Cancer Chemotherapy by Infusion

Cancer Chemotherapy by Infusion

Jacob J. Lokich, M.D.

~ MTP PRESS LIMITED .... ~ a member of the KLUWER ACADEMIC PUBLISHERS GROUP _

.' LANCASTER / BOSTON / THE HAGUE / DORDRECHT -n

Published in the USA by

Precept Press, Inc. 160 East Illinois Street Chicago, Illinois 60611

Published in the UK and Europe by

MTP Press Limited Falcon House Lancaster, England

British Library Cataloguing in Publication Data

Cancer chemotherapy by infusion. 1. Cancer-Chemotherapy I. Lokich, Jacob J. 616.99'4061 RC271.C5 ISBN-13: 978-94-010-7932-7 e-ISBN-13: 978-94-009-3193-0 DOl: 10.1007/978-94-009-3193-0

© 1987 by Precept Press, Inc.

All Rights Reserved Softcover reprint ofthe hardcover 1 st edition 1987

Except for appropriate use in critical reviews or works of scholarship, the reproduction or use of this work in any form or by any electronic, mechanical or other means now known or hereafter invented, including photocopying and recording, and in any information storage and retrieval system is forbidden without the written permission of the publisher.

Library of Congress Catalog Card Number: 86-62057

International Standard Book Number: 0-931028-68-X

91 90 89 88 87 5 4 3 2 1

For my colleagues and collaborators on the nursing team who make medicine possible, and for my children, who make my life meaningful

CONTENTS

Preface xix

SECTION I - RATIONALE AND TECHNICAL ASPECTS

1. Introduction to the Concept and Practice of Infusion Chemotherapy 3 Jacob J. Lokich, M.D.

Categories of Infusion Chemotherapy 5 Rationale for Systemic Infusional Chemotherapy 7 Technologic Impetus to Infusional Chemotherapy 9 Current Clinical Status of Infusional Chemotherapy 10 Summary 11

2. Experimental Rationale for Continuous Infusion Chemotherapy 12 Mark J. Ratain, M.D., and Nicholas J. Vogelzang, M.D.

Introduction 12 Antimetabolites 14 Plant Alkaloids 19 Alkylating Agents 22 Antineoplastic Antibiotics 25 Miscellaneous Agents 31 Summary 32

3. The Clinical Pharmacology of Infusional Chemotherapy 35 Gregory A. Curt, M.D., and Jerry M. Collins, Ph.D.

Pharmacokinetics of Infusional Therapy 36 Regional Therapy 37

4. Drug Administration Systems for Infusion Chemotherapy 41 Elton M. Tucker, B.S.M.E.

Introduction 41 Patient Worn Extracorporal Systems 43

vii

viii CONTENTS

Implantable Infusion Systems 51 Alarms and Performance Status Information 57

5. Technical Aspects of Vascular Access for Infusional Chemotherapy 59 Albert Bothe, Jr., M.D., and John M. Daly, M.D.

Introduction- Venous Access 59 Arterial Access 68 Summary 73

6. Nursing Management of Infusion Catheters 74 Cheryl L. Moore, R.N.

Hickman Catheters 75 Subclavian Catheters 77 Implantable Venous Access Portals 78 Special Considerations 81 Management of Local Skin Effects 82 Complications Associated with Subclavian Catheters 84 Detection and Management of Infection 85 Hepatic Artery Catheters 91 Implantable Infusion Pump 94 Pump Complications 97 Conclusion 99

7. Pharmaceutical Issues in Infusion Chemotherapy Stability and Compatibility 100 John A. Benvenuto, Ph.D., Stephen C. Adams, Pharm.D., Harish M. Vyas, Ph.D., and Roger W. Anderson, M.S.

