Critical Reviews in Oncology/Hematology 46 (2003) S33
/S39

www.elsevier.com/locate/critrevonc

Prognostic factors and clinical trials of new agents in patients with

metastatic renal cell carcinoma
Robert J. Motzer a,b,*
a

Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York,
NY, USA
b
Department of Medicine, Weil Medical College of Cornell University, New York, NY, USA
Accepted 5 December 2002

Contents
1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

S33

2.

Prognostic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

S34

3.

MSKCC experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

S34

4.

Risk-adapted therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

S36

5.

Clinical trials

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

S36

6.

Summary and directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

S37

Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

S37

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

S37

Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

S39

Abstract
Metastatic renal cell carcinoma (RCC) remains a disease highly resistant to systemic therapy. Results of recent reports in the
literature on prognostic factors and clinical trials for patients with metastatic RCC were reviewed. Small numbers of patients exhibit
complete or partial responses to interferon and/or interleukin-2, but most patients do not respond and there are few long-term
survivors. Therefore, the identification of new agents with better antitumor activity against metastases remains the highest priority
of clinical investigation in this refractory tumor. Prospective identification of patients more likely to benefit from cytokine therapy
could be used as a stratification factor in Phase III trials, and in risk-directed therapy.
# 2003 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Renal cell carcinoma; Prognostic factors; Clinical trials

1. Introduction
Prior reviews have shown that renal cell carcinoma
(RCC) is resistant to chemotherapy [1]. Immunotherapy

* Present address: Memorial Hospital, 1275 York Avenue, New

York, NY 10021, USA. Tel.: /1-646-422-4312; fax: /1-212-865-2179.
E-mail address: motzerr@mskcc.org (R.J. Motzer).

with interleukin-2 and/or interferon-a achieve responses

in between 10 and 20% of patients, some of which are
durable [1]. Two randomized trials reported a small but
significant (P B/0.05) improvement in survival with
interferon-a therapy [2,3]. In one, interferon-a was
compared with medroxyprogesterone and resulted in
improvement in median survival of 3 months [2]. In the
second trial, interferon-a plus vinblastine was compared
with vinblastine alone, and the combination showed a

1040-8428/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved.
doi:10.1016/S1040-8428(03)00062-3

R.J. Motzer / Critical Reviews in Oncology/Hematology 46 (2003) S33
/S39

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benefit in median survival of 6 months for interferon-a

therapy [3]. A randomized trial showed a survival
benefit for cytoreductive nephrectomy prior to treatment with interferon-a [4].
Federal Drug Administration approval for high-dose
bolus interleukin-2 was based on results of a multicenter
series of 255 patients treated with high-dose interleukin2 alone [5]. Complete plus partial responses were
achieved in 14% of patients, some of whom had bulky
metastases, and the median duration of response was 23
months [5]. A long-term survival update showed a
subset of these patients had durable responses [6]. Given
the formidable toxicity and supportive care requirements associated with the high-dose bolus regimen,
lower doses of interleukin-2 have been studied. Response rates appear similar (15
/20%) in patients treated
on single arm studies with inpatient high-dose bolus,
other inpatient dose or schedule, and low-dose outpatient schedules [7].
The low response rate, toxicity associated with highdose interleukin-2 therapy, and few long-term survivors
following treatment with interferon-a or interleukin-2
provide the rationale for clinical trials of novel agents as
a priority for management of patients with this disease.
The identification of prognostic factors is important in
assessing treatment outcome of new therapies studied in
phase II and III trials, and in adapting risk-directed
therapy to patients with metastatic RCC who are treated
with immunotherapy.

plete plus partial response) of 30% was reported for

patients with these clinical features [9]. Univariate
analyses performed on patients treated with immunotherapy showed that longer survival was associated
with high performance status, prior nephrectomy, and
lung-predominant metastases [10,11]. Prognostic factors
for patients with metastatic RCC varied among the
studies but consistently included performance status,
nephrectomy, and a measure of extent of disease [12
/
17].
These variables were studied in multivariate analyses
and models for predicting survival were derived. A
summary of multivariate analyses resulting in criteria
for risk stratification is shown in Table 1 [12
/17]. The
first comprehensive analysis was reported by Elson et al.
[12]. The patient population was comprised of 610
patients treated with chemotherapy on Phase II trials
between 1975 and 1984 [12]. The patient population [12]
differs from that of the present era, reflecting improvement in imaging techniques and selection factors used to
choose patients with RCC exclusively for Phase II trials
of cytotoxic agents. The median survival for all patients
treated in that series was 5.6 months [12] compared with
10 months or longer in a more recent series [18]. Recent
efforts have led to models for predicting survival
following treatment with interferon-a or interleukin-2
[19], and a model for predicting survival in patients with
localized and metastatic RCC at initial diagnosis [20].

