Principles and Practice of·
`
`nco ogy
`
`Derek Raghavan, MBBS, PhD, FRACP, FACP
`Chief, Departments of Solid Tumor Oncology
`and Investigational Therapeutics
`Roswell Park Cancer Institute and
`Professor of Medicine and Urology
`State University of New York at Buffalo
`Buffalo, New York
`
`Howard I. Scher, MD
`Chief, Genitourinary Oncology Service
`Associate .Attending Physician
`Division of Solid Tumor Oncology
`Department of Medicine
`Memorial Sloan-Kettering Cancer Center
`New York, New York
`
`Steven A. Leibel, MD
`Vice Chairman and Clinical Director
`Attending Radiation Oncologist
`Department of Radiation Oncology
`Memorial Sloan-Kettering Cancer Center
`New York, New York
`
`Paul Lange, MD, FACS
`Professor and Chair .
`Department of Urology
`University of Washington
`Seattle, Washington
`
`With 226 Additional Contributors
`
`r Lippincott - Raven
`
`_ , P U B L
`
`I S H E R S
`
`Philadelphia • New York
`
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`

`- 1
`
`Developmental Editor: Eileen Wolfberg Jackson
`Project Editor: EUen M. Campbell
`Production Manager. C11TCn Erlichman
`Production Coordinator: MaryClare Malady
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`Indexer. Steve Sorenson
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`Primer: Courier Book Company/Westford
`
`Copyright Cl I 997 by Lippincott-Raven Publishm. All rights reserved. This book is
`protected by copyright. No pan of it may be reproduced, stored in a retrieval system,
`or transmitted, in any form or by any means-electronic, mechanical, photocopy,
`recording, or otherwise-without the prior written peimission of the publisher, except
`for brief quotations embodied in critical articles and reviews. Printed in the United
`States of America. For information write Lippincott-Raven Publishers, 227 East
`Washington Square, Philadelphia, PA 19106-3780.
`
`Materials appearing in this book prepareed by individuals as part of their official duties
`as U.S. Gov~ent employees are not covered by the above-mentioned copyright.
`
`Library of Congress Cataloging-in-Publication Data
`Principles and practice of genitourinary oncology I Derek Raghavan ...
`[et al.] ; with 226 additional contributors.
`p. cm.
`Includes bibliographical references and index.
`ISBN 0-397-51458-1 (alk. paper)
`I. Raghavan, Derek.
`I. Genitourinary organs- Cancer.
`I. Urogenital Neoplasms. WJ 160 P9573 1996)
`(DNLM:
`RC280.U74P746 1996
`616.99'26-dc20
`DNLM/DLC
`for Library of Congress
`
`96-8893
`CIP
`
`Care has been taken to confirm the accuracy of the information presented and 10
`describe generally accepted practices. However, the authors, editors, and publisher are
`not responsible for errors or omissions or for any consequences from application of the
`information in ibis book and make no warranty, express or implied, with respect to the
`contents of the publication.
`The authors, editors, and publisher have exerted every effort t.o ensure that drug
`selection and dosage set forth in this text are in accordance with current
`recommendations and prac1ice 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. Th.is is panicularly imponant when the recommended ageot is a new
`or infrequently employed drug.
`Some drugs and medical devices presented in this publication have Food and Drug
`Administration (FDA) clearance for limited use in restricted research settings. It is the
`responsibility of the health care provider to ascertain the FDA status of each drug or
`device planned for use in their clinical practice.
`
`9 8 7 6 5 4 3 2 I
`
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`

`

`w·
`
`,,,
`
`... .1
`
`..
`
`Principles and Practice of Genitourinary Oncology, edited by
`Derek Raghavan, Howard I. Scher, Steven A. Leibel, and Paul H.
`Lange. Lippincott-Raven Publishers, Philadelphia,«:> 1997.
`
`CHAPTER 85
`
`Chemotherapy for Renal Cell Carcinoma
`
`Robert]. Motzer and Nicholas]. Vogelzang
`
`Renal cell carcinoma (RCC) is a frequent cause of cancer mor(cid:173)
`tality, responsible for more than 10,000 deaths per year in the
`United States. 1 This is the result of a lack of effective systemic
`treatment for patients with metastatic disease. Advanced RCC
`is characterized by a high level of resistance to all treatment
`modalities that have been studied, including cytotoxic agents,
`hormonal therapy, and biologic response modifiers. Although
`no single agent consistently shows a response proportion of
`20% or higher, interleukin 2 (IL2) and interferon-a (IFNA)
`have demonstrated a low but reproducible response proportion
`in the 10% to 20% range) with durable responses of 5% or less.2
`The experience with chemotherapy and hormonal treatment are
`reviewed in this chapter, along with the general principles of
`management for patients with advanced RCC.
