0022-5347/00/1632-0408/0
`THE JOURNAL OF UROLOGY®
`Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.®
`
`Vol. 163, 408–417, February 2000
`Printed in U.S.A.
`
`Review Article
`
`SYSTEMIC THERAPY FOR RENAL CELL CARCINOMA
`
`ROBERT J. MOTZER* AND PAUL RUSSO
`From the Department of Medicine, Division of Solid Tumor Oncology, Genitourinary Oncology Service and Department of Surgery,
`Urology Service, Memorial Sloan-Kettering Cancer Center, and Departments of Medicine and Urology, Cornell University Medical College,
`New York, New York
`
`ABSTRACT
`Purpose: We review the status of systemic therapy for patients with advanced renal cell
`carcinoma.
`Materials and Methods: A literature search was performed on MEDLINE and CANCERLIT to
`identify results of systemic therapy for patients with renal cell carcinoma published from
`January 1990 through December 1998. Treatment results of chemotherapy agents, immunother-
`apy, combination programs and adjuvant therapy were reviewed.
`Results: No chemotherapy agent has produced response rates that justify its use as a single
`agent. Interferon-aand interleukin (IL)-2 demonstrated low response rates ranging from 10% to
`20%. The results of 2 randomized trials suggest that treatment with interferon-a compared to
`vinblastine or medroxyprogesterone achieves a small improvement in survival. Response rates in
`patients treated with low dose IL-2 are similar to those achieved with a high dose bolus schedule
`but whether the responses are as durable is being addressed in an ongoing randomized trial. A
`randomized trial of interferon-a plus IL-2 compared to monotherapy with either agent showed
`increased toxicity but no improvement in survival. In 3 randomized trials no survival benefit was
`associated with adjuvant interferon-a therapy following complete resection of locally advanced
`renal cell carcinoma.
`Conclusions: Despite extensive evaluation of many different treatment modalities, metastatic
`renal cell carcinoma remains highly resistant to systemic therapy. A few patients exhibit
`complete or partial responses to interferon and/or IL-2 but most do not respond, and there are few
`long-term survivors. Preclinical research, and clinical evaluation of new agents and treatment
`programs to identify improved antitumor activity against metastases remain the highest prior-
`ities in this refractory disease.
`KEY WORDS: carcinoma, renal cell; drug therapy; interleukins; interferons
`
`Estimates of annual new diagnoses of renal cell carcinoma
`have been increasing steadily.1 Surgical resection of the pri-
`mary tumor for patients with localized disease remains the
`mainstay of therapy. However, renal cell carcinoma is char-
`acterized by a lack of early warning signs, resulting in a high
`proportion of patients with metastases at diagnosis or re-
`lapse following nephrectomy. The outlook for patients with
`distant metastases is poor, with a 5-year survival rate of less
`than 10% for those presenting with stage IV disease.1 Prior
`reviews have shown that renal cell carcinoma is resistant to
`chemotherapy.2–5 Immunotherapy with interleukin (IL)-2
`and/or interferon-a achieves responses in 10% to 20% of
`patients,6, 7 some of which are durable.8 Management of ad-
`vanced renal cell carcinoma remains a significant challenge
`to the clinician. We review the status of systemic therapy for
`renal cell carcinoma based on a review of the literature from
`1990 through 1998.
`
`identify the activity of a drug or combination in a defined
`patient population with a particular tumor type. Dose and
`schedule are based on an earlier phase I trial. The intent is to
`assess efficacy and toxicity for patients with a specified ma-
`lignancy, and thereby decide if further testing is worthwhile.
`A phase III trial is a randomized comparison between a new
`treatment program or agent and a standard care program. In
`the phase III trial the effect of treatment relative to the
`natural history of the disease, and whether a new treatment
`is more effective and/or less toxic than standard therapy are
`evaluated.
`A phase II trial requires a clearly defined end point to
`evaluate efficacy accurately. For solid tumors disease must
`be measurable by physical examination or radiography so
`that response to the agent can be followed. The clinical re-
`sponse is determined to be complete, partial, stable disease
`or progression.9 The primary end point for phase III trials is
`usually survival but may include response, progression or
`relapse-free survival and quality of life. The clinical method-
`ology for evaluating an antitumor effect is determination of
`the proportion of patients who achieve a major response or
`response, defined as disappearance of all evidence of tumor
`(complete) or more than 50% decrease in tumor burden (par-
`tial).9 To ascertain response summations of the cross-
`408
`
`EVALUATION OF THERAPY
`Clinical trial methodology. Phases II and III clinical trials
`are the primary means of evaluating the efficacy of new
`agents and combinations. A phase II trial is designed to
`
`* Financial interest and/or other relationship with Roche, Bristol-
`Myers and Imclone.
