`
`incent I DeVz’ta,Jo:
`Samuel Hellman
`StevenA. Rosenberg
`
`_-
`_
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`.-....,_ T‘nna
`Ah '-
`fl“
`JG. {TIM :w.1,£.;,;*j“-,33.E..~.'.EJ-_,;$5; _V'lflfl}_ if;w‘frfvtwrgr
`
`ALVOGEN, Exh. 1017, p. 0001
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`- 419..
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`.
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`..‘__
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`

`

`CANCER
`
`Principles & Practice
`ofOncology
`
`
`
`
`Ill-l...
`IIII
`
`Illlllll.
`III
`
`III-III.
`Ill
`
`Illllll‘.
`.lhlll
`
`
`
`
`4th Edition
`
`
`
`J. B. LIPPINCOTT COMPANY
`
`I’Iw‘frtc'im’pbm
`
`ALVOGEN, Exh. 1017, p. 0002
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`ALVOGEN, Exh. 1017, p. 0002
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`

`

`
`
`Project Editor: Dina K. Rubin
`Indexer: Sandra King
`Design Coordinator: Doug Smock
`Production Manager: Caren Erlichrnan
`Production Coordinator; Sharon McCarthy
`Compositor: Tapsco Incorporated
`Printer/Binder: Courier Book Company/Westford
`Color insert Printer: Village Craftsmen/ Princeton Polychrorne Press
`
`4th Edition
`
`Copyright © 1993. by .l. B. Lippincott Company.
`Copyright © 1989. 1985. 1982 by l. B. Lippincott Company.
`All rights reserved. No part of this book may be used or reproduced in any manner whatsoever
`without written permission except for brief quotations embodied in critical articles and reviews.
`Printed in the United States of America. For information write J. B. Lippincott Company.
`227 East Washington Square. Philadelphia. Pennsylvania 19106.
`6 5 4 3 2
`
`Library of Congress Cataloging in Publications Data
`
`Cancer: principles and practice of oncology! [edited by] Vincent T. DeVita. Jr.. Samuel Hellman.
`Steven A. Rosenberg; 214 contributors—4th ed.
`p.
`cm.
`Includes bibliographical references.
`Includes index.
`ISBN 0-397—51214—7 (one-vol. ed.)
`ISBN 0-397613‘21—6 (two—vol. set)
`[SBN 0—397—51322-4 (vol. 1)
`ISBN 0‘397—51323—2 (vol. 2)
`ISSN 0892-0567
`1. Cancer.
`2. Oncology.
`[11. Rosenberg. Steven A.
`
`I. DeVita. Vincent T., Jr.
`
`ll. Hellman. Samuel.
`
`The authors and publisher have exerted every effort to ensure that drug selection and dosage
`set forth in this text are in accord with current recommendations and practice at the time of
`publication. However, in view of ongoing research. changes in government regulations. and
`the constant flow of information relating to drug therapy and drug reactions. the reader is
`urged to check the package insert for each drug for any change in indications and dosage and
`for added warnings and precautions. This is particularly important when the recommended
`agent is a new or in frequently employed drug.
`
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`

`

`CONTENTS
`
`PART I
`
`1
`
`3
`
`PRINCIPLES OF ONCOLOGY ...............................
`
`1 P
`
`rinciples of Molecular Cell Biology of Cancer: introduction
`to Methods in Moiecniar Biology ..........................................
`SUSAN VANDE WOUDE
`GEORGE F. VANDE WOUDE
`
`Structure of DNA 3
`
`Gene Expression
`
`5
`
`5
`DNA Structural Analysis
`Detection of Genes and Gene Products
`Isolation and Characterization of Genes
`Characterization of the Human Genome
`
`9
`
`I 1
`l 4
`
`_ _ __ Models Using Recombinant DNA Technology
`Implications for Oncology
`1'?
`Glossary of Terms Used in Molecular Biology
`and Oncogene Research
`18
`
`16
`
`xxi
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`