`
`CHEMOTHERAPY
`
`Investigative efforts with chemotherapeutic agents have been
`extensive. Prior to 1975, nitrogen mustard,3 hydroxyurea,4 lo(cid:173)
`mustine,5 dacarbazine,6 and hexamethylmelamine6 were stud(cid:173)
`ied and did not show antitumor activity for RCC. A comprehen(cid:173)
`sive review of the published literature shows that from 1975
`through 1994, 80 single agents were studied in 155 trials (Table
`85-1). Overall, 143 (4%) responses were achieved in 3951 eva(cid:173)
`luable patients. No agent has been shown to achieve major
`responses (complete or partial) in more than 20% of evaluable
`patients (with a sample size of 14 or more patients). Because
`or" the lack of antitumor activity with conventional agents, the
`study of new agents remains justifiable in chemotherapy-naive
`patients.
`The two agents that have been reported to have some, albeit
`minimal, antitumor activity are vinblastine .and floxuridine
`(FUDR). Early studies suggested vinblastine had activity as a
`single agent, with a 26% response proportion reported in 135
`patients. 7 This study served as the basis for the inclusion of
`vinblastine in trials as a part of combined therapy with IFN or
`with agents that modulate multidrug resistance (MDR). How(cid:173)
`ever, the results of more recent trials with vinblastine showed
`only nine responses in 135 (6%) eyaluable patients (see Table
`85-l).74.90.l95-199
`
`A 20% response proportion was reported with continuous
`intravenous infusion of FUDR administered according to a cir(cid:173)
`cadian schedule.8 Response proportions ranged from 0% to 14%
`in seven subsequent trials. of FUDR given in a similar fashion;
`one of these trials included folinic acid.9- 15 Enthusiasm promp(cid:173)
`ted by the first trial resulted in the conduction of a randomized
`multicenter phase III trial of FUDR administered by flat contin(cid:173)
`uous infusion versus a circadian modified 14-day infusion
`schedule. The preliminary report of this trial indicated that the
`response proportion for 82 evaluable patients treated in both
`arms was 9% (95% confidence interval, 4% to 17%).16
`In addition to the trials of.single agents, many combinations
`of chemotherapy agents have been studied. 17- 25 These have not
`shown superior antitumor activity over the single agents, and
`toxicity was generally increased. The lack of antitumor activity
`for any of the many chemotherapy agents that have been studied
`emphasizes the need for novel treatment strategies in patients
`with advanced RCC.
`
`HORMONAL THERAPY
`
`The rationale for the study of hormonal agents in RCC was
`provided by results obtained in animal models in the 1940s
`and the low concentrations of progesterone receptors found in
`human RCC.26 The animal models showed hormone depen(cid:173)
`dence and responsiveness in renal cancers induced in the Syrian
`hamster model.26
`27 initially reported a 16% to 21 % response propor(cid:173)
`Bloom26
`•
`tion for medroxyprogesterone (l\1P) in RCC. In the four trials
`published since 1980, the response proportion declined to 5%
`(Table 85-2).28- 31 Other hormonal agents also have been exten(cid:173)
`sively studied. Testosterone and various other androgens
`achieved an overall 7% response proportion (see Table 85-:2).
`The direct androgen antagonist flutamide was shown to be inac(cid:173)
`tive. 32 The antiestrogens-tamoxifen, nafoxidine, and tormi(cid:173)
`fene-were also studied in multiple trials and found to be rela(cid:173)
`tively inactive, with a 6% response proportion achieved in 318
`patients treated in 11 trials.
`The addition of hormonal therapy to chemotherapy does not
`add efficacy~ this was evident from the results of single-arm
`
`885
`
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`

`

`886
`
`I CHAPTER 85
`
`Agent
`
`Acivicin
`Aclacinomycin
`L-Alanosine
`6-Aminonicatinamide
`Ametantrone
`Aminothiazide
`Amonafide
`Amsacrine
`
`5' -Aza-2-deoxycytidine
`Bisantrene
`
`Bleomycin
`
`Carboplatin
`
`Chlorozotocin
`Cisplatin
`
`Cyclophosphamide
`
`4-Demethoxydaunorubicin
`Dianhydrogalactitol
`
`Diaziquone
`
`Dibromodulcitol (Mitolactol)
`
`Didemnin B
`
`Docetaxel
`Doxorubicin
`Echinomycin
`Elliptinium
`
`4'-Epi-adriamycin (Epirubicin)
`
`Estramustine
`Etoposide
`
`Plus misonidazole
`Dactinomycin
`10-Deazaaminopterin
`2-Deoxycoformycin (Pentostatin}
`
`4'-Deoxydoxorubicin (Esorubicin)
`
`TABLE 85-1. Results of chemotherapy for renal cell carcinoma
`j
`No. of
`Year and
`patients
`reference
`198874
`27
`198475
`15
`198874
`36
`198976
`19
`198577
`25
`198874
`46
`1991 78
`24
`198079
`16
`198080
`21
`198381
`61
`198382
`42
`198783
`12
`198284
`26
`198285
`37
`198586
`20
`198587
`14
`198719
`29
`197588
`15
`197689
`8
`197790
`7
`198891
`19
`199092
`18
`197993
`21
`197894
`23
`197995
`10
`197596
`10
`197997
`44
`198098
`12
`198699
`30
`1981 23
`61
`1984100
`12
`1991 101
`18
`1992102
`25
`1986103
`12
`1986104
`27
`1987105
`24
`1989106
`19
`1990107
`15
`1985108
`19
`1981 97
`53
`1982109
`41
`1982110
`20
`1984111
`29
`1986112
`55
`1986113
`15
`1981 114
`13
`1986115
`31
`1990116
`21
`1992117
`22
`1994118
`18
`1977119
`38
`1993120
`47
`1985121
`8
`1985122
`38
`1988123
`14
`1982124
`20
`1983125
`19
`1981 126
`16
`197997
`43
`
`--f-
`
`I
`! .
