Cytokine combinations: therapeutic use in patients with advanced renal cell carcinoma

Treatment of metastatic renal cell carcinoma (RCC) remains unsatisfactory. To enhance the antitumor effects of various cytokines, combinations of these agents have been investigated. Interleukin-2 (IL-2) and interferon-alfa (IFN-alpha) have been combined based on data from preclinical studies suggesting synergism. A review of available phase I and II trials in more than 1,400 patients indicates that response rates are approximately 20%. Complete regressions are seen in 3% to 5% of patients. To demonstrate that this combination increases overall response rates, randomized trials were required. The results of a phase III study demonstrate a significantly improved response rate (18.6%) and 1-year event-free survival (20.9%) for patients treated with continuous infusion recombinant (r) IL-2 and subcutaneous IFN-alpha compared with either cytokine alone. The toxicity of rlL-2 and IFN-alpha is related to cytokine dose and schedule, but appears less than that reported with high-dose rIL-2. Analysis of prognostic factors and surrogate marker changes have been conducted. Performance status and number of disease sites predict response. rIL-2 and IFNalpha were then combined with fluorouracil, with initial reports suggesting response rates greater than 40%. Recent reports indicate 1% to 39% of patients responding. In a group of 836 patients with metastatic RCC receiving this therapy, 25.3% responded. Randomized trials comparing chemoimmunotherapy to rIL-2 and/or IFN-alpha are now required. The biologic basis and rationale for utilization of cytokines are strong. Clinical results are consistent with improved response rates in patients receiving rIL-2 and IFN-alpha. Continued investigation of novel and new treatment approaches remains a priority.