Fo4Se
`
`aeee
`i
`SLSSeSorate ere
`
`incent T. DeVita,Jr.
`Samuel Hellman
`Steven A. Rosenberg
`
`yn re ee eg| eae tet foarr
`att be ae
`ad
`oa
`a
`ba FS SE Se
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`ALVOGEN, Exh. 1017, p. 0001
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`oepe eet
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`Ts ee
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`

`

`CANCER
`Principles & Practice
`of Oncology
`
`
`
`
`SERRE oe
`SHEEE
`
`
`BERBERS
`SEEEE
`
`SERRE oe
`Zon
`
`BERR eee Oe
`OE2Z EEE
`
`
`
`
`
`4th Edition
`
`
`
`J. B. LIPPINCOTT COMPANY
`Philadelphia
`
`ALVOGEN, Exh. 1017, p. 0002
`
`ALVOGEN, Exh. 1017, p. 0002
`
`

`

`
`
`Project Editor: Dina K. Rubin
`Indexer: Sandra King
`Design Coordinator: Doug Smock
`Production Manager: Caren Erlichman
`Production Coordinator: Sharon McCarthy
`Compositor: Tapsco Incorporated
`Printer/Binder: Courier Book Company/Westford
`Color Insert Printer: Village Craftsmen/Princeton Polychrome Press
`
`4th Edition
`
`Copyright © 1993, by J. B. Lippincott Company.
`Copyright © 1989, 1985, 1982 by J. 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.
`65432
`
`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 0-397-51321-6 (two-vol. set)
`ISBN 0-397-51322-4 (vol. 1)
`ISBN 0-397-51323-2 (vol. 2)
`ISSN 0892-0567
`1. Cancer.
`2. Oncology.
`III. Rosenberg, Steven A.
`
`I. DeVita, Vincent T., Jr.
`
`IJ. 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 readeris
`urged to check the package insert for each drug for any changein indications and dosage and
`for added warnings and precautions. This is particularly important when the recommended
`agentis a new or infrequently employed drug.
`
`ALVOGEN, Exh. 1017, p. 0003
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`

`

`CONTENTS
`
`PART 1
`
`PRINCIPLES OF ONCOLOGY° 2! 00000.00000005.2.20205.008
`
`1
`
`1 P
`
`rinciples of Molecular Cell Biology of Cancer: Introduction
`to Methods in Molecular Biology ...... 2.00000 ee 3
`SUSAN VANDE WOUDE
`GEORGE F. VANDE WOUDE
`
`Structure of DNA 3
`Gene Expression
`5
`5
`DNAStructural Analysis
`Detection of Genes and Gene Products
`11
`Isolation and Characterization of Genes
`14
`Characterization of the Human Genome
`____Models Using Recombinant DNA Technology
`Implications for Oncology
`17
`Glossary of Terms Used in Molecular Biology
`and Oncogene Research
`18
`
`9
`
`16
`
`xxi
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`