`

`Xxll
`
`Contents
`
`...............
`
`23
`
`2 P
`
`rinciples of Molecular Cell Biology of Cancer: General Aspects
`of Gene Regulation ....................................
`ARUN SETH
`TAKIS S. PAPAS
`
`...............
`
`35
`
`23
`Transcription
`30
`Regulation of the Regulators
`Transcription Factors in Muscle Cell Development
`Transcription Factors in Oncogenesis
`32
`
`3i
`
`3 P
`
`rinciples of Molecular Cell Biology of Cancer: Oncogenes ......
`ARCHIBALD S. PERKINS
`GEORGE F. VANDE WOUDE
`
`Identification of Oncogenes and Tumor Suppressor Genes
`Tumor Suppressor Genes or Recessive Oncogenes
`4]
`Dominant Oncogenes Involved in Signal Transduction
`
`47
`
`36
`
`Transformed Cell Phenotype, Antineoplastic Drugs, and the Cell Cycle
`
`54
`
`.
`
`.
`
`.
`
`...............
`
`60
`
`4 P
`
`rinciples of Molecular Cell Biology of Cancer: The Cell Cycle
`REN ATO BASERGA
`
`The Cell Cycle
`Tumor Growth
`
`60
`60
`
`Gene Expression and Cell Proliferation
`Molecular Biology of the Cell Cycle
`
`62
`
`6i
`
`...............
`
`67
`
`5 P
`
`rinciples of Molecular Cell Biology of Cancer: Chromosome
`Abnormalities in Human Cancer and Leukemia ...............
`
`jANET D. ROWLEY
`FELIX MITELMAN
`
`Chromosome Nomenclature
`
`67
`
`Myeloid Disorders
`
`68
`
`Malignant Lymphoid Disorders
`Solid Tumors
`78
`Conclusions
`8?
`
`73
`
`Glossary of Cytogenetic Terminology
`
`87
`
`...............
`
`92
`
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`6 P
`
`rinciples of Molecular Cell Biology of Cancer: Molecular
`Approaches to Cancer Diagnosis .........................
`JEFFREY SKLAR
`
`General Considerations
`
`92
`
`Purposes of Molecular Tests in Cancer Diagnosis
`
`93
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`

`

`fi
`
`Contents
`
`xxlll
`
`93
`Molecular Markers in Cancer Diagnosis
`Techniques for Detection of Molecular Markers in Cancer Diagnosis
`Molecular Approaches to Diagnosis in Selected Cancers
`100
`Considerations for the Future
`1 10
`
`95
`
`.
`
`.
`
`7 P
`
`rinciples of Molecular Cell Biology of Cancer: Growth Factors
`JOHN MENDELSOHN
`MARC E. LIPPMAN
`
`.——..
`
`Autocrine Stimulation
`
`114
`
`Growth Factors and Their Receptors
`Growth Factors and Malignancy
`119
`Specific Growth Factors
`120
`
`1 16
`
`126
`Growth Inhibitory Cytokines
`Growth Factors and Their Receptors as Targets for Anticancer Therapy
`
`127
`
`Principles of Molecular Cell Biology of Cancer: Cancer Metastasis
`LANCE A. LIOTTA
`WILLIAM G. STETLER—STEVENSON
`
`The Clinical Significance of Invasion and Metastasis
`
`134
`
`135
`Heterogeneity of the Metastatic Phenotype
`Multiple Gene Products Are Involved in the Complex Metastatic Cascade
`Circulating Tumor Cell Arrest and Extravasation
`137
`Metastasis Organ Distribution
`13'?
`
`136
`
`Basement Membrane Disruption During Transition From In Situ
`to Invasive Tumors
`139
`
`Three-Step Theory of Invasion
`Laminin Receptors
`140
`140
`RGD Recognition Receptors (Integrinsl
`Cadherins: Role of Cell-Cell Adhesion in Tumor-Cell Invasion
`
`139
`
`140
`
`140
`Tumor—Cell Motility Factors
`Proteinases and Tumor-Cell Invasion: From Correlation to Causality
`Natural Proteinase Inhibitors Are Invasion Suppressors
`143
`144
`Angiogenesis and Tumor Invasion Are Functionally Related
`Metastasis and Tumorigenicity Can Be Under Separate Genetic Control
`Metastasis Suppressor Genes
`146
`New Strategies for Metastasis Diagnosis and Therapy
`
`146
`
`141
`
`145
`
`150
`
`9 E
`
`pidemiology of Cancer ................................
`JOSEPH F. FRAUMENI, JR
`SUSAN S. DEVESA
`ROBERT N. HOOVER
`LEO I. KINLEN
`
`Historical Perspective
`Aims of Epidemiology
`151
`Descriptive Studies
`Patterns of Cancer Occurrence
`
`150
`151
`
`154
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`

