Abstract 4673: A randomized, double-blind, multicenter trial evaluating the chronotherapeutic role of concomitant melatonin in the treatment of stage IIIB and IV non-small cell lung carcinoma.

Background: A recently published meta-analysis suggests that melatonin administered concurrently with chemotherapy leads to significant improvements in tumor response and survival in solid tumors, however, the role of melatonin in cancer treatment still remains disputable. We investigated the impact of chronotherapeutic administration of melatonin on tumor response and overall survival in stage IIIB and IV non-small cell lung cancer (NSCLC) patients undergoing conventional chemotherapy. Methods: Veteran Affairs Medical Center (VAMC) and Cancer Treatment Centers of America® at Midwestern Regional Medical Center (MRMC), a non-VA site, entered 42 patients each. The patients were randomized to receive placebo 8 am and placebo 8 pm (arm 1; n=29), or melatonin 20 mg 8 am and placebo 8 pm (arm 2; n=27), or placebo 8 am and melatonin 20 mg 8 pm (arm 3; n=28). All study participants received treatment with cisplatin (25 mg/m2/day) followed by etoposide (100 mg/m2/day) chemotherapy. Patient survival was defined as the time between the study start date and date of death from any cause/date of last contact. Kaplan-Meier analysis with log-rank test was used to evaluate the equality of survival distributions across the three treatment arms. Tumor response was evaluated using the RECIST guidelines. Results: 64 patients had stage IV while 20 had stage IIIB disease. 65 patients were males while 19 were females. All patients had expired at the time of this analysis. Mean age at study entry was 61.3 years (57 years for MRMC versus 65.7 for VAMC). There were no significant differences in the three treatment arms with respect to age, gender, tumor stage and performance status. Median survival time in the 3 treatment arms was 10.4 (arm 1), 6.8 (arm 2) and 8.0 (arm 3) months respectively (log rank p=0.81). Similarly, there was no significant difference in the treatment arms with regard to tumor response, such that 48.3%, 37.0% and 32.1% patients had stable disease in arm 1, arm 2 and arm 3 respectively (Chi-square p=0.49). Conclusions: Contrary to the recently reported meta-analysis, we found that neither the addition nor the timing of a high oral dose of melatonin added therapeutically to the combination of cisplatin and etoposide. The melatonin dose used in this study is at least 20x the usual replacement dose and this may have resulted in melatonin being inappropriately present in the circulation during both day and night, an un-physiologic state, which might be responsible for the apparent lack of efficacy of this particular regimen. Citation Format: Robert D. Levin, James F. Grutsch, Christopher G. Lis, Digant Gupta, Patricia A. Wood, William JM Hrushesky. A randomized, double-blind, multicenter trial evaluating the chronotherapeutic role of concomitant melatonin in the treatment of stage IIIB and IV non-small cell lung carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4673. doi:10.1158/1538-7445.AM2013-4673