A phase II study of chemoneuroimmunotherapy with platinum, subcutaneous low-dose interleukin-2 and the pineal neurohormone melatonin (P.I.M.) as a second-line therapy in metastatic melanoma patients progressing on dacarbazine plus interferon-alpha.

Immunochemotherapeutic combinations containing IL-2 theoretically represent the most effective therapies for metastatic melanoma, particularly in association with cisplatin (CDDP); however, both IL-2 and CDDP have been generally utilized at high doses, with the consequence of considerable toxicity. According to psychoneuroimmunological knowledge, the antitumor activity of IL-2 has been proven to be enhanced by the immunomodulating pineal neurohormone melatonin (MLT), which has also been shown to increase the cytotoxicity of cancer chemotherapy and reduce its toxicity. On this basis, a study was planned with low-dose IL-2 and CDDP in association with MLT as a second-line therapy for metastatic melanoma patients progressing on dacarbazine plus interferon-alpha. The study included 13 evaluable patients. CDDP was injected i.v. at 30 mg/m2/day for 3 days every 21 days. IL-2 was administered s.c. at 3 million IU/day from days 4 to 9 and from days 11 to 16 of the cycle. Finally, MLT was given orally at 20 mg/day in the evening, every day without interruption. One patient obtained a complete response (CR), while partial response (PR) was achieved in 3 other patients. Therefore, the objective tumor response-rate (CR + PR) was 4 out of 13 (31%). A stable disease occurred in 5 patients, whereas the remaining 4 patients had a progressive disease. The treatment was extremely well-tolerated in all patients and, in particular, no CDDP-related neurotoxicity was observed. The results of this preliminary study would suggest that low-dose CDDP and IL-2 in association with the pineal hormone MLT (P.I.M. schedule), given as a second line therapy, is an effective and well-tolerated treatment for metastatic melanoma, with a clinical efficacy at least comparable to that obtained with a first-line therapy of dacarbazine plus interferon-alpha.