Concepts and Definitions 100 Procedures for Study of Stability 102 Short-Term Stability 103 Long-Term Stability 109 Admixtures III Conclusion 113

SECTION II - CHEMOTHERAPEUTIC AGENTS

8. Antipyrimidines: 5-Fluorouracil and 5-Fluoro-2' -Deoxyuridine 117 Michael J. O'Connell, M.D.

Clinical Trials of Fluorinated Pyrimidines Given by Short- and Long-Term Intravenous Infusions 118

Studies of Protracted Venous Infusion of the Fluorinated Pyrimidines 120

9. Mexthotrexate 123 Carmen J. Allegra, M.D., and Gregory A. Curt, M.D.

Introduction 123 Theoretical Considerations 124 Clinical Investigations 126 Summary 129

10. Anthracyclines 130 Sewa S. Legha, M.D., Gabriel N. Hortobagyi, M.D., and Robert S. Benjamin, M.D.

Introduction 130 General Considerations 131 Methods of Doxorubicin Infusion 132

Contents ix

Therapeutic Implications of Continuous Venous Infusion of Doxorubicin 137

Anthracycline Analogues 138

11. Cisplatin, Platinum Analogues, and Other Heavy Metal Complexes 145 Stephen P. Ackland, M.B., B.S., F.R.A.C.P., and Nicholas J. Vogelzang, M.D.

Cisplatin 145 Intra-Arterial Cisplatin 153 Platinum Analogues 155 Gallium Nitrate (Ga(NOl)l) 157 Spirogermanium 159

12. Cytosine Arabinoside 161 Gregory A. Curt, M.D., Carmen J. Allegra, M.D., and Bruce D. Cheson, M.D.

Background 161 Clinical Research 162

13. Periwinkle Alkaloids I: Vinblastine and Vindesine 167 Mark J. Ratain, M.D., Nicholas J. Vogelzang, M.D., and Gerald P. Bodey, M.D.

Background 167 Rationale for Infusion 168 Vinblastine (Phase 1 Trials) 169 Vinblastine (Phase 2 Trials) 171 Vindesine (Phase 1 Trials) 174 Vindesine (Phase 2 Trials) 176 Conclusions 180

X CONTENTS

14. Periwinkle Alkaloids II: Vincristine 181 Don V. Jackson, Jr., M.D.

Clinical Trials 185 Results 191 Discussion 195

15. Bleomycin 200 Robert B. Catalano, Pharm.D., and Robert L. Comis, M.D.

Introduction 200 Mechanism of Action 200 Pharmacology 201 Bleomycin Toxicology 202 Animal Studies 202 Pharmaceutical Data 203 Clinical Trials in Humans 204 Testicular Cancer 204 Head and Neck Cancer 205 Cervical Cancer 205 Lymphomas 206 Other Tumors 207 Discussion 209

16. The Epipodophyllotoxins: VP-16 and VM-26 211 Nancy Phillips, R.Ph., and Robert L. Comis, M.D.

Mechanism of Action 211 Clinical Pharmacology 212 Schedule Dependency 215 Pharmaceutical Data 215 Clinical Trials 215 Discussion 219

17. Alkylating Drugs and Other Agents 221 Jacob J. Lokich, M.D.

Alkylating Agents 222 Antimetabolites 226 Miscellaneous Cytotoxic Agents 227 Summary 230

Contents xi

18. Investigational Agents 231 Merrill J. Egorin, M.D., F.A.C.P.

19. Protracted Infusional Chemotherapy 243 Jacob J. Lokich, M.D.

Preclinical Pharmaceutical Studies 244 Phase 1 Studies 245 Summary of Phase 1 Trials of Protracted Infusion Chemotherapy 254 Phase 2 Studies 256 Phase 3 Trials 261

SECTION III - SYSTEMIC INFUSION BY TUMOR CATEGORY

20. Head and Neck Cancer 265 Efstathios Tapazoglou, M.D., and Muhyi AI-Sarraf, M.D., F.R.C.P.(C), F.A.C.P.

Background 265 Rationale of Infusion Chemotherapy 269 Clinical Trials 271 Summary 279

21. Esophageal and Anal Cancer 281 Lawrence Leichman, M.D., Jacob J. Lokich, M.D., and Cynthia Leichman, M.D.

Preoperative Versus Postoperative Therapeutic Concepts 281 Anal Canal Tumors 282 Squamous Cell Cancer of the Esophagus 285 Present and Future Status of Anal and Esophageal

Cancer Therapy 289

22. Colorectal Cancer 291 Jacob J. Lokich, M.D.

Standard Bolus 5-Fluorouracil 292 5-Fluorouracil and FUDR Continuous Infusion 294 Other Agents 300 Infusional 5-FU Concomitant with Radiation 301 Adjuvant Infusional Chemotherapy 302 Summary 302

xii CONTENTS

23. Gastric, Pancreas, and Biliary Tract Cancer 304 Geoffrey Falkson, M.D., and Baruch Klein, M.D.

Conventional Treatment 304 Chemotherapy by Infusion for Stomach, Pancreas, and Biliary

