Originally published as JCO Early Release 10.1200/JCO.2004.00.8128 on October 31 2005

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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

From the Department of Dermatology, Medical University of Graz; Section of Medical Statistics and Department of Dermatology, Medical University of Vienna; Department of Dermatology, Danube Hospital; Department of Dermatology, Wilhelminen Hospital; Roche Austria GmbH, Vienna; Department of Dermatology, Medical University of Innsbruck; Department of Dermatology, Hospital of St Pölten; Department of Dermatology, Hospital of Wels; Department of Dermatology, Hospital of Klagenfurt; Department of Dermatology, Hospital of Salzburg; Department of Dermatology, Hospital of Lainz; and Department of Dermatology, Rudolfsstiftung, Wien, Austria

Address reprint requests to Hubert Pehamberger, MD, Department of Dermatology, Medical University of Vienna, Währingergürtel 18-20 A-1090 Vienna, Austria; e-mail: hubert.pehamberger{at}meduniwien.ac.at

PURPOSE: The combination of interferon alfa (IFN) and isotretinoin has shown a direct antiproliferative effect on human melanoma cell lines, but it remained unclear whether this combination is more effective than IFN alone in patients with metastatic melanoma. We evaluated safety and efficacy of IFN and isotretinoin compared with IFN 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 IFN and isotretinoin (isotretinoin group; 206 patients) or IFN and placebo (placebo group; 201 patients) after excision of the primary tumor. IFN 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 IFN in patients with stage IIA and IIB melanoma had no significant effect on disease-free or overall survival and is therefore not recommended.

Supported by Roche Austria GmbH, Vienna, Austria.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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