`
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`SYSTEMIC THERAPY FOR RENAL CELL CARCINOMA
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`409
`
`sectional area for measurable tumors before and after (or
`during) treatment are compared.
`Evaluation of treatment outcome for renal cell carcinoma.
`Several aspects of efficacy assessment are particularly rele-
`vant to clinical trials for renal cell carcinoma. Spontaneous
`regression must be considered when treatment results show
`low response activity. Metastatic renal cell carcinoma is
`characterized by variability in clinical course, and spontane-
`ous regressions are well documented.10 A phase II trial was
`performed on referral patients with metastatic renal cell
`carcinoma who were identified prospectively and treated
`with observation only until evidence of progression. Of 73
`patients 5 (7%) had spontaneous complete or partial response
`and 12% remained progression-free for 12 months or more.11
`A randomized trial comparing interferon-g to placebo in 197
`patients with advanced renal cell carcinoma showed a 7%
`response rate in the placebo group, which was higher than
`that for the group treated with interferon-g.12 Therefore,
`tumor regression or prolonged stabilization of disease follow-
`ing treatment with an investigational agent must be consid-
`ered in the context of the natural history of renal cell carci-
`noma.
`The relative efficacy of a treatment program cannot be
`assessed by comparison of response rates from individually
`conducted phase II trials. Responses to high dose bolus IL-2
`administration vary from 33%13 to 0%14 according to patient
`selection. Phase III randomized trials are required for defin-
`itive comparison of treatment programs. Also, the impor-
`tance of independent response assessment was noted in a
`recent phase III trial comparing interferon-a, IL-2 and com-
`bination therapy.15 Response assessment by a blinded peer
`review evaluation committee revealed major disagreements
`in 40% of patients achieving a major response as determined
`by the treating physician.16 The authors concluded that the
`discrepancy was due to the increasing complexity of response
`assessment based on modern imaging techniques requiring
`collaboration between well trained clinicians and radiolo-
`gists. They recommended updated guidelines of response as-
`sessment based on new imaging techniques and formal re-
`view of response by an independent evaluation committee for
`therapeutic trials.
`Clinical trials for renal cell carcinoma may consider addi-
`tional end points of treatment outcome, such as progression-
`free survival. Standard response criteria were based on as-
`sessment of cytotoxic agents. Patients showing response to
`immunotherapy with shrinkage of metastatic disease in the
`setting of a relatively stable bulky renal primary tumor may
`not meet standard criteria for partial response, due to the
`large bi-dimensional area of the tumor.17 This factor may
`contribute
`to higher
`response
`rates associated with
`interferon-aand IL-2 treatment in phase II trials with a high
`proportion of nephrectomy cases. Also, immunotherapy and
`recent treatment strategies, such as angiogenesis inhibitors,
`could show an antitumor effect by producing prolonged sta-
`bilization of disease or slowing tumor regression during the
`course of many months. Therefore, time to progression and
`measurements of selected metastatic sites may be considered
`additional therapeutic end points of phase II clinical trials for
`renal cell carcinoma.
`
`THERAPY FOR METASTATIC RENAL CELL CARCINOMA
`Chemotherapy and resistance modulation. Studies con-
`tinue to show that renal cell carcinoma is resistant to cyto-
`toxic chemotherapy. From 1990 through October 1998, 33
`chemotherapy agents were studied in 51 phase II trials com-
`prising 1,347 patients (table 1).18 – 68 The most extensively
`studied drugs were floxuridine and fluorouracil. In 1 trial a
`20% response rate was reported with continuous intravenous
`infusion of floxuridine administered according to a circadian
`schedule.36 In 7 subsequent trials of floxuridine given simi-
`
`larly response rates ranged from 0% to 14%.37–39, 41, 69 –71 A
`randomized multicenter trial of floxuridine administered by
`flat continuous infusion versus a circadian modified 14-day
`infusion schedule has been performed. The preliminary re-
`port on 82 patients demonstrated an overall 9% response
`rate.72 Responses were generally short,
`lasting several
`months. To our knowledge there has been no benefit from the
`addition of fluorouracil modulators, such as calcium folinate.
