Seely D, Legacy M, Auer RC, et al. Adjuvant melatonin for the prevention of recurrence and mortality following lung cancer resection (AMPLCaRe): a randomized placebo controlled clinical trial. EClinicalMedicine. 2021;33:100763.
To evaluate the impact of melatonin on lung cancer recurrence and mortality after surgical resection within a 5-year period, as well as to elaborate on impacts of quality of life, symptoms, and immune function
Multicenter, 2-arm, placebo-controlled, double-blind, phase 3, randomized, controlled trial with participants receiving 20 mg melatonin versus placebo
Adults with primary non–small cell lung cancer (NSCLC) eligible for complete surgical resection participated in the study. Researchers excluded patients if they were already taking melatonin, had an incomplete resection, or were pregnant or breastfeeding. They enrolled and randomized a total of 709 patients (356 melatonin group, 353 placebo group) from across 8 centers. Mean age was 67.2 ± 8.5 years. In the melatonin group, 46.6% of participants were male, and 40.7% of participants in the placebo group were male. Of the participants, 2.2% in the melatonin group received preoperative chemotherapy or radiation versus 3.9% of the placebo group. In the melatonin group, 13.2% were current smokers, and 14.6% of the placebo group were current smokers. The melatonin group had 78.6% who were past smokers, and 73.9% of the placebo group were past smokers.
Study Parameters Assessed
The 2 groups of lung cancer patients, those taking melatonin and those not taking melatonin, were compared using numerous statistical tests to see if melatonin delayed the cancer from progressing or increased how long the patients survived. The primary outcome was 2-year disease-free survival (DFS). DFS up to 5 years post-surgery was also compared to Kaplan-Meier curves.
Primary Outcome Measures
Primary outcome was 2-year DFS, assessing incidence of recurrence or mortality 2 years after surgical resection. The study used clinical examination by the thoracic surgeon and radiological evidence of disease as markers of recurrence. In most centers, the clinicians used annual computed tomography (CT) scan and clinical exams. However, they also used a number of other imaging studies for evaluation, depending on the clinician’s preferences.
Two-year DFS in patients taking melatonin had an adjusted relative risk of 1.01 (95% CI 0.83–1.22, P=0.94) compared to placebo. The per-protocol analysis showed an adjusted relative risk of 1.12 (95% CI 0.96–1.32, P=0.14).
Neither arm reached 5-year median DFS. The melatonin group showed a hazard ratio of 0.97 (95% CI 0.86–1.09, P=0.84) for 5-year DFS compared to the placebo group. The melatonin group showed a hazard ratio of 0.97 (95% CI 0.85–1.11, P=0.66) in the early-stage group (I and II) and a hazard reduction of 25% (HR 0.75, 95% CI 0.61–0.92, P=0.005) in the late stage (III and IV) group. The early-stage group did not reach 5-year median DFS. In the late-stage group, there was no difference in median DFS (melatonin arm: 18.0 months [95% CI 9.426.6]; placebo arm: 18.0 months [95% CI 2.223.8]). The study showed no benefit in the use of melatonin for chemotherapy and radiation side effects, quality of life, fatigue, sleep, depression, anxiety, and pain at a dose of 20 mg in this population.
Melatonin has long been a favorite substance used within the naturopathic and allopathic medicine world for its notable benefits in addressing insomnia and circadian regulation.1
This study’s relevance goes beyond improvements in sleep, as it speaks to the potential for improvement in survival, specifically for late-stage lung cancer patients.
Lung cancer continues to be the cancer with the second-highest incidence in both sexes, behind prostate cancer for men and breast cancer for women; it also has the highest mortality rate among all cancers for both sexes around the world.2 Additionally, there has been a trend of new cancer diagnoses in nonsmokers who tend to be women with adenocarcinoma, found at a later and more advanced stage.3 All these factors have us looking for more avenues for improved treatment with less impact on quality of life.
Studies looking at the benefit of melatonin in NSCLC patients undergoing chemotherapy show favorable outcomes, specifically in enhancing effectiveness of chemotherapy and reducing toxicity.4 There have been fewer studies looking at outcomes following surgical resection, which makes this current study significant.
Melatonin continues to be studied, with recent articles referencing its multitude of benefits.5 There are many therapeutic potentials for this substance for lung cancer, as well as a variety of other tumor types. Gurunathan et al mention specifically in their review that “The combination of melatonin with conventional drugs improves the drug sensitivity of cancers, including solid and liquid tumors.”5
Studies looking at the benefit of melatonin in NSCLC patients undergoing chemotherapy show favorable outcomes, specifically in enhancing effectiveness of chemotherapy and reducing toxicity.
Further studies ideally should also look at the combination of melatonin with some of the more novel oral-targeted medications such as erlotinib and osimertinib, which clinicians are implementing as first-line treatment for late-stage disease.
We as clinicians are eternally searching for methods to improve quality of life and extend survival for our patients. Although the numbers of late-stage patients in this trial were small, the implications are very positive and will likely help to usher in similar studies.
This study will likely encourage more practitioners to supplement their stage III and stage IV NSCLC patients with 20 mg of melatonin, especially after surgical resection. However, given the abundance of data on benefit during chemotherapy as well, there is a greater likelihood that the majority of late-stage patients would benefit from the addition of melatonin.
- Tordjman S, Chokron S, Delorme R, et al. Melatonin: pharmacology, functions and therapeutic benefits. Curr Neuropharmacol. 2017;15(3):434-443.
- Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584-594.
- Casal-Mouriño A, Valdés L, Barros-Dios JM, Ruano-Ravina A. Lung cancer survival among never smokers. Cancer Lett. 2019;451:142-149.
- Lissoni P, Chilelli M, Villa S, Cerizza L, Tancini G. Five years survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial. J Pineal Res. 2003;35(1):12-15.
- Gurunathan S, Qasim M, Kang MH, Kim JH. Role and therapeutic potential of melatonin in various type of cancers. Onco Targets Ther. 2021;14:2019-2052.