Prospective, Randomized, Multicenter, Double-Blind Placebo-Controlled Trial Comparing Adjuvant Interferon Alfa and Isotretinoin With Interferon Alfa Alone in Stage IIA and IIB Melanoma: European Cooperative Adjuvant Melanoma Treatment Study Group

Abstract

Purpose The combination of interferon alfa (IFNα) and isotretinoin has shown a direct antiproliferative effect on human melanoma cell lines, but it remained unclear whether this combination is more effective than IFNα alone in patients with metastatic melanoma. We evaluated safety and efficacy of IFNα and isotretinoin compared with IFNα alone as adjuvant treatment in patients with primary malignant melanoma stage IIA and IIB. Patients and Methods In a prospective, randomized, double-blind, placebo-controlled trial, 407 melanoma patients in stage IIA (301 patients) and IIB (106 patients) were randomly assigned to either IFNα and isotretinoin (isotretinoin group; 206 patients) or IFNα and placebo (placebo group; 201 patients) after excision of the primary tumor. IFNα was administered three times a week at a dose of 3 million units subcutaneously for 24 months. Isotretinoin at a dose of 20 mg for patients ≤ 73 kg, 30 mg for patients greater than 73 kg, or placebo daily for 24 months. Results A scheduled interim analysis revealed no significant differences in survival rates, with the isotretinoin group and the placebo group showing 5-year disease-free survival rates of 55% (95% CI, 46% to 65%) and 67% (95% CI, 59% to 75%), respectively, and overall 5-year survival rates of 76% (95% CI, 67% to 84%) and 81% (95% CI, 74% to 88%), respectively. The trial was stopped for futility. Conclusion The addition of isotretinoin to an adjuvant treatment of low-dose IFNα in patients with stage IIA and IIB melanoma had no significant effect on disease-free or overall survival and is therefore not recommended.