`g Mgrs % HR A Dee
`
`23
`
`gk Rae eae HOMER
`
`35
`
`xii
`
`Contents
`
`2 P
`
`rinciples of Molecular Cell Biology of Cancer: General Aspects
`Of Gene ROMANO a4. csp ee es &
`8 Be yewn a ee oye
`ARUN SETH
`TAKIS S. PAPAS
`
`23
`Transcription
`30
`Regulation of the Regulators
`Transcription Factors in Muscle Cell Development
`Transcription Factors in Oncogenesis
`32
`
`31
`
`O P
`
`rinciples of Molecular Cell Biology of Cancer: Oncogenes ..... .
`ARCHIBALD 5S. PERKINS
`GEORGE F. VANDE WOUDE
`
`Identification of Oncogenes and Tumor Suppressor Genes
`Tumor Suppressor Genes or Recessive Oncogenes
`4]
`47
`Dominant Oncogenes Involved in Signal Transduction
`Transformed Cell Phenotype, Antineoplastic Drugs, and the Cell Cycle
`
`36
`
`54
`
`hd de Pin, ASS 60
`
`& P
`
`rinciples of Molecular Cell Biology of Cancer: The Cell Cycle... .
`RENATO BASERGA
`
`The Cell Cycle
`60
`Tumor Growth
`60
`Gene Expression andCell Proliferation
`Molecular Biology of the Cell Cycle
`
`61
`
`62
`
`ee en ee
`
`67
`
`O P
`
`rinciples of Molecular Cell Biology of Cancer: Chromosome
`Abnormalities in Human Cancer and Leukemia ...............
`
`JANET D. ROWLEY
`FELIX MITELMAN
`
`67
`
`Chromosome Nomenclature
`Myeloid Disorders
`68
`Malignant Lymphoid Disorders
`Solid Tumors
`78
`Conclusions
`87
`Glossary of Cytogenetic Terminology
`
`73
`
`87
`
`‘b
`Principles of Molecular Cell Biology of Cancer: Molecular
`Approaches to Cancer Diagnosis
`.........0 0.6. cee
`JEFFREY SKLAR
`
`92
`General Considerations
`Purposes of Molecular Tests in Cancer Diagnosis
`
`93
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`

`re
`
`Contents
`
`xxill
`
`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
`110
`
`95
`
`114
`
`a 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
`126
`Growth Inhibitory Cytokines
`Growth Factors and Their Receptors as Targets for Anticancer Therapy
`
`116
`
`127
`
`Principles of Molecular Cell Biology of Cancer: Cancer Metastasis .............
`LANCE A. LIOTTA
`WILLIAM G, STETLER-STEVENSON
`
`134
`
`134
`
`136
`
`139
`
`The Clinical Significance of Invasion and Metastasis
`Heterogeneity of the Metastatic Phenotype
`135
`Multiple Gene Products Are Involved in the Complex Metastatic Cascade
`Circulating Tumor Cell Arrest and Extravasation
`137
`Metastasis Organ Distribution
`137
`Basement Membrane Disruption During Transition From In Situ
`to Invasive Tumors
`139
`Three-Step Theory of Invasion
`Laminin Receptors
`140
`140
`RGDRecognition Receptors (Integrins)
`Cadherins: Role of Cell-Cell Adhesion in Tumor-Cell Invasion
`Tumor-Cell Motility Factors
`140
`Proteinases and Tumor-Cell Invasion: From Correlation to Causality
`Natural Proteinase Inhibitors Are Invasion Suppressors
`143
`144
`Angiogenesis and TumorInvasion Are Functionally Related
`Metastasis and Tumorigenicity Can Be Under Separate Genetic Control
`Metastasis Suppressor Genes
`146
`NewStrategies for Metastasis Diagnosis and Therapy
`
`140
`
`141
`
`145
`
`146
`
`150
`
`9 P
`
`andenmology Of Caller or ee ak, ob knee a ee wena sen mmmeaals GOSs 4 cone
`JOSEPH F. FRAUMENI,
`JR.
`SUSAN S. DEVESA
`ROBERT N. HOOVER
`LEO J. KINLEN
`Historical Perspective
`Aimsof 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
`
`10
`Principles of Carcinogenesis: Viral
`PETER M. HOWLEY
`
`Human Retroviruses
`Hepatitis B Virus
`Papillomaviruses
`Epstein-Barr Virus
`Burkitt's Lymphoma
`
`183
`
`185
`188
`194
`195
`
`.........--+++++:
`
`Pins Ces Ae
`
`8 eas
`
`182
`
`11
`Principles of Carcinogenesis: Chemical ............--
`PETER G, SHIELDS
`CURTIS C. HARRIS
`200
`Multistage Carcinogenesis
`204
`Assessmentof Cancer Risk in Humans
`Molecular Epidemiology of Human Cancer
`Carcinogenicity of Chemotherapy
`208
`
`207
`
`Oe cle eae ws
`
`200
`
`12
`Principles of Carcinogenesis: Physical ...........-++-
`ERIC J. HALL
`213
`Ionizing Radiations
`Ultraviolet Radiation Carcinogenesis
`Asbestos
`221
`223
`Electric and Magnetic Fields
`Hyperthermia and Erythema AbIgne
`
`224
`
`220
`
`.
`
`SSL. SSR eRe
`
`213
`
`2 ee 6S os oe 228
`
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`13
`Principles of Oncologic Pathology ............-.5++>:
`JUAN ROSAI
`Classification of Tumors
`Grading of Tumors
`229
`Precancerous Conditions and Carcinoma In Situ
`Methods in Oncologic Pathology
`230
`Image Analysis
`233
`233
`Diagnostic Cytology
`Intraoperative Consultation
`
`228
`
`235
`
`229
`
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`

