P: im ip/m imr/ Prtu'liz'r of(imi'tuiirimnji‘ ()nt‘nlnav. edited by
`Derek Rughavun. Howard L Scher. Steven A Leibelt and Paul H
`Lange. Lippincott-Raven Publishers. Philadelphia. 1C3
`l997.
`
`CHAPTER 85
`
`Chemotherapy for Renal Cell Carcinoma
`
`add efficacy: this was evident from the results of single—arm
`
`Investigative efforts with chemotherapeutic agents have been
`extensive. Prior to l975, nitrogen mustard," hydroxyurea," lo‘
`mustine,S dacarbazine,6 and hexamcthylmelamine6 were stud-
`ied and did not show antitumor activity for RCC. A comprehen~
`sive review of the published literature shows that from 1975
`through 1994. 80 single agents were studied in 155 trials (Table
`85—1). Overall. l43 (4%) responses were achieved in 3951 eva—
`luztble 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
`of the lack of antitttmor 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 tloxuridine
`(FUDR). Early studies suggested vinhlastine 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 [FN or
`with agents that modulate multidrtig resistance (MDR). How-
`ever, the results of more recent trials with vinblastine showed
`only nine responses in 135 (6%) evaluable patients (see Table
`8571 Li’lflttl‘h H)”
`
`Robert Motzer and Nicholas Vogelzang
`
`
`Renal cell carcinoma (RCC) is a frequent cause of cancer mor-
`tality, responsible for more than l0,t)00 deaths per year in the
`United States,‘ 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 (1L2) and interferon—a (IFNA)
`have demonstrated a low but reproducible response proportion
`in the [0% to 20% range, with durable responses of5% or less.Z
`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
`
`A 20% response proportion was reported with continuous
`intravenous infusion of FUDR administered according to a cir—
`cadian schedule.8 Response proportions ranged from 0% to t4%
`in seven subsequent trials of l’UDR given in a similar fashion;
`one of these trials included folinic acidfMS Enthusiasm promp—
`ted by the first trial resulted in the conduction of a randomized
`multicenter phase III trial of FUDR administered by flat contin~
`uous infusion versus a circadian modified [4-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.” 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 l940$
`and the low concentrations of progesterone receptors found in
`human RCCt26 The animal models showed hormone depen-
`dence and responsiveness in renal cancers induced in the Syrian
`hamster model.26
`
`8100mm!" initially reported a l6% to 21% response propor—
`tion for medroxyprogesterone (MP) in RCC. in the four trials
`published since 1980. the response proportion declined to 5%
`(Table 85—2).‘“““ Other hormonal agents also have been exten‘
`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—
`live.32 The antiestrogens—ctamoxifen‘ nafoxidine, and tormi-
`fene—H were also studied in multiple trials and found to be rela-
`tively inactive. with a 6% response proportion achieved in 318
`patients treated in l
`i
`trials.
`The addition of hormonal therapy to chemotherapy does not
`
`885
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`

`

`TABLE 85-1. Resu/ts of chemotherapy for renal cell carcinoma
`
`Year and
`reference
`
`N0. of
`patients
`
`Complete response/
`partial response (%)
`
`0/1 (4‘)
`0/0 (0)
`1/0 (3 :1
`1/0 (5)
`/2 (8)
`/1 (2)
`0/0 (0)
`0/0 (0)
`/O (0
`0/
`
`0/1 (2)
`0/0 (0)
`0/0 (0)
`0/1 (2)
`
`27
`15
`36
`19
`25
`46
`24
`16
`21
`61
`42
`12
`26
`37
`20
`14
`29
`15
`8
`7
`19
`18
`21
`23
`10
`10
`44
`12
`30
`61
`12
`18
`25
`12
`27
`24
`19
`15
`19
`53
`41
`20
`29
`55
`15
`13
`31
`21
`22
`18
`38
`47
`8
`38
`14
`
`20
`19
`16
`43 V
`
`886 /
`
`(In-wrtk
`
`Agen1
`
`Acivicin
`Aclacmomycin
`L—Alanosine
`6-Aminonicatinamide
`Amelamrone
`Aminothiazzde
`Amonafide
`Amsacrine
`
`S’vAzaVEAdeoxycytidine
`Bisantrene
`
`Bleomycin
`
`Carboplatin
`
`Chlorozotocin
`Cisplatin
`
`Cyclophosphamide
`
`Plus misonidazole
`Dactinomycin
`10—Deazaaminopterin
`2-Deoxycoformycin (Pentostatin)
`
`4’—Deoxydoxorubicin (Esorubicin')
`
`4—Demethoxydaunorubicin
`Dianhydrogalactitol
`
`Diaziquone
`
`Dibromodulcitol (Mitolacto1)
`
`Didemnin B
`
`Docetaxel
`Doxorubicin
`Echinomycin
`EHiptinium
`
`4’-Ep1~adriamycin (Epirubicin)
`
`Estramustine
`Etoposide
`
`‘
`‘
`
`"
`
`‘*
`
`198874
`198475
`198874
`198976
`198577
`198874
`199178
`198079
`198080
`198381
`198382
`198783
`198284
`198285
`198585
`198587
`198719
`197588
`197689
`197790
`19889‘
`199092
`1979C33
`197894
`197995
`197596
`197997
`198098
`1981399
`198123
`1984100
`1991 ‘0‘
`1992102
`“986m
`
`
`
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`

`

`CHEMOTHERAPY FOR RENAL CELL CARCINOMA / 887
`
`TABLE 85-1. Continued.
