Immunotherapy for advanced renal cell cancer.
BACKGROUND
The course of advanced renal cell carcinoma is extremely variable, ranging from spontaneous remission to disease progression refractory to chemotherapy. Immunotherapy has held promise of improved outcomes based on uncontrolled studies and randomized controlled trials generally limited by small size and low power.


OBJECTIVE
To evaluate immunotherapy for advanced renal cell carcinoma by comparing: (1) high dose interleukin-2 to other options and (2) interferon-alpha to other options.


METHODS
A search of MEDLINE, Cancerlit, EMBASE and Cochrane Library databases from 1966 through the end of 1999. Handsearches were made of the proceedings of the annual meetings of the American Urologic Association, ASCO, and biennial European ECCO meetings, and the references of identified studies.


METHODS
Randomized controlled trials that selected (or stratified) patients with advanced renal cell carcinoma, utilized an immunotherapeutic agent in at least one study arm, and reported response or survival by allocation. Forty-two studies involving 4216 patients were eligible and reported response and 26 of these reported survival outcome (3089 patients).


METHODS
Two independent reviewers abstracted each article by following a prospectively designed protocol. Dichotomous outcomes for treatment response (partial plus complete) and for deaths at one year were used for the main comparisons. Survival hazard ratios were also used for studies of interferon-alpha versus controls.


RESULTS
The average response rate was 10.2 % (range by arm, 0 - 39%) and complete response rate was 3.2% (123/3852; n = 38 studies). Median survival averaged 11.6 months (range by arm, 6 - 28 months) and two-year survival averaged 22% (16 studies, range by arm 8 - 41%). There were no placebo-controlled studies and no randomized controlled studies examined survival for high dose interleukin-2 versus controls. Results from 6 studies (n = 963) indicate that interferon-alpha is superior to controls (OR for death at one year = 0.67, 95% CI 0.50 - 0.89. The pooled hazard ratio for survival of 0.78 (0.67 - 0.90) indicates that the treatment effect persisted until 24 months from randomization. The weighted average median improvement in survival was 2.6 months. Additional comparisons failed to prove a survival benefit from the addition of other agents to either modified schedules of interleukin-2 or to interferon-alpha. Dose-response studies examining survival for either agent could not be identified. The difference in response rate between arms was correlated with the difference in survival (P<0.001) suggesting that response rate difference may be a surrogate intermediate endpoint for survival.


CONCLUSIONS
Interferon-alpha provides a modest survival benefit compared to other commonly used treatments and should be considered for the control arm of future studies of systemic agents. Interleukin-2 has not been validated in controlled randomized studies.
Coppin
C
C
Division of Medical Oncology, Fraser Valley Cancer Centre, 13750-96th Avenue, Surrey, BC, Canada, V3V 1Z2. ccoppin@bccancer.bc.ca
Porzsolt
F
F
Kumpf
J
J
Coldman
A
A
Wilt
T
T
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy; D016898:Interferon-alpha / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000473:pathology / Q000628:therapy*; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis
D000970:Antineoplastic Agents; D016898:Interferon-alpha; D007376:Interleukin-2