A Randomized Study of Low-Dose Subcutaneous lnterleukin-2 Plus Melatonin versus Supportive Care Alone in Metastatic Colorectal Cancer Patients Progressing under 5-Fluorouracil and Folates

Abstract

Chemotherapy with 5-fluorouracil (5-FU) and folates represents the first-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, interleukin-2 (IL-2) could constitute a new promising therapy of advanced colon cancer. Generally, IL-2 may determine tumor regressions in colon cancer only when it is given at high toxic doses. Our preliminary studies have shown that the pineal hormone melatonin may amplify IL-2 activity, which becomes active also at low doses in several tumor histotypes. On this basis, we have performed a clinical trial to evaluate the impact of low-dose IL-2 plus melatonin on the survival time in metastatic 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 chemotherapy with 5-FU and folates. Patients were randomized to receive supportive 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 spontaneous tumor regression occurred in patients receiving supportive care alone. A partial response was achieved in 3/25 patients treated with immunotherapy. Percent survival at 1 year was significantly higher in patients treated with immunotherapy than in those treated with supportive care alone (9/25 vs. 3/25, p < 0.05). This study suggests that low-dose 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.

Randomized Phase II Trial of High-Dose Melatonin and Radiation Therapy for RPA Class 2 Patients With Brain Metastases (RTOG 0119)

“…(19,20,21,22,23,11,24,25,26,27,28,29,30,31,32,33) Three independent randomized trials, including this trial, have been run. (34,35) It is noteworthy that all of the trials from Lissoni and colleagues have had positive outcomes and, as of yet, there have been no confirmatory publications from outside of his group.…”

Reduction in cytokine production in colorectal cancer patients: association with stage and reversal by resection

“…The use of IL-12, either as a preoperative treatment or in metastatic colorectal cancer is claimed to be associated with an improved survival (compared to current best supportive care) (Barni et al, 1995;Brivio et al, 1996). Reithmuller and colleagues reported that a monoclonal antibody (17-1A) to a colorectal antigen resulted in an improved survival for patients with Dukes' stage C colon cancer when given post resection (Reithmuller et al, 1994).…”

Cost-effectiveness analysis of cetuximab/irinotecan vs active/best supportive care for the treatment of metastatic colorectal cancer patients who have failed previous chemotherapy treatment

“…This was selected principally, as the supportive care arm represented the appropriate group for the comparator of ASC/BSC where 31% of the patients had received ASC. Two other trials of chemotherapy in the second/subsequent-line treatment vs supportive care for of metastatic CRC (Barni et al, 1995;Rao et al, 2004) were considered inappropriate proxies in this analysis as the supportive care arms comprised BSC alone and no ASC. Of note, survival figures differed between these studies such that use of alternative studies may have led to different cost-effectiveness outcomes such as cost per QALY.…”