`The low antitumor effect prompted the inclusion of floxuri-
`dine or fluorouracil, with interferon-a with or without IL-2.
`Results of phases I73 and II74 trials suggest synergy for flu-
`orouracil with gemcitabine, and further study is warranted.
`Several studies in the 1970s and early 1980s suggested
`that vinblastine had activity as a single agent against met-
`astatic renal cell carcinoma.4 This finding was the basis for
`including vinblastine as a part of combined therapy with
`interferon-aor more recently with agents that modulate mul-
`tidrug resistance. Multidrug resistance was first recognized
`in the laboratory when models exposed to a single drug had
`broad cross-resistance to a group of distinct cytotoxic agents,
`and was associated with the MDR1 gene and its protein
`product, P-glycoprotein. Attempts to modulate multidrug re-
`sistance were judged particularly relevant to renal cell car-
`cinoma since there is nearly uniform expression of
`P-glycoprotein on these cells. Multidrug resistance reversal
`agents were studied in 14 clinical trials for renal cell carci-
`noma in combination with vinblastine75– 85 or doxorubi-
`cin86, 87 (table 1). None was shown to enhance an antitumor
`effect. Moreover, the response rate to vinblastine alone or
`with a modulating agent in these more recent trials was 3%
`in 277 patients.68, 75, 76, 78 – 85 This lack of antitumor activity
`demonstrates that vinblastine is ineffective and emphasizes
`the need for new insight into overcoming drug resistance.
`The results of hormonal therapy have been equally disap-
`pointing (table 1).88 –91 In addition to single agents, combina-
`tions of chemotherapy plus hormonal agents have been stud-
`ied but likewise are ineffective and result in additive toxicity.
`No chemotherapy or hormonal therapy has produced re-
`sponse rates that justify use as a single agent. The study of
`new agents is indicated in chemotherapy naive patients.
`Immunotherapy. The 2 agents extensively studied in phase
`II trials in the 1980s that demonstrated low antitumor activ-
`ity were interferon-a and IL-2.1, 6 Interferon-g showed simi-
`lar activity in phase II trials6 but a randomized placebo
`controlled trial showed no difference in response or surviv-
`al.12 IL-12, which showed antitumor activity in phase I trials,
`was the most promising new agent studied in phase II
`trials.88, 92–106 The randomized phase II-III trial was stopped
`early due to a low response rate with IL-12 as a single
`agent.107 Based on synergy with IL-2 in animal models,108
`study of this combination is warranted.
`Interferon. Overall response to interferon-a in 1,042 pa-
`tients was 12%.6 Longer survival is associated with high
`performance status, prior nephrectomy and lung predomi-
`nant metastases,109, 110 and a 30% response (complete plus
`partial) rate has been reported.111 Average time from start of
`treatment to objective response is 3 to 4 months.6 Response to
`interferon-a as well as other immunotherapies is character-
`ized by slow regression of tumors, with patients meeting
`criteria for a partial response after as long as 12 months of
`therapy. Duration of response rarely has exceeded 2 years
`but
`long-term survivors
`following
`treatment with
`interferon-a have been reported.109 A dose of 5 to 20 million
`units of recombinant interferon-adaily appears to have max-
`imal efficacy and avoids the greater toxicity associated with
`higher doses.112
`The potential role of interferon-a in prolonging survival
`compared to treatment with medroxyprogesterone or vin-
`blastine has been evaluated in 4 randomized trials (table 2).
