CLINICAL
`ONCOLOGY
`
`Edited by
`
`Martin D. Aheloff, M.D.
`Eli Kennerly Marshall, Jr. Professor
`Department of Oncology
`The Johns Hopkins University School of Medicine
`Oncologist-in-Chief
`The Johns Hopkins Hospital and Health Systems
`Baltimore, Maryland
`James 0. Armitage, M.D.
`Professor and Chairman
`Department of Internal Medicine
`University of Nebraska College of Medicine
`Omaha, Nebraska
`Allen S. Lichter, M.D.
`Isadore Lampe Professor and Chair
`Department of Radiation Oncology
`University of Michigan Medical School
`Ann Arbor, Michigan
`John E. Niederhuber, M.D.
`Emile Holman Professor and Chair
`Department of Surgery
`Professor
`Department of Microbiology and Immunology
`Stanford University School of Medicine
`Chief of Surgery
`Stanford University Hospital
`Stanford, California
`
`Churchill Livingstone
`New York, Edinburgh, London, Melbourne, Tokyo
`
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`Library of Congress Cataloging-in-Publication Data
`
`Clinical oncology I edited by Martin D. Abeloff ... [et al. ].
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 0-443-08941-8
`2. Cancer. I. Abeloff, Martin D.
`I. Oncology.
`[DNLM: I. Neoplasms-therapy. 2. Medical Oncology. QZ 266
`C64185 1995]
`RC26l.C6512 1995
`616.99'4-dc20
`DNLM/DLC
`for Library of Congress
`
`© Churchill Livingstone Inc. 1995
`
`95-744
`CIP
`
`All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted
`in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior per(cid:173)
`mission of the publisher (Churchill Livingstone, 650 Avenue of the Americas, New York, NY 10011).
`
`Distributed in the United Kingdom by Churchill Livingstone, Robert Stevenson House, 1-3 Baxter's -Place,
`Leith Walk, Edinburgh EH! 3AF, and by associated companies, branches, and representatives throughout the
`world.
`
`Chapter 83 was prepared by government employees and is not subject to copyright.
`
`Accurate indications, adverse reactions, and dosage schedules for drugs are provided in this book, but it is pos(cid:173)
`sible that they may change. The reader is urged to review the package information data of the manufacturers
`of the medications mentioned.
`
`The Publishers have made every effort to trace the copyright holders for borrowed material. If they have inad(cid:173)
`vertently overlooked any, they will be pleased to make the necessary arrangements at the first opportunity.
`
`Acquisitions Editor: Kerry Willis
`Assistant Editor: Marc Strauss
`Production Editor: Paul Bernstein
`Production Supervisor: Laura Mosberg Cohen
`Cover Design: Jeannette Jacobs
`
`Printed in the United States of America
`
`First published in 1995
`
`7654321
`
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`Contents
`
`PART I. SCIENCE OF CLINICAL
`ONCOLOGY 1
`
`Section 3. Principles of Cancer Diagnosis and
`Therapy
`
`Section 1. Cellular and Molecular Biology of
`the Cancer Cell
`
`11. Economic Analysis of Cancer Treatment 187
`Charles L. Bennett, Bruce E. Hiltner, and
`Thomczs ] . Smith
`
`1. Structure and Function of the Gene 3
`David Batstein
`
`2. Oncogenes and Tumor Suppressor Genes 11
`Eric R. Fearon
`
`3. Cytogenetics 41
`Jeffrey M. Trent
`
`4. Invasion and Metastasis 55
`Isaiah]. Fidler
`
`5. Regulation of Tumor Cell Growth 77
`Venil N. Sumancran and Max Wicha
`
`6. Immunology of the Cancer Cell 89
`
`Introduction 89
`John E. Niederhuber
`
`T-Lymphocyte Responses 90
`Thierry Boon, Pierre G. Coulie, Vincent Brichard, and
`Marie Marchand
`
`12. Chemotherapy 201
`Ross C. Donehawer, Martin D. Abelaff, and
`Michael C. Perry
`
`13. Radiation Therapy 219
`·
`Allen S. Lichter
`
`14. Surgical Therapy 265
`John E. Niederhuber
`
`15. Biologic Therapy 275
`Ellen R. Gaynor and Richard I. Fisher
`