`XXIV
`
`Contents
`
`165
`Analytic Studies
`Strengths and Limits of Epidemiology
`Interpretation of Epidemiologic Studies
`Causes of Cancer
`170
`
`168
`169
`
`I0
`Principles of Carcinogenesis: Viral .....................................
`PETER M. HOWLEY
`
`182
`
`Human Retroviruses
`
`183
`
`Hepatitis B Virus
`Papillomaviruses
`Epstein-Barr Virus
`Burkitt’s Lymphoma
`
`185
`188
`194
`195
`
`11
`Principles of Carcinogenesis: Chemioai ..................................
`PETER G. SHIELDS
`CURTIS C. HARRIS
`
`200
`
`200
`Multistage Carcinogenesis
`204
`Assessment of Cancer Risk in Humans
`Molecular Epidemiology of Human Cancer
`Carcinogenicity of Chemotherapy
`208
`
`20?
`
`12
`Principles of Carcinogenesis: Physical ...................................
`ERIC 1. HALL
`
`213
`
`213
`Ionizing Radiations
`Ultraviolet Radiation Carcinogenesis
`Asbestos
`221
`
`220
`
`223
`Electric and Magnetic Fields
`Hyperthermia and Erythema Ab Igne
`
`224
`
`13
`Principies of Oncoiogio Pathology .....................................
`JUAN ROSA]
`
`228
`
`Classification of Tumors
`
`228
`
`229
`Grading of Tumors
`Precancerous Conditions and Carcinoma In Situ
`Methods in Oncologic Pathology
`230
`Image Analysis
`233
`233
`Diagnostic Cytology
`Intraoperative Consultation
`
`235
`
`229
`
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`

`

`Contents
`
`xx"
`
`14
`Principles of Surgical Oncology
`STEVEN A. ROSENBERG
`
`Historical Perspective
`The Operation
`239
`Roles for Surgery
`242
`
`238
`
`15
`Principles of Radiation Therapy
`SAMUEL HELLMAN
`
`Physical Considerations
`
`248
`
`Biologic Considerations
`Tumor Radiobiology
`Clinical Considerations
`
`255
`264
`268
`
`16
`Principles of Chemotherapy ..........................................
`
`276
`
`VINCENT T. DEVITA, JR
`
`276
`History
`276
`Chemotherapy As Part of the Initial Treatment of Cancer
`277
`Clinical Endpoints in Evaluating Response to Chemotherapy
`278
`Principles Governing the Use of Combination Chemotherapy
`Impact of the Goldie-Coldman Hypothesis on Design of Clinical Trials
`Using Combination Chemotherapy
`279
`Response to Chemotherapy Is Affected by the Biology of Tumor Growth
`Biochemical Resistance to Chemotherapy Is the Major lmpediment
`to Successful Treatment
`281
`
`280
`
`283
`Concept of Dose Intensity
`In Vitro Tests to Select Chemotherapeutic Agents for Individualized Treatment
`Cancer Drug Development
`286
`288
`Early Clinical Trials of Antitumor Agents
`Overcoming the Limitations of Cancer Treatment
`
`289
`
`286
`
`17
`Principles and Applications of Biologic Therapy ..........................
`STEVEN A. ROSENBERG
`
`293
`
`Basic Principles of Tumor Immunology
`1mllliu‘lotherapy
`305
`
`293
`
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`

`nvi
`
`Contents
`
`18
`Anticancer Drugs ..................................................
`BRUCE A. CHABNER
`
`325
`
`scenes 1
`
`Cancer Drug Discovery and Development
`MICHAEL R. GREVER
`BRUCE A. CHABNER
`
`328
`
`329
`Drug Discovery
`Drug Development
`337
`Conclusion
`339
`
`semen 2 Mechanisms of Antineepiastic Drug Resistance
`CHARLES S. MORROW
`KENNETH H. COWAN
`
`340
`
`General Mechanisms of Resistance to Antineoplastic Drugs
`Resistance to Multiple Drugs
`342
`Approaches for the Prevention or Reversal of Clinical Drug Resistance
`
`34]
`
`344
`
`SECTiON 3 investigatienai Agents
`MICHAEL J. HAWKINS
`
`349
`
`Amsacrine
`
`349
`
`Topoisomerase I Inhibitors
`Anthrapyrazoles
`353
`Retinoids
`354
`
`351
`
`sscnon 4 Antimetaboiites
`EDWARD CHU
`CHRIS H. TAKIMOTO
`
`358
`
`Antifolates
`
`358
`
`362
`
`Fluoropyrimidjnes
`Cytarabine
`365
`369
`Purine Analogs
`Adenosine Analogs
`
`370
`
`SECTiON 5 Antitumor Antibiotics
`BRUCE A. CHABNER
`CHARLES E. MYERS
`
`374
`
`37’4
`Bleomycin
`Anthracyclines
`Mitomycin C
`Dactinomycin
`Mithramycin
`
`376
`381
`382
`383
`
`scenes 6 Misceiianeous Agents
`BRUCE A. CHABNER
`
`385
`
`385
`
`Hexamethylmelamine
`Dacarbazine
`385
`Procarbazine
`386
`
`L-Asparaginase
`
`38?
`
`
`
`ALVOGEN, Exh. 1017, p. 0009
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`

