Phase II and Biologic Study of Interferon Alfa, Retinoic Acid, and Cisplatin in Advanced Squamous Skin Cancer

PURPOSE: The purpose of this study was to test interferon alfa (IFNα), 13-cis-retinoic acid (13cRA), and cisplatin biochemotherapy in advanced squamous cell carcinoma (SCC) of the skin. PATIENTS AND METHODS: Patients with advanced skin SCC received IFNα (5 × 10 6 IU/m 2 , subcutaneous injection, three times a week), 13cRA (1 mg/kg, orally, daily), and cisplatin (20 mg/m 2 , intravenous injection, weekly) in a phase II trial. The growth inhibition, cell-cycle, and apoptosis activity of these agents was evaluated in two skin SCC cell lines (SRB1-m7 and SRB12-p9). RESULTS: Thirty-nine patients were enrolled. All were assessable for survival, 35 for response and toxicity (median follow-up was 38 months). The overall and complete response rates were 34% and 17%, respectively, with median durations of 9 and 35.4 months, respectively. The response rate was higher in locally advanced (67%) than metastatic (17%) disease (P = .007). Median survival was 14.6 months. One-, 2-, and 5-year survival rate estimates were 58%, 32%, and 21%, respectively. Toxicity included generally mild to moderate fatigue and mucocutaneous dryness, moderate to severe neutropenia (38%), and neutropenic fever (6%). There were no treatment-related deaths. In vitro growth inhibition and apoptosis effects of cisplatin were differential and inversely associated with those of retinoic acid and especially IFNα in two skin SCC lines. CONCLUSION: The rising incidence, morbidity, and mortality of advanced skin SCC are a major challenge for clinical oncologists. Combined 13cRA, IFNα, and cisplatin was clinically active in extensive locally advanced disease. Each agent had independent, non–cross-resistant biologic effects in vitro, which may account for the combination’s clinical activity.