`16. Bone Marrow Transplantation 295
`James 0 . Armitage, Anne Kessinger, Elizabeth C. Reed,
`Philip Bierman, Julie M. Vose, Michael R. Bishop, and
`Stefano Tarantola
`
`17. Multimodality Therapy 307
`Allen S. Lichter, Martin D. Abel.off, James 0. Armitage,
`and John E. Niederhuber
`
`Section 4. Understanding Risk
`
`B-Lymphocyte Responses 100
`Michael]. Campbell and John E. Niederhuber
`
`18. Epidemiology 315
`David Schottenfe!d
`
`7. Hematapoietic Stem Cells 12 7
`William H. Fleming and Irving L. Weissman
`
`19. Biostatistics for Clinical Trials 339
`Steven Piantadosi
`
`Section 2. Causes of Cancer
`
`8. Tumor Viruses 135
`Elliot Kieff
`
`9. Chemical and Physical Agents in Our
`Environment 151
`Paul T. Strickland and Thomas W. Kensler
`
`10. lnherited·Cancer 167
`Ronald]. Weigel
`
`PART II. PROBLEMS COMMON TO CANCER
`AND ITS THERAPY
`355
`
`Section 1. General Problems
`
`20. Pain 357
`Stuart A. Grassman and Vivian R. Sheidler
`
`21. Psychological Distress and Depression 373
`] . Stephen McDaniel and Charles B. Nemeroff
`
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`xxiv Contents
`
`22. Weight Loss and Cachexia 393
`D. Scott Lind, Wiley W. Souba, and Edward M. Copeland
`
`36. Spinal Cord Compression 619
`John C. Ruckdeschel
`
`23. The Terminally Ill Patient 409
`Barry M. Kim;brunner
`
`37. Brain Metastases and Carcinomatous Meningitis 629
`Roy A. Patchell
`
`Section 2. Hematologic _Problems
`
`24. Bone Marrow Failure 433
`George D. Demetri and Kenneth C. Anderson
`
`25. Thrombotic Complications 457
`William D. Haire
`
`Section 3. Infections
`
`26. Febrile Neutropenia 485
`James C. Wade
`
`27. Fever Without Neutropenia 501
`Edward A. Dominguez, Mark E. Rupp, and
`Laurel C. Preheim
`
`28. AIDS 513
`John G. Bartlett
`
`Section 4. Metabolic Problems
`
`29. Hypercalcemia 527
`A. Ross Morton: and Allan Lipton
`
`30. Hyponatremia 543
`Jesse M. Goldman and Robert L. Comis
`
`31. Tumor Lysis Syndrome 557
`Michael R. Bishop and Peter F. Coccia
`
`Section 5. Surgical Problems
`
`32. Establishing and Maintaining Vascular Access 563
`William C. Dooley, Carol Dedeo, Georgia Bosserman, and
`John E. Niederhuber
`
`33. Acute Abdomen, Bowel Obstruction, and Fistula 583
`Alfred E. Chang and David A. August
`
`34. Urinary Tract Obstruction 599
`Rodney Davis and Gloria A. Richard-Davis
`
`Section 6. Local Effects of Cancer and Its
`Metastases
`35. Superior Vena Cava Syndrome 609
`Michael]. Murray, James R. Stewart, and
`David H. Johnson
`
`38. Bone Metastases 643
`Robert D. Rubens and Robert E. Coleman
`
`39. Lung Metastases 667
`Patricia M. McCormack and Robert}. Ginsberg
`
`40. Liver Metastases 679
`Nancy E. Kemeny, Margaret Kemeny, and
`Theodore S. Lawrence
`
`41. Effusions 709
`John W. Yarbro
`
`Section 7. Toxicities of Therapy
`
`42. Nausea and Vomiting 727
`John D. Hainsworth
`
`43. Oral Complications 741
`Charles D. Loprinzi, Dennis A. Gastineau, and
`Robert L. Foote
`
`44. Alopecia and Cutaneous Complications 753
`Charles J. McDonald, Jennie J. Muglia, and
`·
`David J. Friedman
`
`45. Neurologic Complications 771
`Mark R. Gilbert
`
`46. Pulmonary Complications 789
`Sandra McDonald, Despina Missaillidou, and
`Philip Rubin
`
`47. Cardiac Complications 809
`James L. Speyer and Robin Freedberg
`
`48. Reproductive Complications 821 ·
`Donald L. Truinp
`
`49. Endocrine Complications 829
`Donnld L. Trump
`
`. 50. Induced Malignancies 833
`Daniel M. Green and Giulio J. D'Angio
`
`PART III. MANAGEMENT OF SPECIFIC
`MALIGNANCIES
`849
`
`51. Central Nervo~s System 851
`William R. Shapiro, Joan Rankin Shapiro, and
`Russell W. Walker
`
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`52. Eye, Orbit, and Adnexal Structures 913
`Victor M. Elner, David S. Bardenstein, and Allen S.