`In the first 2 trials no benefit was shown but both comprised
`few patients and 1113 included a crossover to interferon for
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`410
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`SYSTEMIC THERAPY FOR RENAL CELL CARCINOMA
`
`TABLE 1. Results of phase II trials of new agents against renal cell carcinoma from 1990 to 1998
`No. Complete 1 No. Partial Response (%)
`No. Evaluable
`
`Chemotherapy:
`Altretamine18
`Amonafide19, 20
`Caracemide20
`Carboplatin21
`13-cis-retinoic acid22
`Cystemustine23
`Dexniguldipine24
`49Deoxydoxorubicin25
`Deoxycoformycin26, 28
`Didemnin B29
`Doxetaxel30
`Echinomycin31, 32
`Edatrexate33
`5-Fluorouracil34, 35
`Floxuridine circadian infusion36–42
`Fixed infusion43, 44
`Fotemustine45
`Tegafur 1 uracil46
`Gemcitabine47, 48
`Homoharringtonine20
`Irinotecan49
`Liposomal encapsulated doxorubicin50
`Mafosfamide51
`Menogaril52, 53
`Merbarone54
`Navelbine55, 56
`Paclitaxel57
`Piroxantrone58, 59
`Pyrazine60
`Sulofenar (LY 186641)61, 62
`Suramin63, 64
`6-Thioguanine65
`Topotecan66
`Trimetrexate67
`Chemotherapy 1 drug resistance modifiers:
`Vinblastine alone68
`Vinblastine 1 acrivastine75
`Vinblastine 1 dexverapamil76–78
`Vinblastine 1 dipyridamole79
`Vinblastine 1 cyclosporin80
`Vinblastine 1 nifedipine82
`Vinblastine 1 PSC 83383
`Vinblastine 1 quinidine84
`Vinblastine 1 tamoxifen81
`Vinblastine 1 toremifene85
`Doxorubicin 1 dexniguldipine86
`Doxorubicin 1 87
`Hormonal therapy:
`Tamoxifen88–90
`Toremifene91
`Immunotherapy:
`Cimetidine92
`Granulocyte-macrophage colony-stimulating factor93
`IL-1 b94
`IL-495, 96
`IL-697, 98
`IL-1299, 100, 107
`Lanreotide101
`Levamisole102
`Linomide103, 104
`Lonidamine88
`Ranitidine105
`Angiogenesis inhibitors:
`Razoxane175
`TNP-470176
`
`30
`26, 17
`17
`18
`25
`54
`29
`15
`19, 25
`21
`31
`47, 17
`37
`35, 61
`56, 42, 14, 40, 26, 30, 50
`29, 15
`16
`14
`18, 37
`14
`17
`14
`16
`56, 15
`36
`14, 24
`18
`32, 31
`15
`18, 16
`12, 26
`14
`14
`34
`
`0
`0, 0
`0
`0
`0
`1 1 0 (2)
`0 1 4 (14)
`0 1 1 (7)
`0, 0
`0 1 1 (5)
`0 1 1 (3)
`0 1 1 (2), 0
`0 1 2 (11) (4)
`0 1 4, 1 1 2 (5)
`4 1 7 (20), 3 1 3 (14), 0, 0 1 4 (10), 0 1 2 (8), 0 1 4 (14), 1 1 5 (11)
`1 1 5 (21), 0 1 2 (13)
`0
`0
`0 1 1 (6), 1 1 2 (8)
`0
`0 1 2 (11)
`0
`1 1 0 (6)
`0 1 3 (5), 0
`0 1 1 (3)
`0, 1 1 0 (4)
`0
`0, 0 1 1 (3)
`0
`0, 1 1 0 (6)
`0, 0 1 1 (4)
`0
`0
`0 1 1 (4)
`
`26
`15
`12, 23, 18
`15
`16, 33
`14
`29
`23
`35
`18
`20
`11
`
`25, 34, 59
`36
`
`42
`24
`16
`18, 50
`40, 12
`20, 51, 30
`30
`15
`63, 29
`19
`16
`
`31
`20
`
`0 1 1 (4)
`0
`0, 0, 0 1 1 (8)
`0
`0, 0
`0
`2 1 1 (10)
`1 1 0 (4)
`1 1 0 (3)
`2 1 0 (11)
`0
`0 1 1 (9)
`
`2 1 1 (12), 1 1 3 (12), 0 1 1 (2)
`1 1 5 (17)
`
`2 1 0 (5)
`0
`0
`0, 0 1 1 (2)
`0 1 2 (5), 0
`0 1 1 (5), 1 1 0 (2), 0 1 2 (7)
`0
`0
`1 1 2, 0
`1 1 1 (10)
`1 1 2 (16)
`
`0
`0 1 1 (5)
`
`the other treatment arm.113, 114 The 2 larger, more recent
`randomized trials had a small but significant (p ,0.05) im-
`provement in survival with interferon-a therapy.115, 116 In 1
`study interferon-a resulted in improvement in median sur-
`vival of 3 months compared to medroxyprogesterone.115 In
`the other trial interferon-aplus vinblastine was compared to
`vinblastine alone, and the combination showed a benefit in
`median survival of 6 months.116 The addition of vinblastine
`to interferon-a has been shown not to improve survival com-
`pared to interferon-aalone,109 –111 and several recent trials of
`vinblastine have failed to demonstrate single agent activity
`in renal cell carcinoma.75, 76, 79 – 82 Therefore, the improve-
`ment in survival can be attributed to treatment with
`
`interferon-a. Although these 2 studies suggested a survival
`benefit, interferon-a therapy has resulted in a low response
`rate and rarity of long-term survival. Moreover, the impact of
`interferon on quality of life needs to be evaluated.
