Randomized Phase II/III Trial of Interferon Alfa-2a With and Without 13-cis-Retinoic Acid in Patients With Progressive Metastatic Renal Cell Carcinoma: The European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group (EORTC 30951)

Purpose A randomized phase II/III trial was conducted to determine whether combination treatment with 13-cis-retinoic acid (13-CRA) plus interferon alfa-2a (IFN-α-2a) was superior to IFN-α-2a alone in patients with progressive metastatic renal cell carcinoma. Patients and Methods Three hundred twenty patients were randomly assigned to treatment with IFN-α-2a plus 13-CRA or to IFN-α-2a alone. IFN-α-2a was given daily subcutaneously, starting at a dose of 3 million units (MU). The dose was escalated every 7 days from 3 to 9 MU by increments of 3 MU. Patients randomly assigned to combination therapy received oral 13-CRA 1 mg/kg/d plus IFN-α-2a. Results Median time to progression was 5.1 months for patients treated with the combination and 3.4 months for patients on IFN-α-2a alone (P = .008). Progression-free survival rates at 6 months were 43% for patients receiving combined therapy and 30% for patients on IFN-α-2a, and at 12 months, 27% and 17%, respectively. Median overall survival was 17.3 months for patients on IFN-α-2a and 13-CRA, and 13.2 months for patients treated with IFN-α-2a (P = .048). Twenty-two percent of the patients receiving the combination stopped treatment due to toxicity, as compared with 16% on IFN-α-2a. Conclusion Progression-free and overall survival for patients with progressive metastatic renal cell carcinoma treated with IFN-α-2a plus 13-CRA were significantly longer compared with patients on IFN-α-2a alone (P = .007 and P = .048, respectively). Improvement in efficacy in the combination arm was accompanied by increased, though not serious, toxicity.