`I
`
`_Complete response/
`partial response (%)
`0/1 (4)
`010 {O)
`1/0 (3)
`1/0 (5)
`012 {8)
`0/1 (2)
`010 (0)
`010 (0)
`010 (0)
`0/1 (2)
`0/1 (2)
`010 (0)
`010 (0)
`0/2 (3)
`010 (0)
`010 (0)
`1/2 {10)
`0/0 (0)
`013 (37)
`010 (0)
`010 (0)
`010 (0)
`010 (0)
`0/0 (0)
`0/0 (0)
`010 (0)
`0/2 (4)
`0/0 (0)
`0/1 (3)
`0/1 (2)
`010 (0)
`010 (0)
`010 (0)
`010 (0)
`010 (0)
`010 (0)
`1/1 (10)
`0/1 (7)
`0/0 (0)
`010 (O}
`0/1 (2)
`010 {O)
`010 (0)
`0/1 (2)
`010 {O)
`0/1 (8)
`1/2 (10)
`0/1 (5)
`010 (0)
`010 (0)
`0/2 (5)
`0/1 {2)
`010 (0)
`2/3 (13)
`010 (0)
`0/0 (0)
`0/0.(0}
`010 {O)
`1/0 (2)
`
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`Page 004
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`

`

`CHEMOTHERAPY FOR RENAL CELL CARCINOMA
`
`I 887
`
`TABLE 85-1. Continued.
`
`Agent
`
`Floxurine (circadian)
`
`Plus folinic acid
`By flat infusion
`
`Fludarabine
`
`5-Fluorouracil
`
`Plus folinic acid
`Fosquidone
`Fotemustine
`
`Ftorafur
`Gallium nitrate
`
`Gemcitibine
`
`Hydroxy re a
`ICRF-187
`lfosfamide
`
`Liposomal encapsulated doxorubicin
`Lomustine
`
`Lonidamine
`
`LY186641
`Mafosfamide
`Melphalan
`Menogaril
`
`-1
`
`Methodichlorophen
`Methotrexate
`Mitoguazone (methyl-GAG)
`
`Mitomycin
`Mitotane
`Mitoxantrone
`
`Mitozolomide
`N-methylformamide
`
`Navelbine
`
`Year and
`reference
`19908
`19909
`1991"10
`1991 11
`199212
`199313
`199314
`1991 15
`1991 127
`1993128
`1987129
`1989130
`1991 42
`199343
`199444
`198945
`1992131
`1991 132
`1993133
`1993134
`1984135
`1987136
`1992137
`1993138
`1981 139
`1986140
`1980141
`1981 142
`1987143
`1988144
`1995145
`197790
`1986146
`1986147
`: 1991 148
`1993149
`1992150
`1993151
`1990152
`1991 153
`1979154
`198020
`1981 155
`1981 156
`1982157
`1981 158
`1983159
`1987160
`1981 161
`1984162
`1984163
`1984164
`1986165
`1989166
`1986167
`1989168
`1991 169
`1993170
`
`No. of
`patients
`
`Complete response/
`. partial response (%)
`
`56
`42
`14
`40
`26
`28
`15
`15
`29
`29
`30
`15
`27
`35
`61
`14
`21
`62
`16
`14
`10
`25
`30
`18
`19
`40
`11
`10
`16
`9
`14
`9
`5
`25
`19
`16
`16
`8
`56
`15
`10
`8
`25
`31
`30
`14
`87
`12
`12
`20
`49
`29
`48
`17
`16
`14
`14
`24
`
`417 (20)
`3/3 (14)
`010 (0)
`0/4 (10)
`0/2 (8)
`0/4 (14)
`011 (7)
`010 (0)
`010 (0)
`1/5 (21)
`010 (0)
`010 (0)
`0/2 (7)
`0/4 (11)
`1/2 (5)
`010 (0)
`0/0 (0)
`1/3 (7)
`010 (0)
`010 (0)
`010 (0)
`0/1 (4)
`1/2(10)
`0/1 (6)
`0/1 (5)
`0/0 (0)
`0/1 (9)
`0/2 (20)
`010 (0)
`010 (O}
`010 (0)
`010 (0)
`010 (0)
`0/2 (8)
`1/1 (10)
`1/0 (6)
`1/0 (6)
`0/0 (0)
`0/3 (5)
`010 (0)
`0/3 (30)
`0/2 (25)
`1/3 (16)
`0/0 (0)
`0/3 (10)
`010 (0)
`1/3 (4)
`0/3 (25)
`010 (0)
`010 (0)
`010 (0)
`010 (0)
`010 (0)
`010 (0)
`010 (0)
`010 (0)
`0/0 (0)
`1/0 (4)
`
`-~
`
`(continued)
`
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`Page 005
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`

`

`888
`
`I CHAPTER 85
`
`TABLE 85-1.