`Lichter
`
`67. Prostate 1439
`Howard I. Scher, John T. Isaacs, Zvi Fuks, and
`Patrick C. Walsh
`
`Contents xxv
`
`53. Head and Neck 961
`Sharon L. Collins, Michael Dougherty,
`Roger Stupp, Ralph R. Weichselbaum, and
`Everett E. Vokes
`
`54. Cutaneous Cancer and Malignant Melanoma 1023
`Susan N. Swetter, Bruce R. Smoller, and
`Eugene A. Bauer
`
`55. Endocrine System 1047
`John Macdonald, Daniel Haller, and
`Ronald J. Weigel
`
`56. Lung 1083
`Ronald Feld, Robert}. Ginsberg, David G. Payne, and
`Frances A. Shepherd
`
`57. Pleura and Mediastinum 1153
`Joseph Aisner, Karen H. Antman, and
`Chandra P. Belani
`
`58. Esophagus 1189
`Richard F. Heitmiller and Arlene A. Forastiere
`
`59. Stomach 1209
`Leonard L. Gunderson, John H. Donohue, and
`Patrick A. Burch
`
`60. Small Intestine 1243
`James Stone
`
`61. Colon and Rectum 1267
`Robert W. Beart, Jr.
`
`62. Anal Canal 1287
`Elizabeth Poplin, Norman Nigro, Daniel G. Sheahan,
`and Laurie E. Gaspar
`·
`
`63. Liver and Bile Ducts 1305
`Steven A. Curley, Bernard Levin, and Tyvin A. Rich
`
`64. Pancreas 1373
`J. Augusto Bastidas and John E. Niederhuber
`
`65. Kidney and Ureter 1405
`Jonathan W. Simons and Fray F. Marshall
`
`66. Bladder 1419
`Valerie K. Israel, Ronald B. Natale, and
`Donald G. Skinner
`
`68. Penis and Urethra 1473
`Michael R. Zaragoza and H. Barton Grossman
`
`69. Testes 1493
`Eric]. Small and Frank M. Torti
`
`70. Cervix, Vagina, and Vulva 152 7
`Robin Farias-Eisner, A. Catherine Casey,
`Donna L. Walker, Anne P. Shapter, and Jonathan S .Berek
`
`71. Uterus 1569
`Lowell J. Byers, Jeffrey M. Fowler, and
`Leo B. Twiggs
`
`72. Ovaries and Fallopian Tubes 1595
`James Tate Thigpen
`
`73. Breast 1617
`Marcin D. Abeloff, Allen S. Lichter, John E. Niederhuber,
`Lori J. Pierce, and Douglas C. Aziz
`
`74. Bone Sarcomas 1715
`Julia A. Bridge, Herbert S. Schwarcz. and James R. Neff
`
`7 5. Soft Tissue Sarcomas 1799
`Peter W. T. Pisters and Murray F. Brennan
`
`76. Unknown Primary 1833
`James L. Abbruzzese and Martin N. Raber
`
`77. Pediatric Tumors 1847
`Alberto S. Pappo, John F. Kuttesch, Victor M. Santana,
`and David N. Shapiro
`
`78. Childhood Leukemia 1889
`Donald Pinke! and Theodore F. Zipf
`
`79. Childhood Lymphoma 1911
`Didier Frappaz, Eric Bouffet, J. Yves Blay,
`David Brunat-Mentigny, and Thierry 0. Philip
`
`80. Acute Lymphoid Leukemia· in Adults 1925
`Stanley R. Frankel, Geoffrey P. Herzig, and
`Clara D. Bloomfield
`
`81. Acute Myeloid Leukemia in Adults 1959
`Richard M. Stone and Robert J. Mayer
`
`82. Myelodysplastic Syndromes 1977
`Peter A. Kouides and John M. Bennett
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`xxvi Contents
`
`83. Chronic Lymphoid Leukemias 1999
`Bruce D. Cheson
`
`PART IV. REHABILITATION OF THE
`CANCER PATIENT
`2189
`
`84. Hairy Cell Leukemia 2023
`Alan Saven, Douglas J. Ellison, and Lawrence D. Piro
`
`85. Chronic Myeloid Leukemia 2035
`Issa Khouri, Hagop Kancarjian, Moshe Talpaz,
`Michael Andreeff, Ming-Sheng Lee,
`Richard Champlin, and Albert B. Deisseroch
`
`86. Multiple Myeloma and Related Disorders 2053
`Robert A Kyle and Joan Blade
`
`87. Hodgkin's Disease 2075
`Dwight Kaufman and Dan L. Longo
`
`88. Non-Hodgkin's Lymphomas 2109
`T. Andrew Lister and James 0. Armitage
`
`89. Cutaneous T-Cell Lymphoma 2149
