The times they are a-changin' (Bob Dylan, 1964).

I n this issue of Cancer, the French Immunotherapy Intergroup reports results of the PERCY Quattro trial, which compares medroxyprogesterone acetate (MPA), subcutaneous interferon-alpha (INF-a), subcutaneous interleukin-2 (IL-2 ), or a combination of the 2 cytokines for front-line treatment of patients with intermediate prognosis metastatic renal cell carcinoma (RCC). Between January 2000 and July 2004, 492 patients were accrued to this trial. The primary endpoint of the trial was overall survival. Secondary endpoints included disease-free survival, response rate, toxicity, and quality of life. No significant survival differences were seen between the INF-a and non–INF-a treated patients (15.4 vs 15.1 months; hazard ratio [HR], 1.00; 95% CI, 0.81–1.24; log rank, 0.99) or between the IL-2 and non–IL-2 treated patients (15.7 vs 14.9 months; HR, 1.07; 95% CI, 0.87–1.33; log rank, 0.52). However, grade 3–4 toxicities were significantly more frequent in patients treated with cytokine. The authors should be commended. Overall this was a well designed, large (n 1⁄4 492), multi-institutional (44 centers) trial by a highly experienced group of investigators. Few criticisms can be made of the overall conduct and report of the trial. However, the question of how results of this trial become current treatment options for metastatic RCC must be asked. Our ability to pose this question is refreshing, as it is a sign the times are finally changing. Metastatic RCC has long been recognized to be resistant to chemotherapy and radiation therapy. Observation of spontaneous remissions in prospective trials with observation or placebo arms and after nephrectomy led to recognition of the importance of immune regulation in RCC and, subsequently, to an era of cytokine therapy including IL-2 and IFN as single agents and as combination therapy. Initial phase 2 trials of high-dose IL-2 showed promising response rates with reports of complete responses. A landmark trial published by Fyfe and colleagues reporting on 255 patients treated with high-dose IL-2 from 7 phase 2 trials with response rates of 14%, including 12 complete responses and 24 partial responses, many of which were durable (median response of more than 80 months for complete responders), led to approval of high-dose bolus IL-2 by the United States Food and Drug Administration (FDA). This approval was based on small numbers of complete but See related original article on pages 2468–77, this issue.