`

`Contents
`
`1“"
`
`SECTION 7 Platinum Analogs
`EDDIE REED
`
`390
`
`390
`Chemistry
`Methods of Measurement of Platinum-DNA Adducts
`
`891
`
`392
`Mechanism of Action
`393
`Determinants of Sensitivity and Resistance
`Clinical Pharmacokinetics and Drug Administration
`Toxicity
`396
`
`394
`
`sermon 8 Alky1ating Agents
`NATHAN A. BERGER
`
`400
`
`401
`
`Nitrogen Mustard
`Melphalan
`402
`Chlorambucil
`403
`Busulfan
`403
`
`Cyclophosphamide
`Ifosfamide
`405
`
`403
`
`4-Hydroperoxycyclophosphamide
`Nitrosoureas
`405
`
`405
`
`Thiotepa
`
`406
`
`SECTION 9 Anticancer Drugs Derived From Plants
`R058 C. DONEHOW'ER
`ERIC K‘ ROWINSKY
`
`409
`
`Vinca Alkaloids
`
`409
`
`Epipodophyllotoxins
`Taxol
`414
`
`412
`
`Mechanism of Action
`
`415
`
`|
`
`’I
`
`
`
`
`19
`Design and Conduct of Clinical Trials ...................................
`RICHARD SIMON
`
`418
`
`
`
`
`Study Objectives
`atient Eligibility
`ndpoint
`420
`eatment Allocation
`
`419
`419
`
`420
`
`e and Duration of the Study
`..
`. Epidemiology of Clinical Trials
`- Data Management
`432
`Ethics
`432
`
`424
`431
`
`433
`Analysis
`1 Reporting Results of Clinical Trials
`With-analysis
`438
`
`436
`
`
`
`ALVOGEN, Exh. 1017, p. 0010
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`
`

`

`xxvtlt
`
`Contents
`
`PART 2
`
`PRACTICE OF ONCOLOGY .................................
`
`441
`
`20
`Cancer Prevention .................................................
`
`SECTION 1 Dietary Fat and Cancer
`PETER GREENWALD
`CAROLYN CLLFFORD
`
`443
`
`Epidemiologic Evidence
`Experimental Evidence
`Clinical Metabolic Studies
`Clinical Intervention Studies
`Alcohol and Cancer
`448
`Conclusion
`448
`
`444
`446
`446
`447
`
`SECTION 2 Dietary Fiber and Cancer
`PETER GREENWALD
`
`450
`
`Dietary Fiber and Colorectal Cancer
`Dietary Fiber and Breast Cancer
`454
`Dietary Fiber and Other Cancers
`455
`Achieving the Guidelines for Dietary Fiber
`
`451
`
`455
`
`SECTION 3 Micronutrients and Chemoprevention
`PETER GREENWALD
`
`45?
`
`457
`Epidemiologic Evidence
`Mechanisms of Carcinogenesis and Chemoprevention Research
`Biologic Markers
`459
`The Chemoprevention Program at the NC]
`Clinical Chemoprevention Research
`459
`Future Directions
`462
`
`459
`
`458
`
`SECTION 4 Retinoids and Carotenoids
`iULlE E. BURINC
`CHARLES H. HENNEKENS
`
`464
`
`Vitamin A Analogs and Precursors
`Retinoids
`464
`Carotenoids
`466
`The Need for Randomized Trials
`
`464
`
`469
`
`Ongoing Trials
`Conclusion
`470
`
`469
`
`474
`SECTTON 5 Hormones
`BRIAN E. HENDERSON
`LESLEE BERNSTEIN
`RONALD ROSS
`
`475
`Oral Contraceptives
`Hormone Replacement Therapy
`
`476
`
`ALVOGEN, Exh. 1017, p. 0011
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`ALVOGEN, Exh. 1017, p. 0011
`
`