3. MSKCC experience
2. Prognostic factors
The early experience showed that patients most likely
to respond to interferon-a had prior nephrectomy and
small volume lung-only metastasis [8]. In a randomized
phase III trial conducted by the Eastern Cooperative
Oncology Group, a major response proportion (com-

The relationship between pretreatment clinical features and survival was studied in 670 patients with
advanced RCC treated in Memorial Sloan-Kettering
Cancer Center (MSKCC) clinical trials of immunotherapy (interferon-a, interleukin-2) and chemotherapy
between 1975 and 1996 [18]. The median overall survival

Table 1
Prognostic factors for survival
Author

Year Points Treatment

Elson et al. [12]

1988 610

DeForges [13]

1988 134

Palmer et al. [14]

Jones et al. [15]
Fossa et al. [16]
Lopez-Hannineh et
al. [17]
Motzer et al. [18]

1992
1993
1994
1996

Negrier et al. [19]

2002 782

Zisman [20]

2002 814

327
387
295
215

1998 670

Chemotherapy

Independent pretreatment prognostic factors used in model

Performance Status, Time from initial diagnosis, Number of metastatic sites,

prior chemotherapy, and prior weight loss
Chemotherapy and interferon Hepatic metastasis, Lung metastasis, Time from initial diagnosis, Sedimentation
rate, Weight loss
Interleukin-2
Performance status, Time from initial diagnosis, Number of metastatic sites
Interleukin-2
Performance status, Number of metastatic sites, Time from initial diagnosis
Interferon / chemotherapy Performance status, Sedimentation rate, Weight loss
Interleukin-2 with/without
Erythrocyte Sedimentation Rate, Lactate dehydrogenase concentration, Neuinterferon, FU
trophil count, hemoglobin, extrapulmonary metastases
Interferon, interleukin-2, che- Nephrectomy, Karnofsky performance status, Hemoglobin, Adjusted calcium,
motherapy
Lactate dehydrogenase
Interferon, interleukin-2
Neutrophil count, Time from initial diagnosis, Number of metastatic sites, Liver
metastases
Interleukin-2 or NephrectPerformance status, tumor grade
omy only

R.J. Motzer / Critical Reviews in Oncology/Hematology 46 (2003) S33
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Table 2
Survival according to risk group[18]
Number of risk factors

Percentage

Alive (%)

Median survival (95% CI)

1-year survival (%)

3-year survival (%)

0
1 or 2
3, 4, or 5

25
53
22

18
7
0.7

19.9 (17.1, 27.9)

10.3 (8.9, 11.4)
3.9 (3.4, 5.0)

71
42
12

31
7
0

time was 10 months. The proportion of patients surviving at 1 year was 42%; the 2- and 3-year survival
proportions were 20 and 11%, respectively.
Pretreatment features associated with a shorter survival in the multivariate analysis were low Karnofsky
performance status ( B/80%), high lactate dehydrogenase (/1.5 /upper limit of normal), low hemoglobin
(B/lower limit of normal), high corrected serum calcium
(/10 mg/dl), and absence of nephrectomy. These
prognostic factors were used to categorize patients by
risk into three different groups (Table 2, Fig. 1). The
median time to death in the 25% of patients with zero
risk factors (favorable-risk) was 20 months. Fifty-three
percent of the patients had one or two of these
prognostic features (intermediate-risk) and the median
survival in this group was 10 months. Patients with three
or more risk factors (poor-risk), comprising 22% of the
patients, had a median survival of 4 months.
Reducing heterogeneity due to various therapies and
assessing the role of nephrectomy as a risk factor in the
light of the randomized trial [21] prompted an analysis

Fig. 1.

on prognostic factors for survival following interferon-a

therapy for 463 previously untreated patients [22]. The
median overall survival time was 13 months (95% CI:
12
/15 months). The proportion of patients surviving at
1 and 3 years was 54 and 19%, respectively. The median
time to progression was 4.7 months (95% CI: 4.1
/5.3
months) [22].
Five variables were selected by univariate and multivariate analysis as prognostic, and used as risk factors
for short survival: low Karnofsky performance status
( B/80%), high lactate dehydrogenase (/1.5 /upper
limit of normal), low serum hemoglobin (B/lower limit
of normal), high corrected serum calcium (/10 mg/
dl), and time from initial RCC diagnosis to start of
interferon-a therapy of less than 1 year [22]. Each
patient was assigned to one of three risk groups: those
with zero risk factors (favorable risk), those with one or
two (intermediate risk), and those with three or more
(poor risk). There was a significant difference in survival
distributions of the three risk groups (P -value B/0.0001).
The median time to death of patients deemed favorable

