Purpose: Interleukin-2 (IL-2) and interferon alfa-2a (IFN alpha 2a) have some antitumor activity in metastatic renal cell carcinoma either alone or in combination. To determine whether either of these cytokines might be efficient after failure of the other, we analyzed a series of patients treated with either IL-2 or IFN alpha 2a as second-line treatment after failure of the other cytokine, Patients and Methods: We recently performed a large multicenter study to determine the respective efficacy of IL-2, IFNa2a, or combined treatment in renal cell carcinoma. In this study, patients who progressed on the single-arm treatment could receive the other cytokine in a cross-over trial. IL-2 was administered as a continuous intravenous infusion for 5 days (18 x 10(6) IU/m(2)/d), and IFN alpha 2a was administered three times weekly at 18 x 10(6) IU. Results: A total of 113 patients with progressive disease after first-line treatment received either IFN alpha 2a (n = 48) or IL-2 (n = 65). Toxicity during second-line treatment was similar to that observed during first-line treatment, Only four partial responses were observed (one with lFN alpha 2a and three with IL-2). All partial responders had a performance status of 0 and lung metastases. Moreover, three of these four patients had stable disease or had responded to first-sine therapy. Only one patient with confirmed disease progression after receiving IL-2 subsequently responded to IFN alpha 2a. Conclusion: Cross-over after failure of IL-2 or lFN alpha 2a is poorly efficient in metastatic renal cell carcinoma, especially when progression has been clearly documented. (C) 1999 by American Society of Clinical Oncology.