`

`__—_1
`
`Contents
`
`XXIX
`
`Luteinizing-Hormone-Releasing-Hormone Agonists
`Tamoxifen
`477
`
`477
`
`Chemoprevention of Prostate Cancer
`
`479
`
`SECTION 6
`
`Curtaiiing the Tobacco Pandemic
`ALAN BLUM
`
`480
`
`481
`Lung Cancer
`Laryngeal Cancer
`Oral Cancer
`483
`
`482
`
`483
`Esophageal Cancer
`Cancer of the Uterine Cervix and Ovary
`Other Cancers
`483
`
`Coronary Heart Disease
`Cerebrovascular Disease
`
`484
`484
`
`Chronic Obstructive Pulmonary Disease
`Women and Smoking
`484
`Ethnic Minorities
`485
`
`"Less Hazardous” Cigarettes
`Spitting Tobacco
`486
`involuntary (Passive) Smoking
`Efforts To Curtail Tobacco Use
`
`485
`
`486
`487
`
`483
`
`484
`
`21
`Specialized Techniques of Cancer Management and Diagnosis ................
`
`492
`
`sacnon 1
`
`492
`Endoscopy
`ROBERT C. KURTZ
`CHARLES J. LIGHTDALE
`ROBERT ]. GINSBERG
`
`492
`
`Upper Gastrointestinal Endoscopy
`Endoscopic Ultrasonography
`494
`Sigmoidoscopy
`496
`Colonoscopy
`497
`Laparoscopy
`498
`Endoscopic Retrograde Cholangiopancreatography
`Small Intestinal Endoscopy: Enteroscopy
`500
`Percutaneous Endoscopic Gastrostomy
`50f
`Bronchoscopy
`501
`Mediastinoscopy
`504
`Thoracoscopy
`505
`
`499
`
`scenes 2
`
`Imaging Techniques in Cancer
`RONALD A. CASTELLINO
`ROBERT L. DELAPAZ
`STEVEN M. LARSON
`
`507
`
`Expectation Versus Reality
`Uses of Diagnostic Imaging
`Accuracy
`513
`Imaging Modalities
`
`517
`
`507
`509
`
`ALVOGEN, Exh. 1017, p. 0012
`
`
`
`ALVOGEN, Exh. 1017, p. 0012
`
`

`

`l‘i'im‘iplr-s i- Prat litt’ of Omoiogtt. l-‘rmi-rli lathilun.
`L'itim't'
`edltud by Vincent 'I‘
`lk‘tha. Jr.. Samuel Hellman Steven A Floscnl'rt-‘rtt.
`.I R l.ippintutt Co . Philadelphia 74: 19.93.
`
`Vincent T. DeVita, Jr
`
`
`
`CHAPTER I 6
`
`Prinaples 0f Chemotherapy
`
`
`
`HISTORY
`
`Cancer chemotherapy had its roots in the work of Paul Ehrlich,
`who coined the word chemotherapy. Ehrlich's use of rodent
`models of infectious diseases to develop antibiotics led George
`Clowcs, at Roswell Park Memorial Institute in Buffalo, New
`York, in the early 19005. to develop inbred rodent lines that
`could carry transplanted tumors.1 These types of models
`served as the testing ground for potential cancer chemother—
`apeutic agents and only recently have been effectively sup«
`plemented by human cells grown in culture. Alkylating agents.
`the first modern chemotherapeutic agents. were a product of
`the secret war gas program in both world wars. An explosion
`in Ban' Harbor during World War "2.3 and the expOsure of
`seamen to mustard gas led to the observation that alkyiating
`agents caused marrow and lymphoid hypoplasia. which led to
`their use in humans with hematopoietic neoplasms such as
`Hodgkin‘s disease and lymphoeytic lymphomas.
`first at
`tempted at Yale-New Haven Medical Center in 1943. Because
`of the secret nature of the gas warfare program. this work
`was not published until 1946."4 The demonstration of dra—
`matic regressions in advanced lymphomas with chemicals
`caused much excitement and later much disappointment, be—
`cause the tumors invariably grcw back. After Farber‘s obser—
`vation on the effects of folic acid on leukemic cell growth in
`children with lymphoblastic leukemia and the development
`of the folic acid antagonists as cancer drugs. the chemotherapy
`of cancer began in earnest. The cure of childhood leukemias
`and Hodgkin’s disease with combination chemotherapy in the
`19605 proved that human cancers. even in their advanced
`stages. could be cured by drugs. and the application to the
`chemotherapy of solid tumors began.
`
`276
`
`CHEMOTHERAPY AS PART
`OF THE INITIAL TREATMENT
`OF CANCER
`
`There are four ways chemotherapy is generally usedfi: as an
`induction treatment for advanced disease, as an adjunct to
`the local methods of treatment. as the primary treatment for
`patients who present with localized cancer. and by direct in—
`stallation into sanctuaries or by sitedirected perfusion of spe—
`cific regions of the body most affected by the cancer.
`The term induction chemotherapy has been used to describe
`the drug therapy given as the primary treatment for patients
`who present with advanced cancer for which no alternative
`treatment exists.“ Development of new treatments is based
`on the effectiveness of the cancer drugs in rodent models.
`Combinations of drugs are fashioned based on the effective-
`ness, the level of cross-resistance, and the limiting toxicity
`of the available drugs when used alone in similar patient pop-
`ulations. Patients who fail after one drug treatment and require
`further chemotherapy pose a particularly difficult treatment
`problem because of the volume of tumor, their poor general
`health. and drug resistance. induction chemotherapy in these
`patients is referred to as salt-Inge treatment.
`Adjutant chemotherapy denotes the use of systemic treat—
`ment after the primary tumor has been controlled by an al—
`ternative method. such as surgery and radiotherapy. The SE-
`lection of an adjuvant treatment program for a particular
`patient is based on response rates in separate groups of pa-
`tients with advanced cancers of the same histologic type. The
`determination of a population of patients as suitable for ad—
`juvant treatment is based on available data on their average
`
`ALVOGEN, Exh. 1017, p. 0013
`
`
`
`ALVOGEN, Exh. 1017, p. 0013
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`