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R.J. Motzer / Critical Reviews in Oncology/Hematology 46 (2003) S33
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risk was 30 months [22]. Median survival in the

intermediate-risk group was 14 months [22]. In contrast,
the poor-risk group had a median survival of 5 months.
The prognostic model is suitable for risk stratification of
Phase III trials using interferon-a as the comparative
treatment arm.
Investigational therapies with immunotherapy, angiogenesis inhibition, or other novel treatment strategies
could show an antitumor effect by producing prolonged
stabilization of disease or slow tumor regression over
many months [23]. Therefore, Phase II and III clinical
trials of these agents against RCC may investigate
progression-free survival as an endpoint of treatment
outcome. The 4- and 5-month progression-free survivals
associated with interferon-a therapy were 55 and 42%,
respectively [22].

4. Risk-adapted therapy
In the development of the MSKCC model, the
relationship of survival to treatment program was
studied [18]. Patients were grouped according to whether
they had treatment with cytokine therapy or chemotherapy. The program was classified as cytokine therapy
when interferon-a and/or interleukin-2 were included in
the treatment regimen. Treatment type of chemotherapy
was assigned when the program was comprised of
cytotoxic therapy or hormonal therapy and no interferon-a or interleukin-2 was given. Patients treated with
cytokine therapy had a longer survival compared with
patients treated with chemotherapy regardless of the
year of treatment or risk category based on pretreatment
features. With regard to the latter, the median survivals
for favorable-risk, intermediate-risk, and poor-risk patients treated with cytokines were 27, 12, and 6 months,
respectively [24]. In comparison, the median survivals
for patients treated with chemotherapy were 15, 7, and 3
months for the three risk groups [24]. The magnitude of
difference in median survival was greater in the favorable- and intermediate- risk groups [24]. These observations suggest that patients with favorable prognostic
features according to the model [18] may derive therapeutic benefit from cytokine therapy.

5. Clinical trials
Treatment with gemcitabine plus fluorouracil was
associated with stable disease plus infrequent partial
response in patients who were cytokine refractory [25].
Studies of combination of gemcitabine plus fluorouracil
with interleukin-2 and interferon-a have not shown
benefit for these combinations [26]. Clinical trials of
gemcitabine plus capecitabine are underway.

A randomized trial comparing interferon-a with or

without retinoid showed no benefit for the combination
[27]. Commercially available interferon-a preparations
are characterized by a relatively short plasma half-life
and require frequent dosing. Pegylated interferon is
being developed and have sustained absorption, a slower
rate of clearance, and a longer half-life than unmodified
interferon-a. The pharmacokinetic profile allows weekly
dosing. Phase I and II trials have been completed and
show similar response proportions compared with
interferon-a [28]. A direct comparison of antitumor
effect and toxicity for pegylated interferon-a to interferon-a requires a Phase III trial.
A new cytokine, interleukin-12, showed antitumor
activity in Phase I trials [29,30]. A randomized Phase II
/
III trial was stopped early due to a low response
proportion of interleukin-12 rate as a single agent [31].
Based on synergy with interleukin-2 in animal models,
[32] study of this combination is underway.
Given the formidable toxicity and supportive care
requirements associated with the high-dose bolus regimen, lower doses of interleukin-2 have been studied. The
relative efficacy of three schedules of interleukin-2 is
being addressed in a randomized trial at the National
Cancer Institute. Initially, this was a two-arm study, and
an interim report showed comparable efficacy and less
toxicity associated with a low-dose intravenous interleukin-2 schedule compared with the high-dose bolus
schedule [33]. A third arm was added, comprised of lowdose subcutaneous interleukin-2, and an update showed
improved tolerability and complete and partial responses in 11% of patients, compared with 16% with
high-dose bolus therapy [34]. The major benefit cited for
treatment with high-dose bolus interleukin-2 in prior
studies was durability of response [35], and a comparison of durable responses awaits completion of trial
accrual and long-term follow-up [34].
Allogeneic bone marrow transplantation has been
reported by Childs et al to achieve complete and partial
responses in metastatic RCC as a graft-versus-tumor
effect [36]. A study performed at the University of
Chicago showed that the approach was feasible and
partial responses were observed at the cost of considerable toxicity [37]. However, requirement of a compatible
donor, treatment-related morbidity and mortality, and
delayed treatment effect are recognized limitations for
this approach.
The majority of RCC is comprised of clear cell
carcinoma, which is characterized by mutation in the
VHL gene [38]. Since the VHL protein has been shown
to stabilize vascular endothelial growth factor [39], and
since RCC is a highly vascular tumor with an angiographic pattern that is considered diagnostic [40], the
study of angiogenesis inhibitors appears particularly
relevant in RCC. Studies of thalidomide in patients with
metastatic RCC refractory to cytokine therapy have