`Thomas M. Habermann and Mark R. Pittelkow
`
`90. Adult T-Cell Leukemia/Lymphoma 2173
`Walter]. Urba, Francis W. Ruscetti, and
`Jeffrey W. Clark
`
`91. Physical Rehabilitation 2191
`Richard S. Tunkel, Elisabeth Lachmann,
`Patrick]. Boland, and Margaret L. Ho
`
`92. Management of Sexual Dysfunction 2235
`Sarah S. Auchincloss
`
`93. Psychosocial Rehabilitation 2255
`James R. Zabora, Elizabeth D. Smith, and
`Matthew J. Loscalzo ·
`
`94. Support Systems for Patients and
`Their Families 22 71
`Jeanne D. Kennedy
`
`Index 2277
`
`Color places follow page 934.
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`Chemotherapy
`Ross C. Donehower
`Martin D. Abeloff
`Michael C. Perry
`
`INTRODUCTION
`
`Although chemotherapy is a relatively recent addition to i:he
`therapeutic armamentarium for the treatment of patients with
`cancer, its role is expanding and drugs are used at some point
`during treatment for most patients with cancer. Historically,
`chemotherapy has been used principally as therapy for metastatic
`cancer that has developed after failed local therapies. Drugs remain
`the treatment of choice for patients with metastatic cancer. How(cid:173)
`ever, the evolution of cancer therapy over the past several decades
`has resulted in increased recognition of the important role that
`chemo- and radiation therapy can play in the management of
`apparently locali~ed and surgically resectable disease. This has led
`to the development of other applications for systemic therapy de(cid:173)
`signed to decrease postsurgical recurrences, when given as adju(cid:173)
`vant therapy, or to allow more limited organ- and function-sparing
`surgical procedu~es to be done when given as preoperative chemo(cid:173)
`therapy or concurrently with radiation therapy. Perhaps more than
`any other disease, cancer requires close interaction among medical
`specialties. As our knowledge of how to combine surgery, radia(cid:173)
`tion, and chemotherapy optimally evolves and the efficacy and
`specificity of available chemotherapeutic agents improve, the role
`of chemotherapy will expand further and play an even greater role
`in improving both the survival and quality of life for patients with
`cancer.
`
`HISTORY OF DRUG DISCOVERY
`
`Chemotherapy has its origins in the work of Paul Ehrlich, who
`coined the term in reference to the systemic treatment of both
`infectious disease and neop\asia. Many of Ehrlich's concepts re(cid:173)
`garding the experimental evaluation of new therapies using murine
`or rat models have survived to the present day and have provided
`a number of important biologic insights that have been successfully
`applied to the clinical setting. Although the concept of treating
`cancers with drugs can be traced back several centuries, there
`were no examples of truly successful systemic cancer chemotherapy
`until the 1940s. Gilman and Philips1 began the first clinical trial
`of nitrogen mustard. in patients with malignant lymphomas at Yale
`University in 1942. The use of nitrogen mustard as a chemothera(cid:173)
`peutic agent was suggested by the serendipitous findings of marrow
`
`and lymphoid hypoplasia in seamen exposed to mustard gas follow(cid:173)
`ing the explosion of a ship containing material manufactured for.
