

ADULT URINARY TRACT SARCOMA

Rhabdomyosarcoma

Primary sarcomas arising from the genitourinary system are extremely rare lesions overall and comprise only 1% to 2% of urologic tumors in adults. Only 800 to 1000 such tumors have been described from multiple genitourinary sites. Although many small clusters go unreported, practice principles in the diagnosis and treatment of these tumors must therefore be derived from anecdotal pooled data.127,128 General treatment principles are also extrapolated and applied from the clinical experience with primary retroperitoneal sarcomas. These lesions behave differently from pediatric genitourinary sarcomas, notably pediatric rhabdomyosarcoma, which is discussed separately in Chapter 49. Thus, treatment strategies, especially for advanced disease, tend to be empiric. Despite their rarity, the collective data regarding sarcomas of the genitourinary tract provide significant data with regard to clinical presentation and clinical outcome that provide rough guidelines for treatment when these uncommon lesions are encountered. The most common sarcomatous lesions of the urinary system originate in the spermatic cord and paratesticular structures, which are not strictly speaking retroperitoneal. In decreasing incidence, sarcomas of the kidney, the bladder, and the prostate are encountered (Table 39-6).

Fibrosarcoma Spindle cell sarcoma Spermatic cord, testis, paratestis Leiomyosarcoma Rhabdomyosarcoma Liposarcoma Fibrosarcoma Malignant fibrous histiocytoma

RENAL SARCOMA Approximately 1% to 2% of kidney tumors are true renal sarcomas. This excludes the sarcomatoid variant of renal cell carcinoma (RCC) that demonstrates spindle cells or giant cells and a rapidly progressive clinical course. The most frequent histologic subtypes of sarcoma encountered in the kidney are listed in Table 39-6. Leiomyosarcoma is the most common renal sarcoma, comprising 30% to 40% of most reported series.

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Part VI Testis

Liposarcoma and MFH are then encountered in near equal frequency. Other histologies include rhabdosarcoma, osteosarcoma, and hemangiopericytoma.129–132 Renal sarcoma usually presents at a slightly younger age than the average patient with RCC with pain and flank mass as the common symptoms. Hematuria is seen less frequently with classic RCC. They have no distinguishing imaging characteristics but tend to be hypervascular. When small, they are hard to distinguish from RCC, but hypovascularity combined with contiguous tumor spread may suggest sarcoma. Treatment for renal sarcoma is similar to RCC, namely, wide surgical excision. The principles for a standard radical nephrectomy conform to those for sarcoma surgery, and the modified thoracoabdominal approach is particularly suited to large lesions. As is the case in all soft tissue sarcomas, tumor size reflected in complete resectability, and grades are the major determinants of clinical outcome. There are no data to support chemotherapy or radiation in the adjuvant setting, and it is unlikely that these modalities will confer a survival benefit for patients with advanced disease. The overall 5year survival for these patients is approximately 30%. Those individuals with liposarcoma or hemangiopericytoma perform much better than patients with leiomyosarcoma. The survival rate at 5 years is in the 80% to 90% range for liposarcoma yet 4 cm. Kiltie et al.61 reported a local failure rate of 60% for tumors >4 cm and 14% for tumors

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