`
`Continued.
`
`Agent
`
`Pacfitaxet
`PALA {sparfosic acid)
`
`PCNU
`
`Pirarubicin
`
`Piperazinedione
`Piroxantrone
`Spirogermanium
`
`Streptozocin
`Sulofenur
`Su ram in
`
`Tauromustine
`Taxotere
`Teniposide
`
`6-Thioguanine
`Thiotepa
`Topotecan
`Triazinate
`1 ,2,4-Triglycidyl-urazo
`
`Trimetrexate
`
`Vinblastine
`
`Vindesine
`
`Yoshi-864*
`
`* Plus medroxyprogesterone acetate.
`
`Year and
`reference
`1991 171
`1982172
`198381
`1984173
`198719
`1987174
`1993175
`1977176
`1992177
`1987178
`1984179
`1987180
`1992181
`1991 182
`1992183
`1989184
`1993185
`1979186
`1984187
`1987188
`1991 189
`197790
`1994190
`1981 23
`1986191
`1987192
`1989193
`1992194
`197790
`1984195
`1984196
`1985197
`1987198
`198874
`1992199
`1977200
`1983201
`1982202
`
`No. of
`patients
`
`Complete response/
`partial response (%)
`
`18
`15
`52
`34
`45
`16
`34
`23
`32
`26
`36
`18
`·18
`10
`26
`33
`33
`12
`32
`51
`30
`7
`14
`59
`14
`16
`14
`34
`10
`19
`10
`14
`21
`35
`26
`17
`24
`30
`
`0/0 (O}
`010 (0)
`0/2 (4)
`0/1 (3)
`010 (0)
`0/1 (6)
`0/1 (3)
`010 (0)
`010 (0)
`0/0 (0)
`010 (0)
`011 (6)
`010 (0)
`010 (0)
`0/1 (4)
`010 (0)
`0/2 (6)
`010 (0)
`0/3 (9)
`0/1 (2)
`012 (7)
`0/1 {14)
`0/0 (0)
`1/2 (5)
`010 (0)
`010 (0)
`010 (0)
`0/1 (3)
`010 (0)
`0/3 (16)
`010 (0)
`010 (0)
`1/1 (9)
`013 (9)
`1/0 (4)
`0/0 (0)
`010 (0)
`0/2 (6)
`
`1
`
`I
`
`,.
`I
`
`phase II trials25•33- 35 as well as a randomized trial that showed
`no increase in the response proportion when MP combined with
`IFN was compared with IFN alone. 36 Hormonal therapy has
`little antitumor effect against RCC; responses are infrequent
`and generally of short duration. The role of honnones in the
`treatment of RCC may be best considered as a component of
`supportive care for the properties of progestins in promoting
`appetite and weight gain.
`
`COMBINATION THERAPY
`
`Based on the low but reproducible response proportion of
`immunotherapeutic agents such as IL2 and IFN, combinations
`of chemotherapy and immunotherapy have been studied in RCC
`(Table 85-3). The combination that has been most extensively
`~tudied is IFN plus vinblastine. The results of 13 studies that
`mc~uded 307 patients showed an overall 24% response rate,
`which appeared to be somewhat higher than that reported with
`IFN alone 2 Thr
`d
`·
`.