`use in chemical warfare in World War II.2 This supported previous
`evidence of a systemic lympholytic effect from alkylating agents
`of this type. The dramatic regressions of the lymphomas noted in
`this original study generated tremendous excitement for this new
`field of medicine, although enthusiasm was dampened by the fact
`that regrowth of tumor seemed inevitable. The results, initially
`published in 1946, could be said to mark the beginning of modem
`chemotherapy. This same combination of"experimenrs of nature"
`and the observations of well-trained scientists have yielded a num(cid:173)
`ber of other important leads in the search for improved cancer
`therapy. This includes, among others, the recognition by Farber
`et al. 3 of the importance of folates in cell growth in acute leukemia
`in chi!Clren and the subsequent development of the first antifolate
`antimetabolites. This class of compounds produced perhaps the
`first examples of drug-induced cures of a widespread cancer in
`gestational choriocarcinoma4 and remains in wide clinical use
`today. For their recognition of the importance of nucleic acid
`synthesis to inhibition of cell growth and for the development of
`effective antipurine analogues for cancer and other diseases, Elion
`and Hitchings were awarded the Nobel Prize in Medicine in 1988.5
`Serendipity has also played a role in the recognition of the poten(cid:173)
`tial of vinca alkaloids, epipodophyllotoxins, and platinum coordi(cid:173)
`nation complexes as chemotherapy agents.6•7 This scenario has
`been repeated with sufficient frequency that drug discovery pro•
`grams such as that of the National Cancer Institute (NCI) have
`extensively used the approach of mass screening of natural prod(cid:173)
`ucts, as well as synthetic compounds, to identify lead compounds
`wi·i:h unique mechanisms of action.
`Screening is a key in the process of drug development because
`it narrows the enormous number of candidate drugs to a more
`manageable number for further study and possible clinical evalua(cid:173)
`tion. Traditionally, this screening system has used transplantable
`murine tumors to search for evidence of biological activity.8 Al(cid:173)
`though chis system identified a series of compounds for clinical
`trial there was continued uncertainty regarding the relevance of
`these murine cell lines to human cancers. The current screening
`system employs a panel of human cancer cell lines grown in culture
`in defined medium that represents the major histologic subtypes
`and sites of origins of human cancer. It is also possible, and proba(cid:173)
`bly important, to include cell lines that express various drug resis(cid:173)
`tance phenotypes, such as multidrug resistance (MOR) to evaluate
`
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`202 Science of Clinical Oncology / I
`
`new agents against tumor cells manifesting these potentially clini·
`cally important cellular characteristics. Importantly, it has been
`possible to automate the testing of candidate drugs in this system
`so that high-volume screening can be maintained.9 Since this
`;creening system uses human cancer cell lines, it is hoped that it
`will identify agents with unique promise against advanced solid
`tumors that would not be identified using other methods.
`The history of cancer chemotherapy and of the discipline of
`medical oncology has been that of drug discovery. The pioneering
`discoveries of the early days of chemotherapy have allowed the
`development of a paradigm for drug discovery that persists with
`modifications to the present day. However, this organized ap·
`proach to random screening of large numbers of compounds must
`be complemented in the drug development effort by attempts to
`exploit new therapeutic targets identified in ongoing basic cancer
`research. When a putative target is identified based on its biologic
`significance in the cancer cell, this strategy suggests that the ability
`of potential therapeutic agents to interact with this target and to
`inhibit or modify its function should be evaluated as a primary
`screening procedure. This mechanism-based screening is often per(cid:173)
`formed in simple cell-free systems in which the target and effector
`are isolated. Drugs identified as promising candidates by this mech(cid:173)
`anism-based approach to drug development will also require the
`test systems that have been developed to validate their biologic
`activity in whole cells and experimental animal tumor models.
`Active new agents are needed for the treatment of many common
`human cancers. The ongoing work in drug development is crucial
`if our use of chemotherapy is to continue to improve and its role
`in potentially curative therapy is to expand. A number of promis·
`ing and novel strategies are being considered for clinical trials,
`including antiangiogenesis factors, drugs that affect intracellular
`signalling pathways, differentiating agents, agents that affect a
`cell's ability to undergo apoptosis, and gene-specific therapies such
`as antisense oligonucleotides and ribozymes. These approaches and
`others, which will undoubtedly follow, offer great promise for the
`future of cancer treatment.