R.J. Motzer / Critical Reviews in Oncology/Hematology 46 (2003) S33
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shown a low response proportion and stable disease

[41
/44]. The potential effect of thalidomide on progression-free and overall survival for patients with advanced
RCC is being addressed in the ECOG randomized phase
III trial comparing low-dose interferon-a with or without thalidomide. Since one report of the combination of
thalidomide plus interleukin-2 showed responses, a
phase III trial of interleukin-2 with or without thalidomide is also planned [45]. New immunomodulatory
analogs of thalidomide that have shown potentially
greater antitumor effects in preclinical models [46] also
warrant study in metastatic RCC.
A randomized phase II double blind clinical trial to
evaluate the activity of a neutralizing antibody to VEGF
was performed. Patients were randomized to receive
placebo or the antibody at one of two doses. After 110
patients were randomized, the trial was stopped because
Bevacizumab showed significant prolongation of time to
progression when given at the high dose [47]. A
randomized phase III trial is warranted to study effect
on survival.
Epidermal growth factor expression is common in
RCC, and has prompted study of agents that inhibit this
pathway. Both Cetuximab (C225) and Iressa (ZD1839)
were studied but showed no activity against RCC
[48,49]. CCI-779 inhibits mTOR kinase activity and
causes G1 arrest. A randomized phase II trial in
cytokine refractory patients showed the median time
to progression and survival for the group was long
compared with historical control [50]. Combination
studies with interferon-alfa are underway and a randomized phase III trial is being considered.

6. Summary and directions

Metastatic RCC remains a disease highly resistant to
systemic therapy. Small numbers of patients exhibit
complete or partial responses to interferon and/or
interleukin-2, but most patients do not respond and
there are few long-term survivors. Therefore, the
identification of new agents with better antitumor
activity against metastases remains the highest priority
of clinical investigation in this refractory tumor. Prognostic models based on pretreatment clinical and
laboratory variables can help define patients more likely
to benefit from standard therapies, as well as assist in
the interpretation of drug effectiveness in phase II
clinical trials. Investigations into new prognostic factors
based on the biology of the cancer and pathology of
patient immune response are useful in that they may
lead to new therapeutic strategies in the future. Prospective identification of patients more likely to benefit
from cytokine therapy could be used in Phase III trials,
and in risk-directed therapy.

S37

Reviewers

Cora N. Sternberg, Department of Medical Oncology, San Camillo and Forlanini Hospitals, Pavilion
Cesalpini, Circonvallazione Gianicolense 87, I-00152
Rome, Italy.
Sylvic Negrier, Department of Medical Oncology,
Center Leon Berard, 28, rue Laennec, F-69373 Lyon
Cedex 8, France.
Professor Nicholas J. Vogelzang, Fred C. Buffett
Professor of Medicine, Surgery (Urology), Ben May
Institute for Cancer Research, University of Chicago
Cancer Research Center, 5841 S. Maryland Ave.,
MC1140, Chicago, IL 60637-1470, USA.
Sophie D. Fossa, Clinical Research, The Norwegian
Radium Hospital, Montebello, N-0310 Oslo, Norway.

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[47] Yang JC, Haworth L, Steinberg SM, Rosenberg SA, Novotny W.
A randomized double-blind placebo-controlled trial of bevacizumab (anti-VEGF antibody) demonstrating a prolongation in time
to progression in patients with metastatic renal cancer. Proc Am
Soc Clin Oncol 2002;21:5a (abstract 15).
[48] Motzer RJ, Amato R, Todd M, Hwu W, Cohen R, Baselga J,
Muss H, Cooper M, Yu R, Needle M. Phase II trial of
antiepidermal growth factor receptor antibody C225 in patient
with advanced renal cell carcinoma, Invest New Drugs 2002, in
press.

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[49] Drucker BJ, Schwartz L, Marion S, Motzer R. Phase II trial of
ZD (Iressa), an EGF inhibitor, in patients with advanced renal
cell carcinoma. Proc Am Soc Clin Oncol 2002;21:181a (abstract
720).
[50] Atkins MB, Hidalgo M, Stadler W, Logan T, Dutcher JP, Hudes
G, Park Y, Marshall B, Boni J, Dukart G. A randomized doubleblind phase 2 study of intravenous CCI-779 administered weekly
to patients with advanced renal cell carcinoma. Proc Am Soc Clin
Oncol 2002;21:10a (abstract 36).

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Biography
Robert J. Motzer is an attending physician in the
Genitourinary Oncology Service, Division of Solid
Tumor Oncology, Department of Medicine, Memorial
Sloan-Kettering Cancer Center and a Professor of
Medicine at Weil Medical College of Cornell University,
New York, NY.