`·
`ee ran om1zed trials have addressed the efficacy
`
`of interferon ct (IFNA) plus vinblastine versus IFNA alone. 37- 39
`Although one trial showed a slightly higher response proportion
`for the combination,38 none have shown improved survival
`(compared with survival for patients treated with IFNA alone),
`and the vinblastine added gastrointestinal and hematologic tox(cid:173)
`icity.37
`Combinations of 5-fluorourac~l (5-FU) or FUDR with IL2,
`IFN, or both have been studied. The rationale was based on the
`single-agent activity of FUDR in RCC and the anti tumor effects
`of IFN and 5-FU, another pyridamole analog, against adenocar(cid:173)
`cinoma of the colon. Two studies have shown high response
`rates with a combination of 5-FU, IFN and IL2.40
`41 Although
`•
`these. combinations are promising and warrant further investiga(cid:173)
`tion, caution must be exercised in interpreting the results of
`these studies in the context of standard care of patients with
`advanced RCC. The antitumor activity of single-agent 5-FU
`ranged from 0% to 11 % in four trials.42-45 The combination of
`IL2 and IFN has been extensively studied; response proportions
`range from 0% to 40%, with an overall response proportion of
`
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`Motzer-Raghavan 1997
`Page 006
`
`

`

`I I
`
`I
`
`I
`
`I
`I
`I I
`I
`I
`
`I
`
`j
`
`j
`
`I
`
`I
`-t-(cid:173)
`i
`
`TABLE 85-2. Results of hormonal therapy for renal cell carcinoma
`
`CHEMOTHERAPY FOR RENAL CELL CARCINOMA
`
`I 889
`
`Agent
`
`Medroxyprogesterone (or other progestins)
`
`Testosterone propionate (or other androgens)
`
`Flutamide
`Nafoxidine
`
`Tamoxifen
`
`Toremifene
`
`Year and
`reference
`1969203
`1970204
`1971 205
`1971 206
`1971 207
`1973208
`1974209
`1980210
`1981 28
`198429
`198530
`198631
`1969203
`1971 206
`1974209
`197532
`1984211
`1979212
`1981 139
`1980213
`1980214
`1981 215
`1981 216
`1992217
`1993218
`1993219
`1991 148
`1993220
`
`No. of
`patients
`
`Complete response/
`partial response(%)
`
`8
`15
`60
`35
`21
`61
`17
`23
`9
`13
`18
`21
`11
`27
`23
`20
`25
`20
`19
`15
`12
`79
`10
`34
`59
`20
`25
`25
`
`0/2 (13)
`0/2 (13)
`0/9 (15)
`016 (17)
`0/2 (10)
`5/2 (11)
`010 (0)
`1/2 (13)
`010 (0)
`010 (0)
`010 (0)
`1/2 (14)
`0 (0)
`0(2 (7)
`0 (0)
`0 (0)
`0/1 (4)
`0/1 (5)
`2/1 (16)
`010 (0)
`010 (0)
`2/3 (6)
`010 (0)
`1/3 (12)
`0/1 (2)
`1/0 (5)
`2/1 (12)
`0/3 (12)
`
`TABLE 85-3. Results of selected combination regimens for renal cell carcinoma
`
`Agents
`
`Interferon plus vinblastine
`
`Interferon plus fluorouracil
`
`Interferon plus floxurine
`
`Interleukin 2, interferon, 5-fluorouracil
`
`lnteferon plus 13-cis-retinoic acid
`
`* Plus leukovorin.
`~
`t Results updated for presentation.
`
`Author and
`reference
`1985221
`1986222
`1986223
`1987224
`1987225
`1988226
`1989227
`1989220
`1990228
`1990229
`1990230
`1991 231
`1991 232
`1992233
`1992234
`1993235
`1994236
`1991 237
`1992238*
`1993239
`1993240
`199340
`199441
`199448t
`
`No. of
`patients
`23
`18
`16
`24
`13
`40
`18
`56
`11
`22
`15
`42
`9
`14
`20
`21
`31
`13
`20
`15
`11
`35
`19
`43
`
`Complete response/
`partial response(%)
`
`0/3 (13)
`1/7 (44)
`015 (31)
`1/8 (37)
`0/3 (23)
`1/16 (42)
`1/4 (28)
`0/9 (16)
`0/2 (18)
`3/3 (30)
`0/1 (7)
`1/5 (14)
`010 (0)
`010 (0)
`0/7 {35)
`015 (24)
`1/6 (23)
`014 (31)
`010 {O)
`1/4 (33)
`010 (0)
`4/13 (49)
`3/6 (47)
`3/7 (30)
`
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`.1
`
`890
`
`I CHAPTER 85
`
`19% in 607 patients.46 In a randomized phase II trial, increased
`toxicity was seen with the addition of IFN to IL2 compared
`with IL2 alone. without an increase in response proportion.47
`Combination- therapy generally is associated with additive tox(cid:173)
`icity; the proportion of patients with grade III/IV stomatitis in
`one of the trials of IFN, IL2, and 5-FU was 26%, which is most
`likely attributable to 5-FU.41 Response proportions vary among
`clinical trials of cytokines in patients with RCC, which suggests
`that patient selection plays an important role in the response
`proportion. Although the response proportion of these regimens
`is encouraging, their relative efficacy compared to that of IFN
`or IL2 alone can only be assessed in the context of a randomized
`phase m trial.