`

`Clinical Endpoints in Evaluating Response to Chemotherapy
`
`277
`
`risk of recurrence after local treatment alone and on disease
`variables known to influence prognosis adversely.
`Primary chemotherapy denotes the use of chemotherapy as
`the initial treatment for patients who present with localized
`cancer for which there is an alternative. but less than com-
`
`pletely effective, treatment. This approach also has been called
`aeoadjuea at chemotherapy, but the term primary chemother-
`apy is more accurate.” For chemotherapy to be used as the
`primary treatment of a partially curable, localized cancer.
`there must be considerable evidence for the effectiveness of
`the drug program against advanced disease of the same type.
`
`CLINICAL ENDPOINTS IN EVALUATING
`RESPONSE TO CHEMOTHERAPY
`
`INDUCTION CHEMOTHERAPY
`
`In induction chemotherapy for advanced cancer. it is possible
`to determine the response to drugs on a case-hy—case basis.
`The partial response rate is usually defined as the fraction of
`patients that demonstrates at least a 50% reduction in mea—
`surable tumor mass: such responses usually are not of much
`value clinically. because they usually are brief and offset by
`the drug toxicity associated with continuous treatment. How-
`ever. partial responses are useful
`in the evaluation of new
`drugs, or new drug programs, to determine whether the par-
`ticular experimental approach is worth pursuing further. The
`most important indicator of the efi'ectiveness of chemotherapy
`is the complete response rate—it is the prerequisite for care.
`When new programs consistently produce more than an oc~
`casional complete remission. they have invariably later proved
`of practical value in medical practice. The qualitative and
`quantitative differences in the clinical value between a com-
`plete and a partial response are such that complete responses
`should always be reported separately. The most important
`indicator ofthe quality ofa complete remission is the relapse—
`l‘rce survival from the time all treatment is discontinued. This
`criteria is the only clinical counterpart of the quantifiable cy-
`toreductive effect ofdrugs in rodent systems. A current trend
`among many clinical investigators is the use of “freedom from
`progression“ of patients who have attained complete and par-
`tial responses. measured as a combined group.” This method
`is said to be an indicator of the practical potential of a new
`treatment. but it obscures the value of a relapse—free survival
`of complete responders as the major determinant of the quality
`of remission and the potential for cure. Other endpoints. such
`as median response duration and median survival. are also of
`little practical value until treatment results have been refined
`so that the complete response rate is higher than 50%.
`
`ADIUVANT CHEMOTHERAPY
`
`There was great excitement concomitant with the use of che-
`motherapy as an adjunct to local treatments. The promise
`was great. because tumor volume is at a minimum when ad-
`juvant therapy is initiated. and it was assumed that treatment
`with drugs at this stage would produce a much higher cure
`rate or that treatment intensity could be reduced and side
`effects thereby diminished. without loss of therapeutic effec-
`tiveness. Both assumptions have little scientific basis. Failure
`
`to appreciate the problems surrounding the assessment of the
`response of a group of patients to adj uvant chemotherapy is
`the source of some of the current disillusionment with the
`
`positive. but less than dramatic. results achieved with adjuvant
`chemotherapy in common tumors. such as breast and colo—
`rectal cancersf'”
`it should be remembered that the major indicator of effec—
`tiveness of a chemotherapy program—the complete remission
`rate—is lost in the adjuvant setting. because the primary tu—
`mor has already been removed.
`in the clinic. treatment is
`selected for individual patients based on response rates in an
`entirely different population of patients with advanced disease
`with the same histologic type. Relapse-free survival remains
`the major endpoint. but the micrometastascs in the population
`of adjuvant—trcated patients consist of a mixture of tumor cells.
`some ofwhich can be expected to be sensitive to chemother—
`apy. and others resistant. The relapse-free survival in the ad—
`juvant setting. therefore. measures time to regrowth of cells
`unresponsive. partially responsive. or very sensitive to che-
`motherapy and is the equivalent of the duration of remission
`of complete and partial responders and the interval of re-
`growth in patients who would have been classified as nonre—
`sponders. In this sense. it is similar to the use of freedom
`from progression in patients with advanced disease. Attempts
`to use in vitro assays of drug sensitivity from the biopsy ma-
`terial of primary tumors to overcome the shortcomings ofthc
`absence of an indicator of individual response have not proved
`practical.
`
`PRIMARY CHEMOTH ERAPY
`
`The unique feature of using chemotherapy in patients with
`localized tumor. before or instead of purely local treatments.
`is the preservation of the presenting tumor mass as a biologic
`marker of responsiveness to the drugs. As with induction che-
`motherapy for patients with advanced cancer, it is possible
`to determine. on a case-by-casc basis. the potential effective—
`ness of a new treatment program. By definition. the presenting
`tumor mass is also the largest aggregate oftumor in the body
`and, historically. the oldest. and it is therefore the aggregate
`mass of tumor cells most likely to contain one or more resis-
`tant cell lines.” Being the largest mass of cells. it is also the
`mass with the least favorable cell kinetics. it is reasonable to
`assume. then. that whatever the effect of chemotherapy the
`physician sees on the primary tumor. a similar or greater effect
`is occurring fairly uniformly in micromctastatic deposits. A
`poor response of the primary tumor to chemotherapy indicates
`a group of patients for which alternative methods of treatment
`should he used quickly. Another feature of primary chemo—
`therapy is the ability to delineate partial responders with
`varying degrees of prognosis. as determined by the state of
`the residual tumor mass after an initial good but partial re-
`sponse. Removal of residual tumor and histologic examination
`of the tissue allow determination of the viability of the re-
`maining tumor mass. The response duration of complete and
`partial responders must be catalogued separately.
`The most important issue facing investigators of primary
`chemotherapy is whether an effective primary chemotherapy
`treatment. pursued flexibly and intensively to complete re-
`mission. plus two or more additional cycles oftreatment. will
`define a significant fraction of patients whose disease is cured
`
`ALVOGEN. Exh. 1017. p. 0014
`
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`