Tract Carcinoma 310 Intra-Arterial Therapy 312 Discussion 313

24. Breast Cancer 316 Sewa S. Legha, M.D.

Infusion Studies of Doxorubicin 317 Continuous Infusion of Vinca Alkaloids 319 Continuous Venous Infusion Trials with Other Drugs 320

25. Infusion for Hematologic Malignancies 322 Murray M. Bern, M.D.

Vinca Alkaloids 323 Epipodophyllotoxins 324 Antibiotics 325 Alkylating Agents 326 Antimetabolites 327 Metals 329 New Drugs 330 Combination Chemotherapy 332 Conclusions 337

26. Lung Cancer 338 Lucien Israel, Jean-Luc Breau, M.D., and Jean Franrois Morere, M.D.

Theory and Background 338 Modalities of Administration of DDP-BLM and

Associated Drugs 339 Modalities of Administration of 1 or 2 Complementary Drugs 340 Secondary Therapy Protocols in Relation to Clinical Situations 341 Results 345 Discussion 348 Other Trials of Infusion Chemotherapy 351 Summary 352

27. Testicular Cancer and Other Tumors of the Male Genitourinary Tract 353 Christopher J. Logothetis, M.D.

Vinblastine and Bleomycin Combination in the Management of Germ Cell Tumors 353

Prostatic Carcinoma 365 Urothelial Tumors 367

28. Gynecologic Malignancy 368 Hyman B. Muss, M.D.

Cancer of the Cervix 369 Ovarian Cancer 376 Other Sites 378 Conclusion 379

29. Soft Tissue and Osteogenic Sarcomas 380 Jacob J. Lokich, M.D., Richard Lackman, M.D., and Arthur J. Weiss, M.D.

Standard Bolus Chemotherapy Regional Infusion Chemotherapy Systemic Infusional Chemotherapy

381

Combined Modality Therapy 386 Summary and Conclusions 386

30. Uncommon Tumors 388 Jacob J. Lokich, M.D.

Malignant Melanoma 389 Hepatocellular Carcinoma 391 Apudomas 393 Thymoma 395 Summary and Commentary 395

383 385

SECTION IV-REGIONAL INFUSION

31. Head and Neck Cancer 399 Richard H. Wheeler, M.D., and Shan R. Baker, M.D.

Regional Infusion: Background and Experience 399

Contents xiii

Limitations and Complications of Regional Infusion 403 Use of External and Implantable Pumps 409 Summary 414

32. Regional Infusion for Metastatic Liver Tumors 415 Yeu-Tsu Margaret Lee, M.D., F.A.C.S.

Incidence and Natural History of Metastatic Liver Tumors 416 Rationale and Methodology of Infusion Chemotherapy via

Hepatic Artery 417 Therapeutic Results of Hepatic Arterial Infusion Chemotherapy 420

xiv CONTENTS

Hepatic Artery Ligation (HAL) and Arterial Infusion Chemotherapy 426

Portal Vein Infusion Chemotherapy 429 Transcatheter Embolization and Arterial Infusion Chemotherapy 431 Summary and Conclusions 433

33. Hepatic Arterial Infusion Chemotherapy: Clinical Trials with the Implantable Pump 435 Alfred E. Chang M.D., Philip D. Schneider, M.D., Ph.D., and Paul H. Sugarbaker, M.D.

Nonrandomized Clinical Trials 436 Prospective Randomized Controlled Trials 439 National Cancer Institute Trial 444 Summary 446

34. Regional Infusion for Primary Hepatic Carcinomas 447 Charles M. Balch, M.D., and Marshall M. Urist, M.D.

The UAB Experience with Regional Adriamycin Chemotherapy for Hepatoma Patients 449

Experience at M.D. Anderson Hospital and Tumor Institute 453 Summary 454

35. Hepatic Artery Ligation and Portal Vein Infusion 455 A. Gerard, M.D., and J.e. Peetor, M.D.

Effects of Hepatic Artery Ligation on Liver Parenchyma 456 Effects of Hepatic Artery Ligation on Liver Metastases 456 Effects of Portal Infusion on Liver Metastases 457 Effect of HAL and Portal Infusion on Liver Metastases 457 Conclusion 464

SECTION V-SPECIAL CATEGORIES OF INFUSION CHEMOTHERAPY

3fj. Regional Infusion for Brain Tumors 467 Fred H. Hochberg, M.D., and Deborah O. Heros, M.D.