`

`i4
`Beeeies, OF OUPeICAl ONCOIORY 6. occas aes oa s és bo ec we co ene ce 5 REM:
`STEVEN A. ROSENBERG
`
`238
`
`Contents
`
`XXV
`
`Historical Perspective
`The Operation
`239
`Roles for Surgery
`242
`
`238
`
`15
`Frinciples of Radiation Therapy... .. 66 cc ce ce ee ee MORFOM CURAHD
`SAMUEL HELLMAN
`
`248
`
`Physical Considerations
`Biologic Considerations
`Tumor Radiobiology
`Clinical Considerations
`
`248
`255
`264
`268
`
`iis [£000 PIA WAG ccc cus aac vewssbanws
`
`276
`
`16
`Principles of Chemotherapy’
`VINCENT T. DEVITA, JR
`History
`276
`276
`ChemotherapyAsPart 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 ChemotherapyIs Affected by the Biology of Tumor Growth
`Biochemical Resistance to Chemotherapy Is the Major Impediment
`to Successful Treatment
`281
`Concept of Dose Intensity
`283
`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
`
`280
`
`286
`
`289
`
`17
`Principles and Applications of Biologic Therapy ...................-........
`STEVEN A. ROSENBERG
`Basic Principles of Tumor Immunology
`Immunotherapy
`305
`
`293
`
`293
`
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`

`xxvi
`
`Contents
`
`13
`FCROET TS esi oder tiie si xoncecea 4
`BRUCE A. CHABNER
`
`+
`
`© on aha «oe MAOWOOND, IADR 25 325
`
`section 1
`
`Cancer Drug Discovery and Development
`MICHAEL R. GREVER
`BRUCE A. CHABNER
`
`328
`
`329
`Drug Discovery
`Drug Development
`337
`Conclusion
`339
`
`section 2 Mechanisms of Antineoplastic Drug Resistance
`CHARLES 5. MORROW
`KENNETH H. COWAN
`
`340
`
`General Mechanismsof Resistance to Antineoplastic Drugs
`Resistance to Multiple Drugs
`342
`Approachesfor the Prevention or Reversal of Clinical Drug Resistance
`
`341
`
`344
`
`SECTION 3 Investigational Agents
`MICHAEL J. HAWKINS
`
`349
`
`349
`Amsacrine
`Topoisomerase I Inhibitors
`Anthrapyrazoles
`353
`Retinoids
`354
`
`35]
`
`section 4 Antimetabolites
`EDWARD CHU
`CHRIS H. TAKIMOTO
`
`358
`
`358
`Antifolates
`Fluoropyrimidines
`Cytarabine
`365
`369
`Purine Analogs
`Adenosine Analogs
`
`362
`
`370
`
`section QO Antitumor Antibiotics
`BRUCE A. CHABNER
`CHARLES E. MYERS
`
`374
`
`374
`Bleomycin
`Anthracyclines
`Mitomycin C
`Dactinomycin
`Mithramycin
`
`376
`381
`382
`383
`
`section 6 Miscellaneous Agents
`BRUCE A. CHABNER
`
`385
`
`385
`
`Hexamethylmelamine
`Dacarbazine
`385
`Procarbazine
`386
`L-Asparaginase
`387
`
`
`
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`

