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Purpose: Subcutaneous recombinant interleukin-2 (rIL-2) and recombinant interferon alfa-2a (rIFNalpha-2a) have been used extensively in the treatment of metastatic renal cancer. Most results, coming from noncontrolled phase II trials, showed inconsistent rates of response. More recently, the addition of fluorouracil (FU) was proposed to improve the efficacy of these regimens.Patients and Methods: The role of a subcutaneous combination of rIL-2 and rIFNalpha-2a with or without FU was investigated. Patients were randomly assigned to receive a combination of rIL-2 and rIFNalpha-2a at weeks 1, 3, 5, and 7 or the same combination together with a continuous infusion of FU at weeks 1 and 5. The major end points of this multicenter, randomized trial were progression-free survival, response rate, and toxicity. Overall survival was a secondary end point. Tumor responses were reviewed by an independent committee. Analysis of the results was performed on an intention-to-treat basis.Results: One hundred thirty-one patients were enrolled. There was no difference in toxicity between the arms, and no toxic death was observed. One partial response was observed in arm A and five in arm B. Progression-free survival did not differ between the arms, and rates at 1 year were 12% and 15% in arms A and B, respectively. No statistically significant differences were detected in any end point.Conclusion: The subcutaneous combination of rIL-2 and rIFNalpha-2a with or without FU does not benefit patients with metastatic renal carcinoma. Neither of these regimens can be recommended as standard treatment. The results of the subcutaneous cytokine regimen seem disappointing.: CommentaryThe treatment of metastatic renal cancer remains a particularly difficult problem given the resistance of this disease to most treatment options. The use of cytokines, particularly IL-2 and interferon, has produced small numbers of responders with durable complete responses occurring in a very small percentage of patients. Of the chemotherapeutic agents studied in the past, the fluorouracils have demonstrated the most consistent, albeit uncommon, activity. It was therefore natural that the combination of IL-2, interferon, and 5-FU (the FUNIL regimen) would be widely tested. Recently we have seen a number of manuscripts describing the efficacy of these agents in combination in the management of relatively large numbers of patients with metastatic renal cancer. Various dosing regimens have also been used. In the phase II trial reported by Allen et al. (Br J Cancer 2000;83:980–5), 55 patients treated using the Atzpodien regimen resulted in a 31% response rate with 3 patients (5.5%) achieving a complete response. Toxicity was significant with 12 patients unable to complete one cycle of treatment and 36% experiencing grade 3-4 toxicity. These response rates, however, were not reproduced in the trials of Elias et al. (Cancer 2000;89:597–603) or Dutcher et al. (Clin Cancer Res 2000;6:3442–50) where response rates of approximately 18% were seen in patients in whom response could be determined. Interestingly, approximately 5% of evaluable patients in these latter two studies also achieved a complete response, in agreement with the work of Allen and associates. In a randomized comparison of subcutaneous IL-2 and interferon alpha-2a with or without continuous infusion 5-FU, Ne´grier et al. (J Clin Oncol 2000;18:4009–15) could not demonstrate an advantage of the addition of 5-FU in a study of 131 patients. Progression–free survival in the two arms was 12% and 15%, respectively.So, what are the take-home messages from these manuscripts? Firstly, the FUNIL regimen is toxic but toxicity is manageable in most patients. A significant percentage of patients, however, may not be able to complete one cycle of therapy, suggesting that this regimen is best suited for fit patients with good performance status. It appears that the regimen can achieve a complete response rate of about 5% and that these responses are durable. Is this regimen better than high dose IL-2 alone? Probably not, although these studies do not directly address this question. Finally, the FUNIL regimen is probably not of sufficient efficacy to be considered standard therapy for metastatic renal cancer.Robert Flanigan, M.D. [Copyright &y& Elsevier]