`
`CLINICAL USES OF CHEMOTHERAPY
`
`Adjuvant Chemotherapy
`
`Chemotherapy can be used in a number of ways in the treatment
`of cancer. The vast majority of cancer chemotherapy is adminis(cid:173)
`tered to patients with clinically obvious disease. The notable ex(cid:173)
`ception is adjuvant chemotherapy, which entails the use of chemo(cid:173)
`therapy in patients who remain at high risk of recurrence after
`the primary tumor and all evidence of cancer have been surgically
`removed or treated definitively with radiation. Despite an appar(cid:173)
`ently successful resection of primary breast, colon, or other primary
`cancers and the regional lymph nodes, patients can be identified
`prospectively who are at high risk of recurrence of their disease.
`These criteria may differ for each tumor, but, in general, the degree
`of local extension of the primary tumor, the presence of positive
`lymph nodes, and certain morphologic or biologic characteristics
`of the individual cancer cells are important determinants of that
`risk. The need for effective adjuvant therapy is strongly emphasized
`by the fact that chemotherapy usually fails to cure the disease once
`recurrence has taken place. The theoretical advantage of treating
`
`Table 12-1. Cancers Effectively Treated by Adjuvant
`Chemotherapy
`
`Wilms tumor
`Osteosarcoma
`Breast cancer
`Colorectal cancer
`
`;:
`
`2
`3
`4
`5
`6
`
`patients with small total body tumor burden is very compelling,
`but in fact, some patients will receive chemotherapy who have
`already been rendered disease free by the local therapy and would
`be cured without it. The use of chemotherapy when tumor burden
`is minimal avoids the adverse effects of increasing tumor cell num(cid:173)
`ber, decreasing growth fraction, decreased vascular supply, hy(cid:173)
`poxia, tumor cell heterogeneity, and the likelihood of emergence
`of drug resistance, all of which occur with increasing frequency
`as tumors enlarge. Considerable experimental evidence suggests
`that cancers are most sensitive to chemotherapy during the early
`stages of growth. This increased sensitivity is believed to be the
`result of the high growth fraction and shorter cell cycle times, so
`that a given dose of drug may exert a greater therapeutic effect
`than in a larger, quiescent tumor.10
`The selection of the specific chemotherapy regimen to be used
`as part of adjuvant chemotherapy for a particular disease is based
`on objective response rates observed for patients with advanced
`cancers of the same type. These regimens should be selected care(cid:173)
`fully, as it is unrealistic to expect a chemotherapy regimen to be
`effective in preventing recurrences in the adjuvant setting if it
`does not have a substantial response rate in advanced disease. The
`selection of patients for adjuvant chemotherapy is based on the
`expected rate of recurrence for their initial clinical stage of disease
`after local treatment alone. Initial demonstration of the efficacy
`of an adjuvant chemotherapy regimen requires comparison with
`a control group receiving no therapy beyond local management
`in a prospective clinical trial. Historical controls are notoriously
`unreliable in this regard and are not adequate to prove efficacy.
`The typical end points of clinical chemotherapy, including s!'trink·
`age of measurable tumor on serial radiographic studies, are lost in
`this situation; in clinical trials, relapse-free survival and overall
`survival are the principles measures of treatment effect. For an
`individual patient receiving adjuvant therapy, there is no means
`by which to determine whether the toxicity and expense of the
`therapy was beneficial or necessary.· However, for those remaining
`disease free, the issue is· moot unless the long-term post-treatment
`sequelae are significant. This strategy has been attempted in a wide
`variety of pediatric and adult tumors with some success (Table 12-
`l). The principles of adjuvant therapy strategy are presented in
`Table 12-2. In the cases of breast cancer and colon cancer, the
`number of lives saved by the adjuvant therapy approach are signift·
`cant because of the large number of affected patients despite the
`modest differences seen between treated and control patients with
`the current treatment programs.