`IL-2. In 3 randomized trials lymphokine activated killer
`cells did not add therapeutic benefit compared to IL-2 alone
`and could be omitted.13, 117, 118 Food and Drug Administration
`approval for high dose bolus IL-2 was based on results of a
`multicenter series of 255 patients treated with high dose IL-2
`alone. Complete plus partial responses were achieved in 14%
`of patients, some of whom had bulky metastases, and median
`duration of response was 23 months.119 A long-term survival
`update showed a median survival of 16 months and a median
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`SYSTEMIC THERAPY FOR RENAL CELL CARCINOMA
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`TABLE 2. Randomized trials of interferon-a in patients with metastatic renal cell carcinoma
`Median
`Survival (mos.)
`
`No. Pts.
`
`% Response
`
`References
`
`411
`
`Survival Benefit for
`Interferon (p value)
`
`No (not given)
`
`No
`
`(0.19)
`
`Yes
`
`(0.0049)
`
`Yes
`
`(0.011)
`
`Steineck et al:113
`Interferon
`Medroxyprogesterone
`Kriegmair et al:114
`Interferon 1 vinblastine
`Medroxyprogesterone
`Pyrhonen et al:116
`Interferon 1 vinblastine
`Vinblastine
`Medical Research Council Collaborators:115
`Interferon
`Medroxyprogesterone
`
`30
`30
`
`41
`35
`
`79
`81
`
`167
`168
`
`6
`3
`
`35
`0
`
`16
`2
`
`16
`2
`
`7
`7
`
`16
`10
`
`17
`10
`
`8.5
`6
`
`duration of response of 54 months (range 3 to 1071).8 These
`results were achieved in a group of patients who were young,
`had a high performance status and were treated at special-
`ized centers.
`Given the formidable toxicity and supportive care require-
`ments associated with the high dose bolus regimen, lower
`doses of IL-2 have been studied. In a quantitative literature
`review of 39 published series of 1,291 patients response rates
`for inpatient high dose bolus, other inpatient dose or sched-
`ule and low dose outpatient schedules were 19%, 15% and
`20%, respectively, with overlapping 95% confidence inter-
`vals.117 The definition of low dose varies but 1 schedule
`consisted of a 5-day cycle administered subcutaneously every
`week for 6 consecutive weeks, with doses of 18 and 9 million
`units daily.120 The relative efficacy of 3 schedules of IL-2 is
`being addressed in a randomized trial at the National Cancer
`Institute. Initially, this was a 2-arm study, and an interim
`report showed comparable efficacy and less toxicity associ-
`ated with a low dose intravenous compared to a high dose
`bolus schedule.121 A third arm of low dose subcutaneous IL-2
`was added, and an update showed improved tolerability, and
`complete and partial responses in 11% of patients compared
`to 16% with high dose bolus therapy.122 The major benefit
`cited for treatment with high dose bolus IL-2 in prior studies
`was durability of response,123 and a comparison of durable
`responses awaits completion of trial accrual and long-term
`followup.122 Prolonged response with high dose bolus IL-2 is
`noteworthy. The low response and 5-year survival rates, and
`formidable toxicity and supportive care requirements associ-
`ated with this therapy emphasize the need to identify im-
`proved therapy through clinical studies.