`
`Year and
`reference
`
`No. of
`patients
`
`Complete response/
`partial response (3/0)
`
`)
`
`)
`
`/7 (20)
`3/3 (14)
`0/0
`0/4 (10)
`0/2 {8)
`0/4 (14)
`0/1 '
`1
`0/0
`0)
`0)
`0/0
`21
`1/5
`0/0
`0)
`0/0
`0)
`(3/2 7)11
`0/4
`1/2
`5)
`0/0
`0)
`0)
`0/0
`1/3
`7)
`0/0 (0)
`0/0 (0)
`0/0 (0)
`0/1 (4)
`1/2 (10)
`0/1 (6)
`0/1 {5)
`0/0 (0)
`0/1 (9)
`0/2 (20)
`
`Agent
`
`Floxurine (circadian)
`
`Plus follnic acid
`By flat infuslon
`
`Fludarablne
`
`5~Fluorouracll
`
`Plus folinlc acid
`Fosquidone
`Fotemustine
`
`Florafur
`Gallium nitrate
`
`Gemcitibine
`
`Hydroxyrea
`lCRF-187
`lfosfamlde
`
`Liposomal encapsulated doxorubicin
`Lomusflne
`
`Lonidamlne
`
`LY186641
`Mafosfamide
`Melphalan
`Menogaril
`
`Methodlchlorophen
`Methoirexale
`Mitoguazone (methyl-GAG)
`
`Mltomycin
`Mitotane
`Mi1oxantrone
`
`Mitozolomlde
`N-methylformamide
`
`Navelbine
`
`56
`42
`14
`40
`26
`28
`15
`15
`29
`29
`30
`15
`27
`35
`61
`14
`21
`62
`15
`14
`10
`25
`30
`18
`19
`40
`11
`10
`16
`9
`14
`9
`5
`25
`19
`16
`16
`8
`56
`15
`1O
`8
`25
`31
`30
`14
`87
`12
`12
`20
`49
`29
`48
`17
`16
`14
`14
`24
`
`(continued)
`
`19908
`19909
`199110
`199111
`199212
`199313
`199314
`1991 ‘5
`1991 ‘27
`1993128
`1987129
`1989130
`199142
`199343
`199444
`198945
`1992’31
`1991 ’32
`1 993133
`1993134
`1984135
`1987136
`1992137
`1993138
`1981139
`1986140
`1980141
`1981142
`1987143
`1988144
`1995145
`197790
`198631136
`1986"17
`1 991 ‘48
`1993149
`1992150
`1993‘?1
`1990132
`1991 “:0
`19791 :4
`198020
`1981155
`1981 ‘56
`1982157
`1981158
`1983159
`1987160
`1981161
`1984162
`1984153
`1984164
`1986155
`1989166
`1986167
`1989168
`1991 ‘69
`1993170
`
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`

`888 /
`
`CHAPTER 85
`
`TABLE 85—1. Continued.
