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. Objectives: To evaluate immunotherapy for advanced renal cell carcinoma by comparing: (1) high dose interleukin-2 to other options and (2) interferon-alfa to other options. The primary outcome of interest was overall survival at one year, with remission as the main secondary outcome of interest. Search methods: A systematic search of the CENTRAL, MEDLINE, and EMBASE databases was conducted for the period 1966 through end of 2005. Handsearches were made of the proceedings of the periodic meetings of the American Urologic Association, the American Society of Clinical Oncology, ECCO - the European Cancer Conference, and the European Society of Medical Oncology for the period 1995 to 2005. Selection criteria: 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 remission or survival by allocation. Fifty-eight identified studies involving 6880 patients were eligible and all but one reported remission; thirty-seven of these studies reported the one-year survival outcome. Data collection and analysis: Two reviewers independently abstracted each article by following a prospectively designed protocol. Dichotomous outcomes for treatment remission (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-alfa versus controls. Main results: Combined data for a variety of immunotherapies gave an overall chance of partial or complete remission of only 12.4%, compared to 2.4% in non-immunotherapy control arms. Twenty-eight percent of these remissions were designated as complete (data from 51 studies). Median survival averaged 13 months (range by arm, 6 to 28 months). The difference in remission rate between arms was poorly correlated with the difference in median survival so that remission rate is not a good surrogate or intermediate outcome for survival for advanced renal cancer. We were unable to identify any published randomized study of high-dose interleukin-2 versus a non-immunotherapy control, or of high-dose interleukin-2 versus interferon-alfa reporting survival. High dose interleukin-2 did not give better overall survival compared to the same therapy at one tenth the dose or to subcutaneous cytokine therapy, but may improve survival in the patients with bad prognostic factors based on subset analysis. Results from four studies (644 patients) suggest that interferon-alfa is superior to controls (OR for death at one year = 0.56, 95% CI 0.40 to 0.77). Using the method of Parmar 1998*, the pooled overall HR for death was 0.74 (95% CI 0.63 to 0.88). Of concern, a recent study currently available as a meeting report did not find a benefit to interferon-alfa in patients with advanced renal cell cancer of intermediate prognosis. The optimal dose and duration of interferon-alfa remains to be elucidated. The addition of a variety of enhancers, including lower dose intravenous or subcutaneous interleukin-2, has failed to improve survival compared to interferon-alfa alone. Two randomized studies have examined the role of initial nephrectomy prior to interferon-alfa therapy in highly selected fit patients with metastases at diagnosis and minimal symptoms; despite minimal improvement in the chance of remission, both studies of up-front nephrectomy improved median survival over interferon-alfa alone in this selected population. Authors' conclusions: Interferon-alfa provides a modest survival benefit compared to other commonly used treatments. In fit patients with metastases at diagnosis and minimal symptoms, nephrectomy followed by interferon-alfa gives the best survival strategy for fully validated therapies. The need for more effective specific therapy for this condition is apparent.