`
`Neoadjuvant Chemotherapy
`
`A second strategy that acknowledges the presence of micromet·
`astatic disease at sites remote from the primary tumor at diagnosis
`is that of neoadjuvant chemotherapy.11 As with adjuvant chemo·
`
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`12 / Chemotherapy 203
`
`Table 12-2. Principles of Adjuvant Chemotherapy
`
`Table 12-3. Cancers Effectively Treated by Neoadjuvant
`Chemotherapy
`
`1. Effective chemotherapy must be available.
`2. Known tumor should be removed by surgery.
`3. Chemotherapy should be started as soon as possible postoperatively.
`4. Chemotherapy should be given in maximally tolerated doses.
`5. Chemotherapy should continue for a limited time period.
`6. Chemotherapy should be intermittent, when possible, co minimize
`immunosuppression.
`
`Soft tissue sarcoma
`Osteosarcoma
`Anal cancer
`Bladder cancer
`Larynx cancer
`Esophageal cancer
`Locally advanced breast cancer
`
`therapy, treatment is directed at the possibility of systemic disease
`in patients with apparently localized disease although in this in(cid:173)
`stance chemotherapy is administered before surgery is performed.
`This approach has several potential advantages over the more
`conventional postoperative adjuvant chemotherapy. First, neoad(cid:173)
`juvant or preoperative chemotherapy provides earlier exposure of
`potential micrometastases to chemotherapy than is achieved with
`the standard adjuvant approach. If the advantage of early chemo(cid:173)
`therapy treatment observed in the laboratory is exportable to the
`clinic, this should be an optimal approach to the treatment of
`micrometastases. Second, an objective response to chemotherapy
`in the primary lesion provides important in vivo evidence that
`the therapy being used has antitumor activity· and suggests that
`the tumor at remote subclinical sites will be sensitive as well. By
`contrast, if the primary lesion does not respond, the likelihood of
`success of the initial chemotherapy regimen in eradicating micro(cid:173)
`merascases would seem to be greatly diminished. This provides an
`early opportunity to consider alternative chemotherapy ap(cid:173)
`proaches. This approach has perhaps best been described for osteo(cid:173)
`sarcoma.12 Third, significant regression of the primary tumor may
`allow the local management to be tailored to the individual pa(cid:173)
`tient. Surgery may be technically easier because of the reduced
`tumor bulk, a more conservative surgical procedure may be consid(cid:173)
`ered, or radiation therapy might be administered in lieu of surgery.
`The latter two approaches may permit organ sparing and func(cid:173)
`tion preservation for some patients. In some situations, preopera(cid:173)
`tive chemotherapy is administered concurrently with radiation
`therapy, to improve local disease control as well as to treat systemic
`micrometastases. For cancer of the anal canal and bladder cancer,
`this approach has allowed organ-sparing procedures for a high per(cid:173)
`centage of patients treated in this manner. It has served as highly
`effective preoperative therapy for other diseases such as esophageal
`cancer and head and neck cancer.
`The potential disadvantages of the neoadjuvant approach are
`also very real. First, chemotherapy is being used as initial therapy
`in a group of patients with a cancer that is potentially curable by
`surgery alone in a small percentage of patients. If chemotherapy
`proves ineffective and the cancer becomes unresectable during
`treatment, great harm has been done. Second, the use of preopera(cid:173)
`tive chemotherapy may obscure the. true pathologic stage of the
`cancer by altering rumor margins and converting histologically
`positive nodes to negative. The inaccuracy of clinical staging for
`many diseases makes it difficult to be confident that a homogene(cid:173)
`ous group of patients has been treated and may confound interpre(cid:173)
`tation of results. Third, if a dramatic clinical response results in
`the performance of an inappropriately conservative procedure or
`
`poor patient acceptance of the recommended procedure, and the
`cancer recurs, a significant disservice has been done to the patient.
`Table 12-3 lists those cancers that have been effectively man(cid:173)
`aged using neoadjuvant chemotherapy. In all cases, this "effective(cid:173)
`ness" may not imply improved survival. In some cases organ spar(cid:173)
`ing or function preservation is routinely possible and is the
`justification for the use of this approach.