`Contents
`
`XXVii
`
`section 7 Platinum Analogs
`EDDIE REED
`
`390
`
`390
`Chemistry
`Methods of Measurementof Platinum-DNA Adducts
`Mechanism of Action
`392
`393
`Determinants of Sensitivity and Resistance
`Clinical Pharmacokinetics and Drug Administration
`Toxicity
`396
`
`391
`
`394
`
`section 8 Alkylating Agents
`NATHAN A. BERGER
`
`400
`
`401
`
`Nitrogen Mustard
`Melphalan
`402
`Chlorambucil
`403
`Busulfan
`403
`Cyclophosphamide
`Ifosfamide
`405
`4-Hydroperoxycyclophosphamide
`Nitrosoureas
`405
`Thiotepa
`406
`
`403
`
`405
`
`section 9 Anticancer Drugs Derived From Plants
`ROSS C. DONEHOWER
`ERIC K. ROWINSKY
`
`409
`
`409
`Vinca Alkaloids
`Epipodophyllotoxins
`Taxol
`414
`
`412
`
`Mechanism of Action
`
`415
`
`!
`
`)
`
`
`
`
`19
`Design and Conduct of Clinical Trials ..... 0.000.000.0000 ce eee
`RICHARD SIMON
`
`418
`
`
`
`
`Study Objectives
`atient Eligibility
`ndpoint
`420
`420
`eatment Allocation
`_ Size and Duration of the Study
`_ Epidemiology of Clinical Trials
`Data Management
`432
`Ethics
`432
`Analysis
`433
`\ Reporting Results of Clinical Trials
`Meta-analysis
`438
`
`419
`419
`
`424
`431
`
`436
`
`
`
`ALVOGEN, Exh. 1017, p. 0010
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`
`

`

`xxvili
`
`Contents
`
`PART 2
`
`PRACTICE OF ONCOBOGY’) 00-0: i085 to foowenwess'4 to soda 441
`
`20
`Cancer Prevention
`
`SECTION 1
`
`Dietary Fat and Cancer
`PETER GREENWALD
`CAROLYN CLIFFORD
`
`443
`
`Epidemiologic Evidence
`Experimental Evidence
`Clinical Metabolic Studies
`Clinical Intervention Studies
`Alcohol and Cancer
`448
`Conclusion
`448
`
`444
`446
`446
`447
`
`SECTION z
`
`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
`
`457
`
`457
`Epidemiologic Evidence
`Mechanismsof Carcinogenesis and Chemoprevention Research
`Biologic Markers
`459
`The Chemoprevention Program atthe NCI
`Clinical Chemoprevention Research
`459
`Future Directions
`462
`
`459
`
`458
`
`SECTION 4
`
`Retinoids and Carotenoids
`JULIE E. BURING
`CHARLES H. HENNEKENS
`
`464
`
`Vitamin A Analogs and Precursors
`Retinoids
`464
`Carotenoids
`466
`The Need for Randomized Trials
`Ongoing Trials
`469
`Conclusion
`470
`
`464
`
`469
`
`SECTION 5
`
`474
`Hormones
`BRIAN E. HENDERSON
`LESLIE BERNSTEIN
`RONALD ROSS
`
`475
`Oral Contraceptives
`Hormone Replacement Therapy
`
`476
`
`ALVOGEN, Exh. 1017, p. 0011
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`