`
`Complete response/
`partial response (‘70)
`0/010)
`0/0 (0)
`0/2 <4)
`0/1 (3)
`0/0 (0)
`0/1 (6)
`0/1 (3)
`0/0 (0)
`0/0 (0)
`0/0 (0)
`0/0 (0)
`
`Year and
`reference
`
`1991 ‘7‘
`1982172
`198381
`1984173
`198719
`1987""
`1993175
`1977‘76
`1992177
`1987178
`19841 79
`198718”
`1992781
`1991182
`1992183
`1989184
`1993185
`1979‘86
`1984187
`1987188
`1991 ‘89
`197790
`1994190
`198123
`1986191
`1987192
`1989193
`1992‘94
`197790
`1984‘95
`1984196
`1985197
`1987198
`198874
`1992199
`1977200
`1983201
`1982202
`
`N0. of
`patients
`18
`15
`52
`34
`45
`15
`34
`23
`32
`26
`36
`18
`1s
`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
`
`range from 0% to 400/}; with an overall response proportion of
`
`ofinterferon 01 (IFNA) plus vinblastine versus IFNA alonev‘w
`Although one trial showed a slightly higher response proportion
`for the combinationym none have shown improved survival
`(compared with survival for patients treated with lFNA alone).
`and the vinblastine added gastrointestinal and hematologic tox-
`icity,37
`Combinations of 5-fluorouracil lS—FU) or FUDR with 1L2,
`IFN, or both have been studied. The rationale was based on the
`single-agent activity of FUDR in RCC and the antitumor effects
`ol‘IFN and S—FU. another pyridamole analog. against adenocan
`Cinoma of the colon. Two studies have shown high response
`rates with a combination of 5-FU, IFN and lL2.4(W Although
`these combinations are promising and warrant further investiga—
`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 singleagent S-FU
`ranged from 0% to l 1% in four trials.‘”"45 The combination of
`1102 and IFN has been extensively studied; response proportions
`
`Agent
`
`Paclitaxel
`PALA (sparfosic acid)
`
`PCNU
`
`Pirarubicin
`
`Piperazlnedione
`Piroxantrone
`Spirogermanium
`
`Streptozocin
`Sulolenur
`Suramin
`
`Tauromustine
`Taxotere
`Teniposide
`
`B-Thioguanine
`Thiotepa
`Topotecan
`Triazinate
`t,2,4-Trig|ycidyl~urazo
`
`Trimetrexate
`
`Vinblastine
`
`Vindesine
`
`Yoshi-864*
`
`* Plus medroxyprogesterone acetate.
`
`phase II trialsz‘m'l’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 hormones 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 ot~
`immunotherapeutic agents such as 1L2 and IFN. combinations
`of chemotherapy and immunotherapy have been studied in RCC
`(Table 85-3). The combination that has been most extensively
`studied is IFN plus vinblastine. The results of 13 studies that
`included 307 patients showed an overall 24% response rate.
`which appeared to be somewhat higher than that reported with
`IFN alone2 Three randomized trials have addressed the efficacy
`
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`

`(ItIKMUI‘HERAPY FUR RENAL CELL CARCINONIA / 889
`
`TABLE 85-2. Results of hormonal therapy for renal cell carcinoma
`
`Year and
`reference
`
`No. of
`patients
`
`Complete response/
`partial response (%)
`
`1969203
`1970204
`1971205
`1971206
`1971207
`1973208
`1974209
`1980210
`198128
`198429
`198530
`198631
`1969203
`1971206
`1974209
`197532
`1984211
`1979212
`1981‘39
`1980213
`1E1802M
`1981215
`19812‘6
`1992?:7
`1993218
`1993219
`1991148
`1993220
`
`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)
`)
`0/6 (17
`0/2 (10)
`5/2 (11)
`0/0 (0)
`1/2 13)
`0/0 (0)
`0/0 0)
`0/0 0)
`1/2 (14)
`O (O)
`0/2 7)
`0 (0)
`0 (0)
`0/1 (
`it
`/‘l
`0/0 (
`0/0
`l3 (
`0/0(
`US (
`0/1
`1/0
`12)
`2/1
`0/3 (12)
`
`
`mwaom'oo—nVVNVVVVmvvV
`
`Amp
`
`TABLE 85-3. Results of selected combination regimens for renal cell carcinoma
`
`
`
`Interferon plus vinblastine
`
`Interferon plus liuorouracil
`
`interferon plus lloxurlne
`
`interleukin 2, interferon, 5~fluorouracll
`
`lnteferon plus 13~cis-retinoic acid
`* Plus leukovorinl
`
`19852”
`1985222
`1986223
`1997224
`19137225
`1988226
`1989227
`1989220
`1990228
`1990M
`1990230
`1991231
`1991232
`1992233
`1992234
`1993235
`1994236
`1991237
`1992238*
`1993239
`1993240
`199340
`199441
`1994481“
`
`23
`18
`16
`24
`13
`40
`18
`56
`11
`22
`15
`42
`9
`14
`20
`21
`31
`13
`20
`15
`1 1
`35
`19
`43
`
`0/3 (13)
`1/7 (44)
`0/5 (31)
`1/8 (37)
`or3 (23)
`1/16 (42)
`
`4/13 (49)
`3/6 (47)
`3/7 (30)
`
`Agent
`
`Medroxyprogesterone (or other progestins)
`
`Testosterone proplonate (or other androgens)
`
`Flutamide
`Nafoxidine
`
`Tamoxifen
`
`Toremitene
`
`T Results updated for presentation.