`278
`
`Principles of Chemotherapy
`
`by chemotherapy alone. without the addition of alternative
`treatments. In carefully selected patients with some stages of
`the commonest tumors for which there is less than satisfactory
`standard treatment. such studies are ethically and theoretically
`sound and are being pursued. Such an approach could result
`in briefer.
`less morbid. and more effective treatment
`
`programs.5
`The use of chemotherapy as the primary treatment is re—
`viewed. when appropriate. in each of the disease—oriented
`chapters. Table 16—] lists tumors in which primary chemo—
`therapy for localized forms of the cancer in question have
`already been incorporated in clinic protocols (first and second
`categories) and in which current clinical trials show consid-
`erable progress (third catcgory_).”"”
`
`SPECIAL USES OF Cl-lEMOTl—IERAPY
`
`Special uses of chemotherapy include ('1 ) the installation of
`drugs into the spinal fluid, directly through a lumbar puncture
`needle or into an implanted Omrnaya reservoir. to treat men-
`ingeal leukemia and lymphoma. and into the pleura] or the
`pericardial space to control eil'usions; (2) splenic infusion to
`control spleen size; (3) hepatic artery infusion to treat hepatic:
`metastases selectively; (4) carotid artery infusion to treat head
`and neck cancers and brain tumors; and ('5) intraperitoncal
`installation of drugs using dialysis techniques. These uses are
`discussed throughout this book in relation to specific cancers.
`in all instances. the rationale for directed chemotherapy is
`based on achieving a higher concentration overtime (C X T)
`against the target tumor tissue while sparing normal tissue.
`The usefulness of intraccrebrospinal fluid and intraplcural
`administration oi’drugs is already established. Hepatic infusion
`
`TABLE IG—I. Primary Chemotherapy
`
`Neoplasms in “thick Chemotherapy Is the Primary
`Therapeutic Modality
`Localized diffuse large cell lymphoma
`Burkitt's lymphoma
`Childhood Hodgkin's disease
`Wilms‘ tumor
`
`Embryonal rhabdomyosarcorna
`Small cell lung cancer
`
`Neoplasms in Which Primary Chemotherapy Can Allow
`Leas Mutilating Surgery
`Anal carcinoma
`Bladder carcinoma
`Breast cancer
`
`Laryngeal cancer
`Osteogenic sarcoma
`Soft tissue sarcomas
`
`Neoplasms in Which Clinical Trials Indicate an Expanding
`Role for Primary Chemotherapy in the Future
`Non—small-cell lung cancer
`Breast cancer
`
`Esophageal cancer
`Nasopharyngcal cancer
`Other cancers of the head and neck region
`
`
`of chemotherapy has been simplilied and improved enough
`by the development of technology for the infusion of drugs
`that a reevaluation of this approach is justified (see Chap. 61.
`section 3}. It is now possible to measure the active principles
`of cancer drugs and their targets within the biologic range.
`and drugs can be infused in timing with the body's circadian
`rhythm (see Chap. 69. section 7).
`The intraperitoneal administration ol‘drugs to treat ovarian
`cancer. a disease that kills almost exclusively by local effects
`in the abdomen. is now being investigated. because it allows
`a wide distribution of antitumor drugs in the smallest inter—
`stices oi‘the abdominal cavity. and because a higher (' X T at
`the tumor is achieved (see Chaps. 18 and 39).”"“ The con-
`centration of drug available in the peritoneal cavity for some
`drugs with this "belly bath" technique far exceeds the plasma
`level achievable with systemic administration. The effects are
`particularly marked for drugs such as 5—Huorouracil. which is
`metabolized in the liver and excreted by the kidney. and
`doxorubicin and cisplalin. which. because of their molecular
`size. diffuse more slowly across the peritoneal membrane. A
`similar approach is being explored with abdominal installation
`of photoal’linity compounds. with subsequent exposure to laser
`light sources (see Chap. 69. section 7).
`Drugs can also be encompassed in lipid bilayer droplets
`called liposomesF‘J'” The surface characteristics of liposomes
`can be altered to direct their delivery to specific organ sites
`or into resistant cell lines. Labile liposomes that dissolve at
`temperatures of 41°C can deposit drugs selectively in pre—
`heated areas.” A disadvantage of liposomes. however. is their
`l'ailure to leave the vascular system except in the sinusoids of
`the liver and the spleen; liposome encapsulation ol‘drugs for
`targeted delivery has been of limited value.”
`
`PRINCIPLES GOVERNING THE USE
`OF COMBINATION CHEMOTHERAPY
`
`With some exceptions (9.9.. choriocarcinoma and Burkitt's
`lymphoma). single drugs do not cure cancer. It became ap-
`parent in the 1960s that drug combinations are necessary to
`produce durable clinical responses. In the early years of che—
`motherapy. drug combinations were developed based on
`known biochemical actions of available anticancer drugs
`rather than on their clinical effectiveness. These programs
`were largely ineffective-9"” The era of effective combination
`chemotherapy began when an array of active drugs from dif-
`ferent classes became available For use in combination in the
`
`treatment of lcultemias and lymphomas. Combination che—
`motherapy has now been extended to the treatment of most
`other malignancies. as described throughout this text.
`Combination chemotherapy accomplishes three important
`objectives not possible with single—agent treatment. It provides
`maximal cell kill within the range of toxicity tolerated by the
`host for each drug; it provides a broader range of coverage of
`resistant cell lines in a hetct‘ogcnous tumor population; and
`it prevents or slows the development of new resistant lines.
`The following principles have been useful in the selection
`of drugs in the most effective drug combinations. and they
`guide the development of new programs:
`
`1. Only drugs known to be partially clfective when used
`alone should be selected for use in combination. il’avail-
`
`ALVOGEN, Exh. 1017, p. 0015
`
`ALVOGEN, Exh. 1017, p. 0015
`
`