Introduction 467 Clinical Experience 471 Review of the Literature 475

Contents xv

37. The Clinical Use of 5-Fluorouracil and Other Halopyrimidines as Radiosensitizers in Man 479 John E. Byfield, M.D., Ph.D.

Introduction 479 Preclinical Studies 480 Pharmacology of Infused 5-FU 484 Clinical Studies of 5-FU Radiosensitization 490 Current Clinical Status of Infused 5-FU and X-rays 492 Current Clinical Status of BUDR and IUDR 500 Conclusions 500

38. Intraperitoneal "Belly Bath" Chemotherapy 502 Maurie Markman, M.D.

Intracavitary Sclerosing Therapy 503 Pharmacokinetic Rationale for Intraperitoneal Chemotherapy 503 Acute and Chronic Toxicities of Intraperitoneal Chemotherapy 509 Trials of Single-Agent Intraperitoneal Chemotherapy 513 Combination Intraperitoneal Chemotherapy 520 Conclusion 524

39. Intraventricular Chemotherapy for Leptomeningeal Carcinoma 525 Deborah O. Heros, M.D., and Fred H. Hochberg, M.D.

Clinical Presentation of Carcinomatous Meningitis 526 'Concentration x Time' Therapy in Carcinomatous Meningitis 528 Drug Delivery System 528 Drug Administration and Toxicity 529 Clinical Management 530 Clinical Experience 531 Case Presentations 532 Conclusions 536

40. Intravesical Chemotherapy for Bladder Tumors 538 Hugh A. O. Fisher, M.D.

Characteristics of Superficial Bladder Cancer 538 Clinical Presentation and Diagnosis 539 Staging and Classification 540 Mechanisms of Recurrence 541 Risk Factors for Recurrence and Progression of Superficial

Bladder Cancer 542 Agents for Intravesical Therapy 544 Comparative Studies 557

xvi CONTENTS

41. Combination Chemotherapy and Infusional Schedules 560

Jacob J. Lokich, M.D.

Tactics of Combination Chemotherapy 562

Combination Chemotherapy with Single-Agent Infusions 562

Combination Chemotherapy Using Drug Admixtures 566

Summary 568

42. Continuous Infusion Antibiotic Therapy for Neutropenic Patients 569

Gerald P. Bodey, M.D.

Infection in Neutropenic Patients 570

In Vitro Studies 570

Experimental Animal Studies 573 Human Pharmacology Studies Clinical Therapeutic Studies

577

582

43. Degradable Starch Microspheres Infusion: Basic Considerations for Treatment of Hepatic Neoplasia 588

Leif Hakansson, M.D., Ph.D., Hans Starkhammar, M.D., Stefan Ekberg, M.Sc., Olallo Morales, M.D., Rune Sjodahl, M.D., Ph.D., and John Svenberg, Ph.D.

Choice of Tracer for Continuous Monitoring of DSM Treatment 589 Monitor for Continuous Registration of the Effect of DSM on the

Passage of Low-Molecular-Weight Substances 590 Effect of DSM on the Passage of Low-Molecular-Weight

Substances in the Treatment of Liver Tumors 592 Effect of Portal Blood Flow in the Passage of 99mTc-MDP Injected

Intra-Arterially with DSM 593

Importance of A V Shunting to the Effect of DSM 595

Kinetics of the Passage of 99mTc-MDP Injected with DSM 595

Conclusion 598

44. Cost-Effectiveness in Cancer Chemotherapy 600

Jacob J. Lokich, M.D.

