Long-term follow-up of patients with metastatic renal cell carcinoma treated with intravenous recombinant interleukin-2 in Europe.

Purpose: The median survival for patients with metastatic renal cell carcinoma (mRCC) is generally < 1 year. Immunotherapy with high-dose recombinant interleukin (IL)-2 has been reported to produce objective responses in approximately 15% of treated patients and is associated with durable complete responses and prolonged survival in responding patients. The impact of IL-2 therapy on survival of metastatic renal cell carcinoma patients has begun to emerge, based on long-term follow-up data from large databases. Combinations of IL-2 and interferon alfa (IFN-alpha) have also been intensively investigated in mRCC.

Patients and methods: Between 1987 and 1990, 281 mRCC patients were treated with continuous infusion IL-2 in three European multinational, single-arm phase II trials. Long-term treatment outcomes for these patients were analyzed, and the results are presented here. The results of a large, randomized French cooperative group trial (the Cancer Renal Cytokine [CRECY] study) that enrolled 425 patients between 1991 and 1995 are also summarized. Patients on this trial were randomized to treatment with IL-2 alone, IFN-alpha alone, or the combination.

Results: Among patients included in the 281-patient database, the objective response rate was 15%. Median survival was 10 months; 41% of patients were alive at 1 year, 22% were alive at 2 years, and 8% were alive at 5 years. Among patients with a complete or partial response, 60% and 18% were alive at 5 years, respectively. No clinical factors were predictive for response or survival; however, no patient with a high endogenous IL-6 level at diagnosis responded to IL-2 therapy. The CRECY trial demonstrated that the combination of IL-2 and IFN-alpha induced a significantly higher response rate (P < 0.01) and significantly improved 1-year event-free survival (P = 0.01) compared with either agent alone, but overall survival was not significantly different between the three treatment groups.

Conclusion: The European experience suggests that the 5-year survival rate for metastatic renal cell carcinoma patients treated with high-dose continuous infusion IL-2 therapy is approximately 8% and that the majority of the therapeutic benefit is restricted to patients achieving a complete response. Therefore, given the toxicity, candidates for IL-2 therapy should be carefully selected. The combination of IL-2 and IFN-alpha does not appear to provide additional survival benefit. Efforts to further improve therapeutic outcome for patients with metastatic renal cell carcinoma should focus on understanding the underlying mechanisms of cytokine-induced tumor regression.