`aeeeTun
`
`Contents
`
`xxix
`
`Luteinizing-Hormone-Releasing-Hormone Agonists
`Tamoxifen
`477
`Chemoprevention of Prostate Cancer
`
`479
`
`477
`
`section 6 Curtailing the Tobacco Pandemic
`ALAN BLUM
`
`480
`
`482
`
`483
`
`484
`
`481
`Lung Cancer
`Laryngeal Cancer
`Oral Cancer
`483
`483
`Esophageal Cancer
`Cancerof the Uterine Cervix and Ovary
`Other Cancers
`483
`484
`Coronary Heart Disease
`484
`Cerebrovascular Disease
`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
`
`21
`Specialized Techniques of Cancer Management and Diagnosis
`section 1
`Endoscopy
`492
`ROBERT C. KURTZ
`CHARLES J. LIGHTDALE
`ROBERTJ. GINSBERG
`Upper Gastrointestinal Endoscopy
`Endoscopic Ultrasonography
`494
`Sigmoidoscopy
`496
`Colonoscopy
`497
`Laparoscopy
`498
`Endoscopic Retrograde Cholangiopancreatography
`Small Intestinal Endoscopy: Enteroscopy
`500
`Percutaneous Endoscopic Gastrostomy
`501
`Bronchoscopy
`9501
`Mediastinoscopy
`504
`Thoracoscopy
`505
`
`499
`
`492
`
`.............+..:
`
`492
`
`
`
`section 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
`
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`

`

`Cancer: Principles & Practice of Oncology, Fourth Edition,
`edited by Vincent T. DeVita, Jr., Samuel Hellman, Steven A. Rosenberg.
`J.B. Lippincott Co., Philadelphia © 1993,
`
`Vincent T. DeVita, Jr
`
`
`
`CHAPTER 1 ip
`
`Principles of Chemotherapy
`
`
`
`HISTORY
`
`Cancer chemotherapyhad 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
`Clowes, at Roswell Park MemorialInstitute in Buffalo, New
`York, in the early 1900s, to develop inbred rodentlines that
`could carry transplanted tumors.' These types of models
`served as the testing ground for potential cancer chemother-
`apeutic agents and only recently have beeneffectively sup-
`plemented by humancells 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 Bari Harbor during World War II** and the exposure of
`seamen to mustard gas led to the observation that alkylating
`agents caused marrow and lymphoid hypoplasia, which led to
`their use in humans with hematopoietic neoplasms such as
`Hodgkin’s disease and lymphocytic 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.'* The demonstration of dra-
`matic regressions in advanced lymphomas with chemicals
`caused much excitementand later much disappointment, be-
`cause the tumors invariably grewback. 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 beganin earnest. The cure of childhood leukemias
`and Hodgkin's disease with combination chemotherapyin the
`1960s proved that human cancers, even in their advanced
`stages, could be cured by drugs, and the application to the
`chemotherapyof solid tumors began.
`
`276
`
`CHEMOTHERAPY AS PART
`OF THE INITIAL TREATMENT
`OF CANCER
`
`There are four ways chemotherapy is generally used®: as an
`induction treatment for advanced disease, as an adjunct to
`the local methodsof treatment, as the primary treatmentfor
`patients who present withlocalized cancer, and by direct in-
`stallation into sanctuariesorby site-directed 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 treatmentfor patients
`who present with advanced cancer for which noalternative
`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 whenused alonein similar patient pop-
`ulations, Patients whofail after one drug treatmentandrequire
`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 salvage treatment.
`Adjuvant 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 samehistologic 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
`
`
`
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`