`Combination programs. Interferon-aplus vinblastine dem-
`onstrated a high response rate in several single arm phase II
`trials.6 However, 3 randomized trials failed to show improved
`survival, and the addition of vinblastine to interferon con-
`tributed gastrointestinal and hematologic toxicity.109 –111 The
`combination of IL-2 and interferon-a was supported by pre-
`clinical studies showing synergistic actions. Many studied
`this combination, with wide variation in doses, schedules and
`routes of administration. Of 607 patients treated with IL-2
`plus interferon-a in 23 clinical trials 19% responded, which
`was similar to that achieved with IL-2 alone.124 The toxicities
`of these 2 agents in combination were additive, and the
`authors concluded that they provided no apparent benefit
`compared to IL-2 alone. A randomized phase II trial of high
`dose IL-2 with interferon-a versus high dose IL-2 alone
`showed no difference in response.125 Moreover, in this ran-
`domized trial increased toxicity was seen with the addition of
`interferon-a to IL-2. Another randomized trial reported a
`higher response rate for the combination of IL-2 plus
`interferon-a compared to either agent alone.15 However, no
`benefit in survival was associated with this combination com-
`pared to interferon or IL-2 monotherapy, and toxicity was
`more severe.
`Combination of 5-fluorouracil and interferon with or with-
`
`out IL-2 has been given in various schedules as inpatient and
`outpatient therapy (table 3).126 –134 In several studies high
`response rates were reported for interferon, IL-2 and
`5-fluorouracil.126, 128, 135 However, others have shown a lower
`response rate for an identical or similar regimen, characterized
`by relatively short response and severe toxicity.129–131, 134
`The 3-drug 5-fluorouracil combination is being compared to
`interferon plus IL-2 in 2 randomized phase III trials under way
`in Europe. Preliminary results of 1 study showed no improve-
`ment in response for the combination of interferon and IL-2 plus
`5-fluorouracil compared to interferon plus IL-2.136 In this trial
`the response rate for the 3-drug regimen was 8%.136 Inclusion of
`a fluoropyrimidine with interferon and IL-2 contributes to tox-
`icity, and a conclusive statement on efficacy awaits further
`study in randomized trials.
`Results of phase II trials suggested that retinoids aug-
`mented the antitumor effect of interferon-aagainst renal cell
`carcinoma.17, 137–139 However, in a recently completed phase
`III trial no benefit was shown for the combination compared
`to interferon-a alone.140 To our knowledge no sufficiently
`powered randomized phase III trial has demonstrated a sur-
`vival benefit for combination therapy compared to single
`agent interferon or IL-2 (table 4).15, 110, 111, 140 –143 Each pro-
`gram showed promise in phase II trials, and reaffirms the
`necessity to conduct phase III trials to prove efficacy of novel
`treatment regimens.
`Surgery. Nephrectomy is not indicated for inducing sponta-
`neous tumor regression of distant metastases, based on the less
`than 1% incidence of this phenomenon, uncertain causality
`between primary tumor removal and spontaneous regression of
`metastases, and morbidity associated with nephrectomy in the
`setting of metastatic disease.144 Nephrectomy in such a setting
`may be justified for select patients when the intent is to improve
`quality of life, such as the alleviation of local symptoms. Surgi-
`cal resection of a solitary metastasis is performed in select
`patients, with a 5-year survival rate of approximately 30%.145
`In this respect patients with a solitary metastasis at initial
`diagnosis generally have an inferior outcome following resec-
`
`References
`
`No.
`Evaluable
`
`TABLE 3. Results of interferon-a, IL-2 and 5-fluorouracil
`combinations
`Median
`No. Complete
`1 No. Partial
`Duration
`Response (mos.)
`Response (%)
`26 1 54 (33)
`Not stated
`246
`Kirchner et al126
`9 1 10 (38)
`12
`34
`Hofmockel et al127
`4 1 12 (31)
`17
`52
`Ellerhorst et al128
`0 1 9 (24)
`Not stated
`38*
`Joffe et al129
`1 1 7 (16)
`9
`50
`Dutcher et al130
`71
`0 1 6 (26)
`23
`Gitlitz et al131
`Not stated
`0
`18
`Olencki et al132
`131
`1 1 11 (19)
`62
`Tourani et al133
`0 1 5
`4
`(2)
`111
`Ravaud et al134
`* Of 54 treated patients 16 were excluded from response evaluation based on
`rapid progression or treatment related toxicity.
