A Randomized Study of Immunotherapy with Low-Dose Subcutaneous Interleukin-2 plus Melatonin Vs Chemotherapy with Cisplatin and Etoposide as First-Line Therapy for Advanced Non-Small Cell Lung Cancer

Abstract

Aims and Background The theraputic role of chemotherapy in advanced non-small cell lung cancer (NSCLC) is controversial because of its potentially detrimental action on host anticancer defenses. On the contrary, IL-2 would seem to prolong survival time by improving the immune status, even though it is generally less effective in determining tumor regression in NSCLC. Our previous studies have suggested the possibility of increasing tumor sensitivity to IL-2 by concomitant administration of immunomodulating neurohormones, such as the pineal hormone melatonin (MLT). On this basis, a study was carried out to evaluate the efficacy of immunotherapy with low-dose IL-2 plus MLT versus chemotherapy in advanced NSCLC. Methods The study included 60 patients with locally advanced or metastatic NSCLC, who were randomized to receive immunotherapy or chemotherapy. The immunotherapy consisted of IL-2 (3 million IU/day subcutaneously for 6 days/week for 4 weeks) and MLT (40 mg/day orally every day, starting 7 days before IL-2); in nonprogressing patients, a second cycle was repeated after a 21-day rest period, then they underwent a maintenance period consisting of one week of therapy every month until progression. Chemotherapy consisted of cisplatin (20 mg/m2) and etoposide (100 mg/m2)/day intravenously for 3 days; cycles of chemotherapy were repeated every 21 days until progression. Results No complete response was obtained. A partial response was achieved in 7/29 patients treated with chemotherapy and in 6/31 patients receiving chemotherapy. The difference was not significant. In contrast, the mean progression-free period and the percentage survival at 1 year was significantly higher in patients treated with immunotherapy than in those treated with chemotherapy. Toxicity was substantially lower in patients receiving immunotherapy than in those given chemotherapy. Conclusions This randomized study showed that immunotherapy with low-dose IL-2 plus MLT is a better tolerated and more effective therapy in terms of survival time than chemotherapy containing cisplatin in patients affected by advanced NSCLC.

Cachexia and anorexia: cancer's covert killer

“…Other trials have used melatonin with interleukin II with benefit. These trials need to be repeated in larger numbers and by multiple investigators before widespread use of melatonin [77,[79][80][81][82][83][84][85][86].…”

Strengths and Weaknesses of Immunotherapy for Advanced Non-Small-Cell Lung Cancer: A Meta-Analysis of 12 Randomized Controlled Trials

“…After referring to full texts, we removed 275 studies that did not meet the selection criteria (Figure 1). As a result, 12 studies [16], [21]–[31] that included a total of 3134 patients were selected for meta-analysis.…”

“…Although six studies did not describe OS [23] or PFS [16], [21], [22], [24], [26] and four studies did not provide the number of patients in CR and/or PR rates [22], [26], [29], [31], all 12 studies were open-labeled and randomized. They mentioned the concealment of allocation clearly in the randomization process, and provided the number of patients who withdrew from the trials.…”

“…An event that was fatal, life-threatening, required hospitalization or prolonged existing hospitalization, or caused a persistent or significant disability/incapacity was defined as an SAE [15]. AEs were graded using the National Cancer Institute Common Toxicity Criteria, version 2.0, except AEs reported by Lissoni et al [16], which were graded using WHO criteria.…”

Intervention in the aging immune system: Influence of dietary restriction, dehydroepiandrosterone, melatonin, and exercise

“…Several clinical studies have shown that MLT therapy, alone or in combination with IL-2, significantly decreases the progression of various tumors, e.g., carcinomas (136), melanoma (135), renal (133,135), lung (135)(136)(137)(138), and breast tumors (139)(140)(141). Cancer patients, who were unable to tolerate the IL-2 therapy alone and who did not respond to standard anti-cancer chemotherapies, were shown to have increased IL-2 tolerance, and they exhibited an effective antitumor defense response when they were treated with a combination of MLT and IL-2 (134,135,(142)(143)(144)(145)(146)(147)(148). Although the exact mechanism responsible for the anti-neoplastic action of MLT has not been determined, it has been suggested that MLT mediates its effect on hematopoietic progenitor cells, i.e., it increases the number of the granulocyte macrophage-colony forming unit (34,117).…”