`The combination of IFN and 13-cis-retinoic acid (CRA) pro(cid:173)
`duced a 30% response proportion in a phase II trial.48 Several
`aspects of this study suggested that CRA added efficacy to
`IFNA:
`.
`
`The response proportion was triple that previously reported
`from the same center in trials of IFNA alone or in combina(cid:173)
`tion with vinblastine (10% in 149 patients).37
`Durable responses were achieved.
`Responses were seen in sites generally considered to be resistant
`to IFNA, (i.e., bone and primary tumor).
`
`Moreover, in vitro studies suggested that CRA augmented the
`antitumor effects of IFNA in several renal cancer cell lines
`and suggested that retinoid effects in renal cancer cells may be
`mediated through the retinoic acid receptor-/3. Therefore, a
`phase III randomized trial has been initiated to study the relative
`efficacy of IFN and CRA compared with IFN.
`
`MODULATION OF DRUG RESISTANCE
`
`The observation that RCC is refractory to chemotherapy has
`prompted studies that attempt to overcome inherent drug resis(cid:173)
`tance. One proposed mechanism of drug resistance is MOR.
`which is associated with the MDRJ gene and its protein product,
`the P-glycoprotein.
`RCC has been shown to arise from the renal proximal tubular
`epithelial cell in more than 85% of cases.49 Phenotypic markers
`that characterize proximal tubule cells are commonly found on
`renal carcinoma cells, an association that may explain the nearly
`uniform expression of P-glycoprotein on renal carcinoma cells,
`because this protein is normally present in the luminal mem(cid:173)
`brane of the proximal tubule cell.49 Expression of P-glyc_opro(cid:173)
`tein, a 170-kd phosphoglycoprotein encoded by the MDRJ gene,
`is necessary for MOR, which was first recognized in the labora(cid:173)
`tory, where models exposed to a single drug developed a broad
`cross-resistance to a group of distinct cytotoxic agents.
`
`The results of phase II trials of MOR reversal agents used
`in clinical trials against RCC are shown in Table 85-4. The
`addition of cyclosporin A, dipyridamole, nifedipine, tamoxifen,
`. or quinidine to vinblastine did not result in enhanced antitumor
`activity. The Cancer and Leukemia Group B has completed
`a randomized phase II trial of vinblastine alone followed by
`treatment with vinbfastine plus either cyclosporin A or tamoxi(cid:173)
`fen. 50 Sixty-four patients were evaluable to response to vinblas(cid:173)
`tine alone; no responses were seen. Twenty-eight patients re(cid:173)
`ceived modulators without an observed objective response. The
`final results of this trial are awaited.
`The prototype of MOR reversal agents is verapamil, which
`since 1981 has been known to substantially reverse MDR in
`vitrQ.51 The clinical application ofverapamil, however, has been
`limited by the profound hypotension, negative inotropic effects,
`and atrioventricular conduction delays associated with plasma
`levels of verapamil that in nearly all instances have been lower
`57
`than those targeted for reversal of resistance.52
`-
`Standard verapamil is a racemic mixture of dextro (d-) and
`levo (1-) stereoisomers. The I-isomer has a markedly greater
`effect on the slowing of atrioventricu.lar node conduction com(cid:173)
`pared with the d-isomer.58 Because both isomers have been
`shown to be equally effective in reversing drug resistance in
`vitro,59•60 the decreased cardiovascular toxi~ity of the d-isomer
`(dexverapamil) made this drug an attractive alternative to the
`standard racemic verapamil preparations for MDR reversal. A
`trial of dexverapamil and vinblastine was conducted in patients
`with advanced RCC.61 Dexverapamil was generally well toler(cid:173)
`ated; however, no antitumor activity was found in 23 assessable
`patients, despite the fact that plasma concentrations of dexvera(cid:173)
`pamil and norverapamil were achieved that were in the range
`that resulted in enhanced cytotoxicity in vitro.61
`The existence of multiple, redundant mechanisms of resis(cid:173)
`tance has been proposed as one explanation for the lack of
`antitumor activity observed in clinical trials utilizing MDR
`modulation in patients with tumors that constitutively express
`MDRJ, which includes RCC.62 The lack of antitumor activity
`found in these trials emphasizes the need for new insights in
`overcoming drug resistance in RCC.