`

`Clinical Endpoints in Evaluating Response to Chemotherapy
`
`277
`
`risk of recurrence after local treatment alone and on disease
`variables knownto 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 approachalso hasbeencalled
`neoadjuvant chemotherapy, but the term primary chemother-
`apy is more accurate.”* For chemotherapyto be used as the
`primary treatment ofa partially curable, localized cancer,
`there must be considerable evidence for the effectiveness of
`the drug program against advanced disease of the sametype.
`
`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-by-casebasis.
`Thepartial responserateis usually defined as the fraction of
`patients that demonstratesat 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 approachis worth pursuing further. The
`most important indicator ofthe effectiveness of chemotherapy
`is the complete response rate—it is the prerequisite for cure.
`Whennewprogramsconsistently 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 responseare such that complete responses
`should always be reported separately. The most important
`indicator of the quality of a complete remissionis the relapse-
`free survival from thetimeall treatmentis discontinued. This
`criteria is the only clinical counterpart of the quantifiable cy-
`toreductive effect of drugs in rodent systems. A current trend
`among manyclinicalinvestigators is the use of“freedom from
`progression” ofpatients whohave attained complete andpar-
`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 determinantof 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 beenrefined
`so that the complete responserate is higher than 50%.
`
`ADJUVANT CHEMOTHERAPY
`There was great excitement concomitant with the use of che-
`motherapy as an adjunct to local treatments. The promise
`was great, because tumor volumeis at a minimum whenad-
`juvanttherapyis initiated, and it was assumed thattreatment
`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 havelittle scientific basis. Failure
`
`to appreciate the problemssurrounding the assessmentofthe
`response ofa group ofpatients to adjuvant chemotherapyis
`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 cancers.*'°
`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 responserates in an
`entirely different population of patients with advanced disease
`with the same histologic type. Relapse-free survival remains
`the major endpoint, but the micrometastasesin the population
`of adjuvant-treated patients consist of a mixture of tumorcells,
`someof which can be expectedto be sensitive to chemother-
`apy. and othersresistant. The relapse-free survival in the ad-
`juvantsetting, therefore, measures time to regrowth ofcells
`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 intervalof 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 overcomethe shortcomings of the
`absenceofanindicator of individual response have not proved
`practical.
`
`PRIMARY CHEMOTHERAPY
`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 massas a biologic
`markerof responsiveness to the drugs. As with induction che-
`motherapy for patients with advanced cancer,it is possible
`to determine, on a case-by-case basis, the potential effective-
`ness of a new treatmentprogram.By definition, the presenting
`tumor massis also the largest aggregate of tumorin the body
`and, historically, the oldest, and it is therefore the aggregate
`mass of tumorcells most likely to contain one or moreresis-
`tant cell lines.!! Being the largest massofcells, it is also the
`mass withthe least favorable cell kinetics.It is reasonable to
`assume, then, that whatever the effect of chemotherapy the
`physician sees on the primary tumor,a similaror greatereffect
`is occurring fairly uniformly in micrometastatic deposits. A
`poorresponse of the primary tumorto chemotherapy indicates
`a groupofpatients for whichalternative methodsof treatment
`should be 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 ofresidual tumor and histologic examination
`of the tissue allow determination ofthe viability of the re-
`maining tumor mass. The response duration of complete and
`partial responders mustbe catalogued separately.
`The most important issue facing investigators of primary
`chemotherapyis whetheraneffective primary chemotherapy
`treatment, pursued flexibly and intensively to complete re-
`mission, plus two or more additional cyclesoftreatment,will
`define a significant fraction ofpatients whosediseaseis 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 thereis 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.°
`The use of chemotherapy as the primary treatment is re-
`viewed, when appropriate, in each of the disease-oriented
`chapters. Table 16-1 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 category).'*"'"
`
`SPECIAL USES OF CHEMOTHERAPY
`
`Special uses of chemotherapy include (1) theinstallation of
`drugs into thespinal fluid, directly through a lumbar puncture
`needle or into an implanted Ommayareservoir, to treat men-
`ingeal leukemia and lymphoma, and into the pleural or the
