Multicenter phase II trial of interleukin-2, interferon-α, and 13-cis- retinoic acid in patients with metastatic renal-cell carcinoma

Purpose: To determine the response rate and toxicity of oral 13-cis- retinoic acid (CRA) added to an outpatient regimen of subcutaneous interleukin-2 (IL2) and interferon-α (IFNA) in previously untreated patients with metastatic renal-cell carcinoma (RCC). Patients and Methods: Eligibility included a performance status of 2 or better, no significant end-organ dysfunction, and written informed consent. Characteristics of 47 of 48 assessable patients included a median performance status of 0, prior nephrectomy in 68% of patients, one metastatic site in 30% of patients, and lung-only metastatic disease in 21% of patients. Therapy consisted of IL2 11 x 10⁶ IU 4 days per weak for 4 weeks, IFNA 9 x 10⁶ IU 2 days per week for 4 weeks, and CRA 1 mg/kg daily on a 6-weak cycle. Results: Eight of 47 patients (17%) responded (one complete response, seven partial responses). Three partial responders were rendered disease free by subsequent surgical resection. Four additional patients experienced a minor response in lung or soft tissue metastases. The median duration of response, which included minor responses, was 42 weeks, and median survival was 74 weeks (17 months). Grades 3 or greater toxicities during the first cycle included flu-like symptoms (21% of patients), fatigue (6% of patients), and nausea and vomiting (15% of patients). Significant cumulative toxicities were hyperlipidemia (four of 18 patients), and cardiomyopathy (one of 18 patients). There was one therapy- related death. Conclusion: Outpatient CRA plus IL2 and IFNA is feasible and modestly effective in metastatic RCC. The prolonged median survival is encouraging, but randomized trials are required to show that the combination represents an improvement over single-agent immunotherapy.