`
`OBSERVATION ALONE
`
`Metastatic RCC is characterized by a variability in clinical
`course. It is one of the few malignancies for which spontaneous
`regressions are well documented.63 A prospective phase Il trial
`was conducted in which patients who were referred to a center
`were identified prospectively and observed. Severa) patients
`were noted to have spontaneous regression, and the proportion
`of patients who remained progression-free for 12 months or
`more was 12%.64 This finding has implications both in clinical
`
`Agents
`
`V!nblast~ne plus cyclosporin A
`Vrnblastme plus dipyridamole
`V!nblast!ne plus nifedipine
`Vrnblastme plus quinidine
`V!nblast!ne plus dexverapamil
`Vmblastrne plus cyclosporin A or tamoxifen
`
`TABLE 85-4. Results of drug resistance reversal agents against renal cell carcinoma
`Author and
`No. of
`Complete response/
`partial response (%)
`reference
`patients
`1991 241
`1994242
`1991 243
`1991 244
`199461
`199450
`
`15
`15
`14
`23
`23
`28
`
`0/0 (0)
`010 (0)
`010 (0)
`1/0 (4)
`010 (0)
`010 (0)
`
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`

`CHEMOTHERAPY FOR RENAL CELL CARCINOMA
`
`I 891
`
`investigations and in patient care. Tumor regressions attributed
`to an investigational agent must be separated from those that
`occur as a consequence of natural history. One means of accom(cid:173)
`plishing this is to include only patients with documented pro(cid:173)
`gressive disease in clinical trials. Additionally, responses to sys(cid:173)
`temic therapies for RCC are infrequent and all are associated
`with some degree of toxicity; therefore, patients who are asymp(cid:173)
`tomatic may be observed until evidence of progression or symp(cid:173)
`toms, at which time systemic treatment can be initiated.
`
`should include prognostic factors based on tumor biology. For
`example, the absence of a kidney-restricted glycoprotein of
`160,000 kd (gp 160) in renal cancer cells is associated with
`marked sensitivity in vitro to inhibition of growth by IFN,
`whereas tumor cells expressing gp160 are resistant to the anti(cid:173)
`proliferative effects of IFN. 73 Whether this correlates to re(cid:173)
`sponse in patients treated with IFN is unknown, but it is an
`example of the. potential application of laboratory findings to
`the management of patients with RCC.
`
`SURGERY IN PATIENTS WITH METASTATIC
`DISEASE
`
`REFERENCES
`
`In patients with metastatic disease, surgical resection may be
`considered in selected patients with solitary metastases. Several
`series have shown a 5-year survival range of 15% to 50%.65- 70
`Resection may also include the renal primary tumor in cases
`of synchronous presentation with a solitary metastasis.
`One controversy in the management of patients with RCC
`is the role of nephrectomy in the setting of metastatic disease.
`Nephrectomy may be justified when the intent is providing im(cid:173)
`proved quality of life, such as the alleviation of local symptoms.
`However, a nephrectomy for the purpose of inducing sponta(cid:173)
`neous regression is not justifiable; the incidence of regression
`after nephrectomy in nine series of 474 patients was only
`0.8%.71 More controversial is the role of nephrectomy as an
`adjunct to imrnunotherapy. Until a benefit for this approach is
`established in a randomized trial, its use should be considered
`investigational and not part of standard care.
`Based on the lack of antitumor effect with systemic therapy
`and the relative resistance of RCC to radiotherapy, surgical
`intervention is an appropriate palliative measure in highly se(cid:173)
`lected instances. These include the resection of solitary brain
`metastasis, surgery to alleviate spinal cord compres~ion, and
`repair of pathologic or impending fractures in weiglit-bearing
`bones.
`
`I
`~-
`
`CONCLUSIONS
`
`•:"
`Despite extensive investigations with many different treat-
`ment modalities: RCC remains a disease that is highly resistant
`to systemic therapy. Novel treatment strategies should be stud(cid:173)
`ied in RCC. The identification of new agents with better antitu(cid:173)
`mor activity remains the highest clinical investigation priority
`in this refractory tumor.
`Although response proportions with IFN and IL2 are low
`(10% to 20%), responses have been reproducible and occasion(cid:173)
`ally are durable. As such, these age~ts represent a direction for
`continued research. In particular, the combinations of IFN and
`CRA or 5-FU, with or without IL2, are encouraging, and their
`relative efficacy must be further investigated in the context of
`a randomized trial. Moreover, the investjgation of new cyto(cid:173)
`kines is warranted. One particularly promising new cytokine is
`interleukin 12, which is entering phase I and II trials in RCC. 72
`Prognostic factors need to be established to help direct ther(cid:173)
`apy to patients who are most likely to benefit. Although features
`such as high performance status and lung-only metastasis are
`predictive of survival and response, more precise pretreatment
`factors are needed.37•39 The limit~tions of prognostic classifica(cid:173)
`tions based on clinical factors are well recognized; future efforts
`
`1. Boring CC, Squires TS, Tong T, Montgomery S. Cancer Statistics,
`1994. Ca Cancer J Clin 1994;44:7.
`2. Wirth MP. Immunotherapy for metastatic renal cell carcinoma. Urol
`Clin North Am 1993;20:283.
`3. Talley RW, Moorehead EL, TuckerW. Treatment of metastatic byper(cid:173)
`nephroma. JAMA 1969;207:322.