`

`lmpttct‘. ofthe Goldie—Coldmon Hypothesis on Design ofClitticol Trials Using Combination Chemotherapy
`
`279
`
`able. drugs that produce some Fraction of complete re-
`mission are preferred to those that produce only partial
`responses.
`2. When several drugs of a class are available and are
`equally effective. a drug should be selected on the basis
`of toxicity that does not overlap with the toxicity of other
`drugs to be used in the combination. Although such se-
`lection leads to a wider range of side effects and more
`general discomfort for the patient. it minimizes the risk
`ofa lethal effect caused by multiple insults to the same
`organ system by different drugs and allows dose intensity
`to be maximized.
`
`Drugs should be used in their optimal dose and schedule.
`saw
`. Drug combinations should be given at consistent inter—
`vals. The treatment-free interval between cycles should
`be the shortest possible time necessary for recovery of
`the most sensitive normal target tissue. which is usually
`the bone marrow.
`
`Omission of a drug from a combination may allow over-
`growth by a cell line sensitive to that drug alone and resistant
`to other drugs in the combination. Also. arbitrarily reducing
`the dose of an effective drug to add other less effective drugs
`may reduce the dose of the most effective agent below the
`threshold of effectiveness and destroy the capacity of the
`combination to cure that particular patient.
`Bone marrow has a storage compartment that can supply
`mature cells to the peripheral blood for 8 to 10 days after the
`stem cell pool has been damaged by cytotoxic drugs. Events
`measured in the peripheral blood are usually a week behind
`events occurring in the bone marrow. In previously untreated
`patients. leukopenia and thrombocytopenia are discernible
`on the ninth or tenth day after initial dosing. Nadir blood
`counts are noted between days 14 to 18. with recovery ap-
`parent by day 21 and usually complete by day 28. Prior treat-
`ment with drugs or x—radiation may alter this sequence by
`depleting the stem cell pool. shortening the time to the ap—
`pearance of leukopenia and thrombocytopenia. and prolonging
`the recovery time. Curiously. when the second half ofa com-
`bination given in the