`pericardial space to control effusions; (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) intraperitoneal
`installation of drugs using dialysis techniques. These uses are
`discussed throughoutthis book in relation to specific cancers.
`In all instances, the rationale for directed chemotherapy is
`based on achieving a higher concentration over time (C x T)
`against the target tumortissue while sparing normal tissue.
`The usefulness of intracerebrospinal fluid and intrapleural
`administration ofdrugs is already established. Hepatic infusion
`
`TABLE 16-1. Primary Chemotherapy
`
`Neoplasms in Which ChemotherapyIs the Primary
`Therapeutic Modality
`Localized diffuse large cell lymphoma
`Burkitt's lymphoma
`Childhood Hodgkin's disease
`Wilms’ tumor
`
`Embryonal rhabdomyosarcoma
`Small cell lung cancer
`
`Neoplasms in Which Primary Chemotherapy Can Allow
`Less Mutilating Surgery
`Anal carcinoma
`Bladder carcinoma
`Breast cancer
`
`Laryngeal cancer
`Osteogenic sarcoma
`Soft tissue sarcomas
`
`Neoplasmsin Which Clinical Trials Indicate an Expanding
`Role for Primary Chemotherapy in the Future
`Non-small-cell lung cancer
`Breast cancer
`
`Esophageal cancer
`Nasopharyngeal cancer
`Other cancers of the head and neck region
`
`
`of chemotherapy has been simplified and improved enough
`by the development of technology for the infusion of drugs
`that a reevaluation of this approachis 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).
`Theintraperitoneal administrationofdrugs to treat ovarian
`cancer, a disease that kills almost exclusivelybylocal effects
`in the abdomen, is nowbeing investigated, because it allows
`a wide distribution of antitumor drugs in the smallest inter-
`stices of the abdominal cavity, and because a higher C x T at
`the tumoris 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. Theeffects are
`particularly marked for drugs such as 5-fluorouracil. whichis
`metabolized in the liver and excreted by the kidney, and
`doxorubicin and cisplatin, which, because of their molecular
`size, diffuse more slowly across the peritoneal membrane. A
`similar approach is being explored with abdominal installation
`of photoaffinity compounds, with subsequent exposure to laser
`light sources (see Chap. 69, section 7).
`Drugs can also be encompassed in lipid bilayer droplets
`called liposomes.””°° Thesurface characteristics ofliposomes
`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 ofliposomes, however,is their
`failure to leave the vascular system exceptin the sinusoids of
`the liver and the spleen; liposome encapsulation ofdrugs for
`targeted delivery has been oflimited value.**
`
`PRINCIPLES GOVERNING THE USE
`OF COMBINATION CHEMOTHERAPY
`
`With some exceptions (¢.g., 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
`werelargely ineffective.”**’ The eraof effective combination
`chemotherapy began when anarray ofactive drugs from dif-
`ferent classes became available for use in combination in the
`treatment of leukemias 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 oftoxicity tolerated by the
`host for each drug; it provides a broader range of coverage of
`resistant cell lines in a heterogenous tumor population; and
`it prevents or slows the development of newresistant lines.
`The following principles have been useful in the selection
`of drugs in the most effective drug combinations, and they
`guide the developmentof new programs:
`
`1. Only drugs known to be partially effective when used
`alone should be selected for use in combination. Ifavail-
`
`ALVOGEN, Exh. 1017, p. 0015
`
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`

`Impactofthe Goldie-Coldman Hypothesis on DesignofClinical Trials Using Combination Chemotherapy
`
`279
`
`able, drugs that produce somefraction of complete re-
`mission are preferred to those that produce only partial
`responses.
`9. 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
`of a lethal effect caused by multiple insults to the same
`organ system bydifferent drugs and allows dose intensity
`to be maximized.
`3. Drugs should beused in their optimal dose and schedule.
`4. 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 normaltarget tissue, which is usually
`the bone marrow.
`
`Omission of a drug from a combination may allow over-
`growthby 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 otherless 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 compartmentthat can supply
`maturecells 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 completeby day 28. Prior treat-
`ment with drugs or x-radiation may alter this sequence by
`depleting the stemcell pool, shortening the time to the ap-
`pearance of leukopenia and thrombocytopenia, and prolonging
`the recovery time. Curiously, when the second half of a com-
`bination givenin the clinic on a day 1, day 8 schedule is omit-
`ted, leukopenia and thrombocytopenia comparable with that
`seen with the full combination usually occur, suggesting that
`the second set of doses does not cause an equal incrementin
`bone marrow suppression, possibly because the stem cell
`compartmentis s