`4. Nevinny HB, Hall TC. Chemotherapy with hydroxyurea (NSC-32065)
`in renal celJ carcinoma. J Clin Pharmacol 1968;8:352.
`5. Mittelman A, Alben DJ, Murphy GP. Lomustine treatment of meta(cid:173)
`static renal cell carcinoma JAMA 1973:225:32.
`6. Carter SK, Wassennan TH. The chemotherapy of urologic oncology.
`Cancer 1975;36:729.
`7. Hrushesky WJ, Murphy GP. Current status of the therapy of advanced
`renal carcinoma. J Surg Oneal 1977;9:277.
`8. Hrushesky WJ, von Roemeling R, Lanning RM, Rabatin JT. Circa(cid:173)
`dian-shaped infusions of floxuridine for progressive metastatic renal
`cell carcinoma. J Clin Oncol 1990;8: 1504.
`9. Damascelli B, Marchiano A, Spreafico C, et al. Circadian continuous
`chemotherapy of renal cell carcinoma with an implantable, program(cid:173)
`mable infusion pump. Cancer 1990:66:237.
`10. Merrouche Y, Negrier S, Lanier F, et al. Phase II study of continuous
`circadian infusion FUDR in metastatic renal cell cancer (RCC). (Ab(cid:173)
`stract) Eur J Cancer Clin On~ol 1991;27:Sl02.
`11. Dexeus FH, Logothetis CJ, Sella A, et al. Circadian infusion of floxur(cid:173)
`idine in patients with metastatic renal cell.carcinoma. J Urol 1991:
`146:709.
`12. Budd GT, Murthy S, Klein E, et al. Time-modified infusion offloxuri(cid:173)
`dine in metastatic renal cell carcinoma (mRCC). (Abstract) Proc Am
`Assoc Cancer Res 1992;33:220.
`13. Conroy T, Geoffrois L, Guillemin F, et al. Simplified chronomodu(cid:173)
`lated continuous infusion of floxuridine in patients with metastatic
`renal cell carcinoma Cancer 1993;72:2190.
`14. Porter RL, Bakker PJM, Kunh KH, et al. Circadian modulated contin(cid:173)
`uous infusion of FUDR in patients with disseminated renal cell cancer
`(RCC). Eur J Cancer 1993;29:116.
`15. Raminski D, Creaven PJ, Rustum YM, et al. Phase I clinical trial
`of floxuridine (FUdr) with leucovorin (L V) in patients (P'fS) with
`advanced genitourinary cancer (AOC). (Abstract) Proc Am Soc Clin
`Oneal 1992;11:206.
`16. Bjamason GA, Hrushesky WJM, Diasio R, et al. Flat versus circadian
`modified 14 day infusion of FUDR for advanced renaJ cell cancer
`(RCC): a phase-III study. (Abstract) Proc Am Soc Clin Oncol 1994:
`13:233.
`.
`17. Dana BW, Alberts OS. Combination chemoimmunotherapy for ad(cid:173)
`vanced renal carcinoma with Adriamycin, bleomycin, vincristine, cy(cid:173)
`clophosphamide, plus BCG. Cancer Clin Trial 1981;4:205.
`18. Droz JP, Theodore C. Ghosn M, et al. Twelve-year experience with
`chemotherapy in adult metastatic renal cell carcinoma at the Institut
`Gustave-Roussy. Semin Surg Oncol 1988;4:97.
`19. Elson PJ, Earhart RH, Kvols LK, et al. Phase II studies of PCNU and
`bisantrene in advanced renal cell carcinoma. Cancer Treat Rep 1987;
`71:331.
`20. Baumganner G, Heinz R, Arbes H, Lenzhofer R, Pridun N, Schuller
`J. Methotrexate-dtrovorum factor used alone and in combination
`chemotherapy for advanced hypemephromas. Cancer Treat Rep 1980;
`64:41.
`21. Jekunen A, Stengard J, Pyrhonen S, et al. Phase II study ofvinblastine
`and doxorubicin in advanced renal cell carcinoma. {Letter) Eur J Can(cid:173)
`cer 1994;30A:245.
`
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`

`I
`I
`
`1.
`
`I.
`
`892
`
`I CHAPTER 85
`
`22. Sommer HH. Fossa SD, Lien HH. Combination chemotherapy of ad(cid:173)
`vanced renal cell cancer with CCNU and vinblastine. Cancer Chemo(cid:173)
`ther Phannacol 1985;14:277.
`23. Hahn RG. Begg CB, Davis T. Phase II study of vinblastine-CCNU.
`triazinate, and dactinomycin in advanced renal ceJ1 cancer. Cancer
`Treat Rep 1981;65:711.
`24. Merrin C. Mittelman A, Fanous N, Walsman Z, Murphy GP. Chemo(cid:173)
`therapy of advanced renal cell c