A RANDOMIZED STUDY OF LOW-DOSE SUBCUTANEOUS INTERLEUKIN-2 PLUS MELATONIN VERSUS SUPPORTIVE CARE ALONE IN METASTATIC COLORECTAL-CANCER PATIENTS PROGRESSING UNDER 5-FLUOROURACIL AND FOLATES

Chemotherapy with 5-fluorouracil (5-FU) and folates represents the fir st-line standard therapy for metastatic colorectal cancer, whereas at present there is no conventional second-time treatment. Because of its importance in generating an effective anticancer immune response, int erleukin-2 (IL-2) could constitute a new promising therapy of advanced colon cancer. Generally, IL-2 may determine tumor regressions in colo n cancer only when it is given at high toxic doses. Our preliminary st udies have shown that the pineal hormone melatonin may amplify IL-2 ac tivity, which becomes active also at low doses in several tumor histot ypes. On this basis, we have performed a clinical trial to evaluate th e impact of low-dose IL-2 plus melatonin on the survival time in metas tatic colon cancer, which progressed in response to 5-FU plus folates. The study included 50 metastatic colorectal cancer patients, who did not respond or progressed after initial response to first-line chemoth erapy with 5-FU and folates. Patients were randomized to receive suppo rtive care alone or low-dose subcutaneous IL-2 (3 million IU/day for 6 days/week for 4 weeks) plus melatonin (40 mg/day orally). No spontane ous tumor regression occurred in patients receiving supportive care al one. A partial response was achieved in 3/25 patients treated with imm unotherapy. Percent survival at 1 year was significantly higher in pat ients treated with immunotherapy than in those treated with supportive care alone (9/25 vs. 3/25, p < 0.05). This study suggests that low-do se subcutaneous IL-2 plus melatonin may be effective as a second-line therapy to induce tumor regression and to prolong percent survival at 1 year in metastatic colorectal cancer patients progressing under 5-FU and folates.