Defining the Cost Basis 601 Comparative Costs of Infusion Chemotherapy 606

Cost Comparisons: Bolus Versus Infusion Chemotherapy 610 Summary 612

Contents xvii

45. Adjuvant Applications of Infusiona) Chemotherapy 613 Jacob J. Lokich, M.D., and Paul H. Sugarbaker, M.D.

Colon and Rectal Cancer 614 Applications of Adjuvant Infusional Chemotherapy to Other

Tumors 622 Protochemotherapy 624 Summary 625

References 627

Index 743

PREFACE

Chemotherapy for-cancer is in a state of evolution. Because some cancers can now be cured with chemotherapy as a singular modality, this therapy can no longer be viewed as simply a palliative contribution. Chemotherapy has assumed an important role as an adjuvant to other modalities, including both surgery and radiation therapy. For some tumors, the primary application of chemotherapy in a combined modality approach to curative therapy has resulted in the application of less radical surgery while achieving substantial cure rates. Nonetheless, with the exception of relatively rare tumors such as childhood tumors, hematologic malignancies, and testicular cancer, the effec­tiveness of chemotherapy in most tumors is severely limited. At the cellular level, greater understanding of the specific mechanism of tumor cell killing and of the phenomenon of drug resistance are elusive, critical ingredients in the improvement of effectiveness in cancer chemotherapy.

Prolonging the exposure time of the tumor cell to drugs is a concept that was addressed in the early phases of the development of chemotherapy. How­ever, technological limitations inhibited the broader application of chemother­apy by infusion until recent years. Also, the convenience of intermittent ther­apy on an outpatient basis, with the predominant theory of drug effect based on a dose response as well as the proven effectiveness of this schedule in some tumors, has slowed the process of subjecting infusion chemotherapy to the rigors of clinical trials.

This book represents an effort to bring together the literature on infusion chemotherapy and to critically review that literature as well as ongoing trials. The organization of the book into five sections permits an independent analy­sis of the rationale and techniques as well as technical considerations involved in infusion chemotherapy, with some overlap of the review of clinical trials as they apply to the individual chemotherapeutic agents and to systemic and regional application of drug therapy.

There are some gaps in the data that may be explored in future editions as ongoing clinical trials progress to their conclusions. These specific areas include extremity infusion and perfusion for melanoma as well as other tumors; the entire spectrum of childhood tumors; and the application of infu­sion therapy in the delivery of analgesia.

The future of infusion therapy is uncertain, awaiting definitive clinical confirmation by prospective clinical trials. Nonetheless, the basic rationale, the experimental studies both in vivo and in vitro, and uncontrolled clinical trials all suggest that infusion delivery systems may well contribute substan-

xix

XX PREFACE

tially to palliative - and potentially, in the future - curative cancer treatment in the same manner that new agents, combination chemotherapy, and adjuvant chemotherapy have been the signposts of progress in chemotherapy over the past three decades.

ABOUT THE AUTHOR

Jacob J. Lokich, M.D., received his medical degree from the University of Pennsylvania School of Medicine. He completed his medical residency at the Peter Bent Brigham Hospital, Harvard Medical School, and then followed with a Hematology fellowship. He currently is assistant professor of medicine, Harvard Medical School, and Medical Director of the Cancer Center, Medical Center of Boston.

xxi

CONTRIBUTORS

STEPHEN P. ACKLAND, M.B., B.S., F.R.A.C.P., Fellow, Joint Section of Hematology/Oncology, University of Chicago Pritzker School of Medicine and Michael Reese Hospital and Medical Center, Chicago, Illinois

STEPHEN C. ADAMS, Pharm.D., Coordinator of Drug Information Service, Department of Pharmacy, St. Luke's Episcopal Hospital, Texas Children's Hospital, Texas Heart Institute, Houston, Texas

MUHYI AL-SARRAF, M.D., F.R.C.P. (C), F.A.C.P., Professor of Medicine, Chief of Head and Neck Cancer Service, Division of Medical Oncology, Department of Medicine, Wayne State University and Harper-Grace Hospi­tals, Detroit, Michigan

CARMEN J. ALLEGRA, M.D., Clinical Pharmacology Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland

ROGER W. ANDERSON, M.S., Head, Division of Pharmacy, University of Texas, M. D. Anderson Hospital and Tumor Institute, Houston, Texas

SHAN R. BAKER, M.D., Vice Chairman, Department of Otolaryngology, Head and Neck Surgery, University of Michigan Hospital, Ann Arbor, Michigan

CHARLES M. BALCH, M.D., Head, Division of Surgery; Chairman, Depart­ment of General Surgery, University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas

ROBERT S. BENJAMIN, M.D., Department of Medical Oncology, University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas