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`TABLE 4. Phase III trial of combination programs against
`monotherapy with interferon-a or IL-2
`Treatment
`References
`Interferon-a 6 vinblastine
`Fossa et al110
`Interferon-a 6 vinblastine
`Neidhart et al111
`Interferon-a 1 IL-2 vs. interferon vs. IL-2
`Negrier et al15
`Interferon-a 6 retinoic acid
`Motzer et al140
`Interferon-a 6 coumarin 1 cimetidine
`Sagaster et al141
`Interferon-a 6 interferon-g
`de Mulder et al142
`IL-2 6 tumor infiltrating lymphocyte
`Figlin et al143
`No survival benefit was noted for any combination therapy.
`
`No. Pts.
`178
`165
`425
`283
`148
`102
`160
`
`tion of the primary tumor plus metastasis compared to those
`who undergo resection of a solitary metastasis at relapse fol-
`lowing nephrectomy.145
`Prognostic factors for survival were evaluated in 278 pa-
`tients who underwent surgical metastasectomy.146 Favorable
`features for 5-year survival were a disease-free interval of
`greater than 12 versus less than 12 months (55% versus 9%),
`solitary versus multiple sites of metastases (overall survival
`54% versus 29%) and age younger than 60 years (49% versus
`35%). The 5-year survival was longer when the solitary site of
`resection was lung (54%) compared to brain (18%).
`Controversy exists regarding nephrectomy to debulk tu-
`mor before treatment with immunotherapy. Theoretical ad-
`vantages are reduction of a large, potentially immunosup-
`pressive tumor burden and prevention of complications
`related to the primary tumor during systemic therapy. Dis-
`advantages include the proportion of patients precluded from
`receiving systemic therapy because of rapid disease progres-
`sion, perioperative complications and surgical mortality. The
`percentage of patients precluded from systemic therapy by
`cytoreductive nephrectomy ranges from 9% to 40%, and de-
`pends on selection by tumor size, performance status and
`co-morbid conditions.147–153
`In 1 series of 28 patients treated during a 6-year period a
`
`39% response to high dose IL-2 was reported after cytoreduc-
`tive nephrectomy, with 26 (93%) eligible for systemic therapy
`postoperatively.154 The largest series to our knowledge of 195
`patients revealed that 121 (62%) were eligible for high dose
`IL-2 following cytoreductive nephrectomy, and the response
`rate of those treated with IL-2 was 18%.152 Of the patients
`40% who underwent nephrectomy did not ultimately receive
`immunotherapy because of complications from the procedure
`or clinical deterioration from progressive disease.
`An alternative approach is to perform nephrectomy follow-
`ing immunotherapy on patients who have achieved a major
`response to assess pathological response and remove residual
`tumor.151, 155 Potential benefits include limiting the number
`of patients undergoing nephrectomy to those showing re-
`sponse and improved resectability of primary tumors.151
`Some have suggested that patients with a partial response at
`metastatic sites might benefit from aggressive surgical resec-
`tion of residual metastatic disease.156 The relative merit of
`initial versus delayed adjuvant nephrectomy for patients
`treated with immunotherapy needs to be further delineated.
`This issue is being addressed in a randomized phase III trial
`by the Southwest Oncology Group comparing interferon
`treatment with intact primary tumor versus nephrectomy
`followed by interferon therapy.
`Prognostic factors. Determination of pretreatment features
`predictive of survival is valuable in directing therapy and
`interpreting results of clinical trials. Prognostic factors for
`patients with metastatic renal cell carcinoma vary but con-
`sistentlyincludeperformancestatus,nephrectomyandameas-
`ure of extent of disease.135, 157–161 The relationship between
`pretreatment clinical features and survival was studied in
`670 patients with advanced renal cell carcinoma treated
`in 24 Memorial Sloan-Kettering Cancer Center clinical trials
`of immunotherapy (interferon-a, IL-2) and chemotherapy be-
`tween 1975 and 1996.162 Median overall survival time was 10
`months. Of the patients 57 (8%) remain alive with a median
`
`Survival stratified according to risk group.163 Risk factors associated with shorter survival were low Karnofsky performance status (less
`than 80%), high lactate dehydrogenase (greater than 1.5 times upper limit of normal), low hemoglobin (less than lower limit of normal), high
`corrected serum calcium (greater than 10 mg./dl., correctes calcium equals total calcium minus 0.707[albumin23.4]) and absence of
`nephrectomy. Patients were grouped as 0 risk factor—favorable, 1 or 2—intermediate risk and 3 or more—poor risk.