`
`Complete response/
`Not of
`Author and
`Agents partial response (°/o) reference patients
`
`
`
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`890 /
`
`Cl IAPT’tiR 85
`
`19% in 607 patients“ In a randomized phase it trial. increased
`toxicity was seen with the addition of IFN to 1L2 compared
`with 112 alone. without an increase in response proportion.47
`Combination therapy generally is associated with additive tox-
`icity: the proportion of patients with grade ill/IV stomatitis in
`one of the trials of IFN. 1L2. and 5—FU was 26%, which is most
`likely attributable to S-FU.“ 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 ofthese regimens
`is encouraging. their relative efficacy compared to that of ll-‘N
`or IL2 alone can only be assessed in the context of a randomized
`phase III trial,
`The combination of IFN and I3~cis‘-retinoic acid (CRA) pro
`duced a 30% response proportion in a phase II trial}8 Several
`aspects of this study suggested that CRA added efficacy to
`IFNA:
`
`The response proportion was triple that previously reported
`from the saute center in trials of IFNA alone or in combina»
`
`tion with vinblastine (l(l% in 149 patients)"7
`Durable responses were achieved.
`Responses were seen in sites generally considered to be resistant
`to IFNA. (i.c., 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 iii renal cancer cells may be
`mediated through the retinoic acid receptor—,8. 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-
`tance. One proposed mechanism of drug resistance is MDR.
`which is associated with the MDR/ 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.” Phenotypic markers
`that characterize proximal tubule cells are corrtmonly 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 lamina] mem»
`brane of the proxtmal tubule cell.“ Expression of P-glycopro-
`tein, a I7tJ-kd phosphoglycoprotein encoded by the MDRI gene.
`is necessary for MDR. which was first recognized in the labora—
`tory. where models exposed to a single drug developed a broad
`cross-resistance to a group of distinct cytotoxic agents.
`
`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."3 A prospective phase II trial
`was conducted in which patients who were referred to a center
`were identified prospectively and observed. Several patients
`were noted to have spontaneous regression, and the proportion
`of patients who remained progression-free for 12 months or
`more was 12%”1 This finding has implications both in clinical
`
`Complete response/
`
`The results of phase II trials of MDR reversal agents used
`in clinical
`trials against RCC are shown in Table 85-4. The
`addition ofcyclosporin A. dipyridamolo nifedipine. tamoxifen.
`or quinidine to vinblastinc did not result in entranced antitumor
`activity. The Cancer and Leukemia Group B has completed
`a randomized phase II trial of vinblastinc alone followed by
`treatment with vinblastine plus either cyclosporin A or tamoxi—
`fen.“ Sixty—four patients were evaluable to response to vinblas—
`tine alone; no responses were seen. Twenty-eight patients re—
`ceived modulators without an observed objective response. The
`final results of this trial are awaited.