JOHN A. BENVENUTO, Ph.D., Department of Medical Oncology, University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas

MURRAY M. BERN, M.D., New England Baptist Hospital and New England Deaconess Hospital, Boston, Massachusetts, Assistant Professor of Medicine, Harvard Medical School, Boston, Massachusetts

xxiii

xxiv CONTRIBUTORS

GERALD P. BODEY, M.D., University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas

ALBERT BOTHE, JR., Director, Residency Training Program, New England Deaconess Hospital, Boston, Massachusetts

JEAN-Luc BREAU, M.D. Clinique de Cancerologie, Centre Hospitalier Universitaire de Bobigny, Universite Paris Nord, Bobigny, France

JOHN E. BYFIELD, M.D., Ph.D., Associate Director and Chief, Radiation Oncology, Kern Regional Cancer Center, Bakersfield, California

ROBERT B. CATALANO, Pharm.D., Associate Professor of Clinical Pharmacy, Department of Pharmacy, Philadelphia College of Pharmacy and Science; Adjunct Professor of Clinical Pharmacy, Temple University School of Phar­macy; Coordinator of Clinical Research, Department of Medical Oncology, American Oncologic Hospital, Fox Chase Cancer Center, Philadelphia, Penn­sylvania

ALFRED E. CHANG, M.D., Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

BRUCE D. CHESON, M.D., Head, Medicine Section, Clinical Investigations Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Institutes of Health, National Cancer Institute, Bethesda, Maryland

JERRY M. COLLINS, Ph.D., Clinical Pharmacology Branch, Division of Can­cer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

ROBERT L. COMIS, M.D., Medical Director and Chairman, Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania

GREGORY A. CURT, M.D., Clinical Pharmacology Branch, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

JOHN M. DALY, M.D., Jonathan E. Rhoads Professor of Surgery, Chief, Division of Surgical Oncology, University of Pennsylvania School of Medi­cine, Philadelphia, Pennsylvania

MERRILL J. EGORIN, M.D., F.A.C.P., Associate Professor of Medicine, Phar­macology and Experimental Therapeutics and Oncology, Head, Division of Developmental Therapeutics, University of Maryland Cancer Center, Balti­more, Maryland

STEFAN EKBERG M.Sc., Department of Radiation Physics, University Hospi­tal, Linkoping, Sweden

Contributors xxv

GEOFFREY FALKSON, M.D., Department of Cancer Chemotherapy, Faculty of Medicine, University of Pretoria, Pretoria, Republic of South Africa

HUGH A. G. FISHER, M.D., Assistant Attending Physician, Albany Medical Hospital; Assistant Professor of Surgery (Urology), Head, Urologic Oncol­ogy, Albany Medical College, Albany, New York

A. GERARD, M.D., Professor of Surgery, Head of the Department of Surgery, Institut Jules Bordet, University of Brussels, Brussels, Belgium

LEIF HAKANSSON, M.D., Ph.D., Department of Oncology, University Hospi­tal, Linkoping, Sweden

DEBORAH O. HEROS, M.D., New England Medical Center; Assistant Profes­sor of Neurology, Tufts University School of Medicine, Boston, Massachusetts

FRED H. HOCHBERG, M.D., Massachusetts General Hospital; Associate Pro­fessor of Neurology, Harvard Medical School, Boston, Massachusetts

GABRIEL N. HORTOBAGYI, M.D., Professor of Medicine, Chief, Medical Breast Service, University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas

LUCIEN ISRAEL, Professor and Head, Division of Oncology, Clinique de Can­cerologie, Centre Hospitalier Universitaire de Bobigny, Universite Paris Nord, Bobigny, France

DON V. JACKSON, JR., M.D., Oncology Research Center, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina

BARUCH KLEIN, M.D., Department of Cancer Chemotherapy, Faculty of Medicine, University of Pretoria, Republic of South Africa

RICHARD LACKMAN, M.D., Assistant Professor, Department of Orthopedic Surgery, Chief, Musculo-Skeletal Tumor Services, Thomas Jefferson Univer­sity Hospital, Philadelphia, Pennsylvania

