A RANDOMIZED STUDY WITH SUBCUTANEOUS LOW-DOSE INTERLEUKIN-2 ALONE VS INTERLEUKIN-2 PLUS THE PINEAL NEUROHORMONE MELATONIN IN ADVANCED SOLIDNEOPLASMS OTHER THAN RENAL-CANCER AND MELANOMA

Our previous experimental studies have shown that the best approach to increase the biological anti-tumour activity of interleukin 2 (IL-2) is not co-administration of another cytokine, but the association with immunomodulating neurohormones, in an attempt to reproduce the physio logical links between psychoendocrine and immune systems, which play a fundamental role in the regulation of the immune responses. In partic ular, the association with the pineal neurohormone melatonin (MLT) has been shown to cause tumour regressions in neoplasms that are generall y non-responsive to IL-2 alone. To confirm these preliminary results, a clinical trial was performed in locally advanced or metastatic patie nts with solid rumours other than renal cell cancer and melanoma. The study included 80 consecutive patients, who were randomised to be trea ted with IL-2 alone subcutaneously (3 million IU day(-1) at 8.00 p.m. 6 days a week for 4 weeks) or IL-2 plus MLT (40 mg day(-1) orally at 8 .00 p.m. every day starting 7 days before IL-2). A complete response w as obtained in 3/41 patients treated with IL-2 plus MLT and in none of the patients receiving IL-2 alone. A partial response was achieved in 8/41 patients treated with IL-2 plus MLT and in only 1/39 patients tr eated with IL-2 alone. Tumour objective regression rate was significan tly higher in patients treated with IL-2 and MLT than in those receivi ng IL-2 alone (11/41 vs 1/39, P<0.001). The survival at 1 year was sig nificantly higher in patients treated with IL-2 and MLT than in the IL -2 group (19/41 vs 6/39, P<0.05). Finally, the mean increase in lympho cyte and eosinophil number was significantly higher in the IL-2 plus M LT group than in patients treated with IL-2 alone; on the contrary, th e mean increase in the specific marker of macrophage activation neopte rin was significantly higher in patients treated with IL-2 alone. The treatment was well tolerated in both groups of patients. This study sh ows that the concomitant administration of the pineal hormone MLT may increase the efficacy of low-dose IL-2 subcutaneous therapy.