`The prototype of MDR reversal agents is verapamil. which
`since l98l has been known to substantially reverse MDR in
`vitro."1 The clinical application of verapamil. 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
`than those targeted for reversal of resistattce,.53"S7
`Standard verapamil is a racemic mixture of dcxtro (d—) and
`levo (l—) stereoisomers. The l—isomer has a markedly greater
`effect on the slowing ofatrioventricular node conduction com—
`pared with the d—isomer.SR Because both isomers have been
`shown to be equally effective in reversing drug resistance in
`viti‘oiq'M‘ the decreased cardiovascular toxicity of the d—isonter
`(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 RCCi‘“ Dexverapamil was generally well tolerA
`ated; however, no antitumor activity was found in 23 assessable
`patientsi despite the fact that plasma concentrations of dexverae
`pamil and norverapamil were achieved that were in the range
`that resulted in enhanced cytotoxicity in vitro."I
`The existence of multiple. redundant mechanisms of resis—
`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
`MDRI, which includes RCC."2 The lack of antitumor activity
`found in these trials emphasizes the need for new insights in
`overcoming drug resistance in RCC.
`
`partial response (%)
`
`TABLE 85—4. Results of drug resistance reversal agents against renal cell carcinoma
`Author and
`No. of
`reference
`patients
`15
`15
`14
`23
`23
`28
`
`Agents
`
`Vinblastine plus cyclosporin A
`Vinblastine plus dipyridamole
`Vinblastine plus nitedipine
`Vinbtasttne plus quinidine
`Vinblastine plus dexverapamit
`Vinblastine plus cyclosporin A or tamoxifen
`
`199124‘
`1994242
`1991243
`19912“4
`199461
`199450
`
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`

`(illl‘,\l()l‘1ll‘,l{.\l"i' r'on Rl-l.\'.\l.
`
`(11411.1. (i;\l\‘( mom
`
`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 accome
`plishing this is to include only patients with documented pro—
`gressive disease in clinical trials. Additionally, responses to sys—
`temiC therapies for RCC‘ are infrequent and all are associated
`with some degree oftoxicity: therefore. patients who are asymp—
`omatic may be observed until evidence of progression or syrup—
`toms. at which time systemic treatment can be initiated.
`
`should include prognostic factors based on tumor biology. For
`example.
`the absence of a kidneywestricted glycoprotein of
`160.000 kd tgplofh in renal cancer cells is associated with
`marked sensitivity in vitro to inhibition of growth by lFN.
`whereas tumor cells expressing gplhll are resistant to the anti-
`proliferative effects of lFN.” Whether this correlates to re—
`sponse in patients treated with th 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
`
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`In patients with metastatic disease. surgical resection may be
`~.:-onsidered in selected patients with solitary metastases. Several
`.eries have shown a 5—year survival range of 15% to 50%.“ '7”
`Etesection may also include the renal primary tumor in cases
`~)f synchronous presentation with a solitary metastasis.
`One controversy in the management of patients with RCC
`s the role of nephrectomy in the setting. of metastatic disease.
`\lephrecromy may be justified when the intent is providing im—
`;7roved quality of life, such as the alleviation of local symptoms.
`However. a nephrectomy for the purpose of inducing sponta
`neous regression is not justifiable: the incidence of regression
`.tfter nephrectomy in nine series of 474 patients was only
`0.8%.“ More controversial is the role of nephrectomy as an
`adjunct to immunotherapy. 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-
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`repair of pathologic or impending fractures in weight—bearing
`bones.
`
`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-
`ied in RCC. The identification of new agents with better antitu-
`mor activity remains the highest clinical investigation priority
`in this refractory tumor.
`Although response proportions with lFN and “.2 are low
`{ 10% to 20%). responses have been reproducible and occasion‘
`ally are durable. As such. these agents represent a direction for
`continued research. in particular, the combinations of lFN and
`CRA or S—FU. with or without lLZ. are encouraging. and their
`relative efficacy must be further investigated in the context of
`a randomi7ed trial. Moreover. the investigation of new cyto—
`kiries is warranted. One particularly promising new cytokine is
`interleukin 12, which is entering phase I and [I trials in RCC.73
`Prognostic factors need to be established to help direct ther—
`apy to patients who are most likely to benefit. Although features
`such as high performance status and lungronly metastasis are
`predictive of survival and response. more precise pretreatment
`factors are neededfi” The limitations of prognostic classifica—
`tions based on clinical factors are well recognized; future efforts
`
`.
`
`NOVARTIS EXHIBIT 2065
`Par v. Novartis, IPR 2016-01479
`Page 7 of 12
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