`
`NOVARTIS EXHIBIT 2008
`Roxane v. Novartis, IPR 2016-01461
`Page 5 of 10
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`SYSTEMIC THERAPY FOR RENAL CELL CARCINOMA
`
`413
`
`followup of 33 months. Survival was 42%, 20% and 11%, at 1,
`2 and 3 years, respectively.
`Pretreatment features associated with shorter survival in
`the multivariate analysis were low Karnofsky performance
`status (less than 80%), high lactate dehydrogenase (greater
`than 1.5 times upper limit of normal), low hemoglobin (less
`than lower limit of normal), high corrected serum calcium
`(greater than 10 mg./dl.) and no nephrectomy. These prog-
`nostic factors were used to categorize cases by risk into 3
`different groups (see figure). Median time to death for the
`25% of patients with no risk factors (favorable risk) was 20
`months. Of the patients 53% had 1 or 2 prognostic features
`(intermediate risk) and median survival was 10 months.
`Patients with 3 or more risk factors (22%, poor risk) had a
`median survival of 4 months. These risk categories can be
`used in clinical trial design and interpretation, and clinical
`management. The low long-term survival rate emphasizes
`the importance of clinical evaluation to identify more effec-
`tive therapy for this disease.
`
`ADJUVANT THERAPY AFTER NEPHRECTOMY
`Relapse occurs in 20% to 30% of patients with completely
`resected renal cell carcinoma after radical nephrectomy.163–165
`Predictors of relapse include renal vein involvement and nodal
`metastasis(es).163–165 Randomized trials show no role for post-
`nephrectomy radiation therapy.166, 167 Interferon-agiven as ad-
`juvant therapy following complete resection of renal cell carci-
`noma with renal vein or nodal involvement showed no delay in
`time to relapse or overall survival compared to observation in 3
`randomized trials.168–170 Results of IL-2 given as adjuvant ther-
`apy in a phase III trial have not been reported to our knowledge.
`Therefore, standard care remains observation following ne-
`phrectomy, since no recognized systemic therapy reduces the
`likelihood of relapse.
`
`CONCLUSIONS AND DIRECTIONS
`The need for continued research is highlighted by the fact
`that nearly half of all patients with renal cell carcinoma die
`within 5 years of diagnosis and 5-year survival for those with
`metastatic disease is 5% to 10%. Despite extensive evalua-
`tion of many different treatment modalities, metastatic renal
`cell carcinoma remains highly resistant to systemic therapy.
`A few patients exhibit complete or partial responses to inter-
`feron and/or IL-2 but most do not respond, and there are few
`long-term survivors. Therefore, identification of new agents
`with better antitumor activity against metastases remains
`the highest priority of clinical study of this refractory tumor.
`Ongoing investigations include monoclonal antibodies, tumor
`specific vaccines, dendritic cell therapy and angiogenesis in-
`hibitors. The 2 monoclonal antibodies under investigation
`target epidermal growth factor receptor171 and the G250
`antigen,172 expressed in all clear cell carcinomas of renal
`origin. Dendritic cells stimulate T cells, and are being studied
`in combination with tumor infiltrating lymphocytes and IL-
`2.173 A phase I trial established safety for vaccination with
`renal cell carcinoma tumor cells transduced to secrete
`granulocyte-macrophage colony-stimulating factor.174
`Its
`highly vascular nature makes renal cell carcinoma ideal to
`study angiogenesis inhibitors. The results of 2 phase II trials
`of 2 such agents were not impressive (table 1)175, 176 but other
`angiogenesis inhibitors are entering clinical trials. Preclini-
`cal research and understanding of molecular genetics are
`paramount in developing a comprehensive strategy.
`
`REFERENCES
`1. Motzer, R. J., Bander, N. H. and Nanus, D. M.: Renal-cell
`carcinoma. N Engl J Med, 335: 865, 1996
`2. Motzer, R. J. and Vogelzang, N. J.: Chemotherapy for renal cell
`carcinoma. In: Principles and Practice of Genitourinary On-
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`cology. Edited by D. Raghaven, H. I. Scher, S. A. Leibel et al.
`Philadelphia: Lippincott-Raven, chapt. 85, pp. 885–