`
`MANAGEMENT OF ADVANCED AND
`METASTATIC DISEASE
`
`The most common use of c~cer chemotherapy is in the man(cid:173)
`agement of advanced or metastatic disease following failed local
`therapies or in disease for which no alternative therapy has been
`found. This is perhaps the sternest test for chemotherapy, since
`tumor volume is significant and patients are often physically com(cid:173)
`promised by the effects of their disease. However, it is this clinical
`situation in which the activity of new anticancer agents and com(cid:173)
`bination chemotherapy regimens are initially evaluated. In treat(cid:173)
`ing patients with advanced cancer, it is possible to determine both
`the antitumor activity of. the therapy on an individual patient
`basis and to define the response rate for the therapy accurately,
`by entering an appropriate number of patients with the same diag(cid:173)
`nosis and similar pretreatment characteristics in a clinical trial.
`The benefit of chemotherapy to patients can be inferred by the
`degree to which measurable or evaluable tumor responds to ther(cid:173)
`apy. Clearly, the most important measure of the efficacy of chemo(cid:173)
`therapy is the achievement of a complete response. Defined as the
`disappearance of all radiographic and clinical evidence of measura(cid:173)
`ble or evaluable tumor, it is a necessary first step to achieve cura(cid:173)
`tive therapy. The achievement of a complete response results in
`a significant decrease or disappearance in disease related symptoms
`and generally translates into a meaningful prolongation of survival,
`even in patients who ultimately relapse. Therapy can only be said
`to be curative when the complete response is maintained after
`treatment is discontinued. The clinical importance of a radio(cid:173)
`graphic complete response is therefore measured by the disease(cid:173)
`free or relapse-free survival. Partial responses-defined as a 50
`percent decrease in cross-sectional area of radiographically meas(cid:173)
`urable tumor masses-may also result in symptomatic benefit for
`patients, although survival is rarely significantly prolonged. To
`maintain the partial response requires continued administration
`of the chemotherapy regimen. Unless the regimen is extremely
`
`9 of 133
`
`Celltrion, Inc., Exhibit 1016
`
`

`

`204 Science of Clinical Oncology / I
`
`Table 12-4. Cancers Curable or Occasionally Curable with
`Chemotherapy Alone
`
`Cancers chat ace curable with chemotherapy alone
`Gestational choriocarcinoma
`Hodgkin's disease
`Germ cell cancer of the .testis
`Acute lymphoid leukemia
`Non-Hodgkin's lymphoma (some subtypes)
`Hairy cell leukemia (probable)
`Cancers occasionally curable with chemotherapy
`Acute myeloid leukemia
`Ovarian cancer
`Small cell lung cancer
`
`well tolerated, the cumulative effects of chemotherapy may ulti(cid:173)
`mately limit the benefit to the patient. The median duration of
`response is often used as an end point in clinical trials of therapies,
`resulting in a significant number of partial responses. Perhaps the
`greatest value of documenting partial responses to clinical investi·
`gators is in the evaluation of experimental new drugs, in which
`preliminary evidence for antitumor activity of new.drugs is often
`first observed. New agents that produce partial responses in pa(cid:173)
`tients with advanced cancer in phase I or II trials may warrant
`further evaluation in earlier stages of disease or in combination
`with other active agents. Patients who have stable disease while
`receiving therapy, that is, not meeting the criteria for either an
`objective response or progressive· disease, are reported in some
`clinical trials, although the scientific value of this measure in eval(cid:173)
`uating therapy can be legitimately questioned. For individual pa(cid:173)
`tients who have extended periods of stable disease and symptom(cid:173)
`atic palliation on treatment following a period of rapid progression,
`the clinician may consider the therapy of value and continue it
`on that basis. The importance of this end point may increase as
`novel agents that are not truly "cytotoxic" enter clinical trial,
`such as antimetastatic agents, differentiating agents, or agents that
`affect intracellular signaling. In these cases, it is possible that evi(cid:173)
`dence of biologic effect may take a different form from that to
`which we have become accustomed with conventional cytotoxic
`agents.
`Although objective responses, duration of survival, and cure
`rates have been our traditional chemotherapy end points, it has
`become increasingly clear that clinical researchers and clinicians
`caring for patients must consider other outcomes or endpoints as
`well. These generally fall under the rubric of palliation of symp(cid:173)
`toms and quality of life.13•14 While these end points may be more
`subjective than the traditional ones, it is important that criteria
`f