YEu-Tsu MARGARET LEE, M.D., F.A.C.S., LTC Medical Corps, Chief, Sur­gical Oncology Section, Department of Surgery, TripIer Army Medical Center, Honolulu, Hawaii; Associate Clinical Professor in Surgery, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii; Clinical Associ­ate Professor, Department of Surgery, F. Edward School of Medicine, Uni­formed Services University of Health Sciences, Bethesda, Maryland

SEWA S. LEGHA, M.D., Associate Professor of Medicine, Department of Medical Oncology, Division of Medicine, University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas

xxvi CONTRIBUTORS

CYNTHIA G. LEICHMAN, M.D., Assistant Clinical Professor of Medicine, University of Southern California, Los Angeles, California

LAWRENCE LEICHMAN, M.D., Associate Professor of Medicine, University of Southern California, Los Angeles, California

CHRISTOPHER J. LOGOTHETIS, M.D., Chief, Genitourinary Oncology, Associ­ate Internist, Associate Professor of Medicine, Department of M~:dical Oncol­ogy, M. D. Anderson Hospital and Tumor Institute, Houston, Texas

MAURIE MARKMAN, M.D., Department of Medicine, Memorial Sloan­Kettering Cancer Center, New York, New York

CHERYL L. MOORE, R.N., Chief Oncology Nurse, Cancer Center, Boston, Massachusetts

OLALLO MORALES, M.D., Department of Diagnostic Radiology, University Hospital, Linkoping, Sweden

JEAN-FRANCOIS MORERE, M.D., Clinique de Cancerologie, Centre Hospita­lier Universitaire de Bobigny, Universite Paris Nord, Bobigny, France

HYMAN B. Muss, M.D., Professor of Medicine, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina

MICHAEL J. O'CONNELL, M.D., Professor of Oncology, Vice Chairman Divi­sion of Medical Oncology, Mayo Clinic, Rochester, Minnesota

J.C. PECTOR, M.D., Staff Surgeon, Department of Surgery, Institut Jules Bordet, University of Brussels, Belgium

NANCY PHILLIPS, R.Ph., Oncology Pharmacy Consultant, Fox Chase Cancer Center, Philadelphia, Pennsylvania

MARK J. RATAIN, M.D., Instructor in Medicine, Joint Section of Hematology/Oncology, University of Chicago Pritzker School of Medicine and Michael Reese Hospital and Medical Center, Chicago, Illinois

PHILIP D. SCHNEIDER, M.D., Ph.D., Surgery Branch, National Cancer Insti­tute, National Institutes of Health, Bethesda, Maryland

RUNE SJODAHL, M.D., Ph.D., Department of Surgery, University Hospital, Linkoping, Sweden

HANS STARKHAMMAR, M.D., Department of Oncology, University Hospital, Linkoping, Sweden

PAUL H. SUGARBAKER, M.D., Director of Surgical Oncology, Emory Univer­sity, Robert W. Woodruff Health Sciences Center, Atlanta, Georgia

Contributors xxvii

JOHN SVEDBERG, Ph.D., Department of Radiation Physics, University Hospi­tal, Linkoping, Sweden

EFSTATHIOS TAPAZOGLOU, M.D., Assistant Professor of Medicine, Division of Medical Oncology, Department of Medicine, Director of Hyperthermia Program, Wayne State University and Harper-Grace Hospitals, Detroit, Mich­igan

ELTON M. TUCKER, B.S.M.E., President, Device Labs, Inc., Medway, Massa­chusetts

MARSHALL M. URIST, M.D., Associate Professor of Surgery, Chief, Section of Surgical Oncology, University of Alabama at Birmingham, Birmingham, Alabama

NICHOLAS J. VOGELZANG, M.D., Assistant Professor of Medicine, Joint Sec­tion of Hematology/Oncology, University of Chicago Pritzker School of Med­icine and Michael Reese Hospital and Medical Center, Chicago, Illinois

HARISH M. VYAS, Ph.D., Oncology Pharmacist, New England Deaconess Hospital, Boston, Massachusetts

ARTHUR J. WEISS, M.D., Assistant Professor of Medicine, Division of Medi­cal Oncology, Thomas Jefferson University Hospital, Philadelphia, Pennsyl­vania

RICHARD H. WHEELER, M.D., Comprehensive Cancer Center, Department of Medicine, Division of Hematology/Oncology, University of Alabama at Bir­mingham, Birmingham, Alabama