Multicenter Phase II Trial of S-1 in Patients With Cytokine-Refractory Metastatic Renal Cell Carcinoma

Purpose This phase II multicenter trial was conducted to evaluate the activity and safety of S-1 in Japanese patients with metastatic renal cell carcinoma (mRCC). We also examined the relation between response and mRNA expression levels of enzymes involved in the metabolism of fluorouracil (FU). Methods Patients with mRCC who had received nephrectomy in whom cytokine-based immunotherapy was ineffective or contraindicated were studied. S-1 was administered orally at 80-, 100-, or 120-mg daily, assigned according to body surface area, on days 1 to 28 of a 42-day cycle. The primary end point was the objective response rate. The mRNA expression levels of FU-related enzymes were measured by reverse-transcriptase polymerase chain reaction in formalin-fixed, paraffin-embedded specimens of tumors obtained at nephrectomy. Results A total of 45 eligible patients were enrolled. Eleven (24.4%) of 45 patients had partial responses to S-1, and 28 (62.2%) had stable disease. Median progression-free survival was 9.2 months. The severity of most adverse events was mild to moderate. The most common grade 3/4 drug-related adverse events were neutropenia (8.9%) and anorexia (8.9%). The expression level of thymidylate synthase (TS) mRNA was significantly lower in patients who responded to treatment (t-test, P = .048), and progression-free survival was significantly longer in patients whose TS mRNA expression levels were below the median value, as compared with those with higher levels (log-rank test, P = .006). Conclusion S-1 is active against cytokine-refractory mRCC. Quantification of TS mRNA levels in tumors before treatment may facilitate prediction of the response of mRCC to S-1. J Clin Oncol 28: 5022-5029. (C) 2010 by American Society of Clinical Oncology