A systematic search of the CENTRAL, MEDLINE, and EMBASE databases was conducted for the period 1966 through end of December 2003. 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 June 2004.
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-three identified studies involving 6117 patients were eligible and all but one reported remission; 32 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, and for two randomized studies of the value of initial
nephrectomy prior to
interferon-alfa in fit patients with
metastases detected at the time of diagnosis.
MAIN RESULTS: Combined data for a variety of
immunotherapies gave an overall chance of partial or complete remission of only 12.9% (99 study arms), compared to 2.5% in 10 non-
immunotherapy control arms, and 4.3% in two placebo arms. Twenty-eight percent of these remissions were designated as complete (data from 45 studies). Median survival averaged 13.3 months (range by arm, 6 to 27+ 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. It has been established that reduced dose
interleukin-2 given by intravenous bolus or by
subcutaneous injection provides equivalent survival to high dose
interleukin-2 with less toxicity. Results from four studies (644 patients) indicate that
interferon-alfa is superior to controls (OR for death at one year = 0.56, 95% confidence interval 0.40 to 0.77). Using the method of Parmar 1998, the pooled overall hazard ratio for death was 0.74 (95% confidence interval 0.63 to 0.88). The weighted average median improvement in survival was 3.8 months. T he 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 recent 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 by 4.8 months over
interferon-alfa alone. Recent studies have been examining anti-angiogenesis agents. A landmark study of
bevacizumab, an anti-
vascular endothelial growth factor antibody, was associated with significant prolongation of the time to progression of disease when given at high dose compared to low-dose or placebo
therapy though frequency of remissions or survival were not improved.
AUTHORS' CONCLUSIONS:
interferon-alfa 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. 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.