A phase II evaluation of all-trans-retinoic acid plus interferon alfa-2a in stage IV melanoma: a Southwest Oncology Group Study

BACKGROUND Interferon alfa has modest but definite activity in the treatment of metast atic melanoma and is the only agent currently available for adjuvant therap y of high-risk resected disease. A variety of retinoic acid derivatives hav e been shown to be synergistic with interferon alfa in vitro and in vivo, w ith nonoverlapping toxicities. If promising combinations of interferon alfa and retinoids could be developed for melanoma patients, they would have cl inical relevance for the treatment of advanced as well as localized disease . PURPOSE To determine the efficacy and toxicity of a combination of interferon alfa- 2a and all-trans-retinoic acid in patients with measurable metastatic melan oma, the Southwest Oncology Group conducted a phase II clinical trial. PATIENTS AND METHODS Fifty-seven patients with measurable metastatic melanoma (American Joint Co mmittee on Cancer stage IV) were entered; five patients were unevaluable. T reatment consisted of oral all-trans-retinoic acid (37.5 to 75 mg/m(2) oral ly twice daily for 21 days followed by 7 days' rest) plus subcutaneously ad ministered interferon alfa-2a (6 MU/m(2) three times a week). RESULTS Two complete and three partial responses were observed among 52 evaluable p atients, for an objective response rate of 10% (95% confidence interval 3% to 21%). Responses were seen only in patients with pulmonary, nodal, or sub cutaneous metastases, and lasted from 4 to 23+ months. Median survival for the 52 patients was 8 months. Side effects were tolerable but significant, with one case of grade IV anemia and 92% of patients experiencing at least grade II toxicity. Flu-like symptoms were the most commonly reported side e ffects. There was one case of grade III hyperlipidemia. CONCLUSION The combination of recombinant human interferon alfa-2a with all-trans-reti noic acid did not result in a greater percentage of objective responses or a longer overall survival than that associated with interferon alfa alone. This combination cannot be recommended for further evaluation in melanoma i n either the advanced disease or the adjuvant settings.