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Relation
Seely D, Legacy M, Auer RC, et al. Adjuvant melatonin for the prevention of recurrence and mortality after lung cancer resection (AMPLCaRe): a randomized placebo-controlled clinical trial.EClinicalMedicine. 2021;33:100763.
Study objective
To evaluate the effects of melatonin on lung cancer recurrence and mortality after surgical resection within a 5-year period and to explain the effects on quality of life, symptoms and immune function
Draft
Multicenter, 2-arm, placebo-controlled, double-blind, randomized, controlled phase 3 study of participants receiving 20 mg melatonin compared to placebo
Participant
Adults with primary non-small cell lung cancer (NSCLC) who were eligible for complete surgical resection participated in the study. Researchers excluded patients who were already taking melatonin, had an incomplete resection, or were pregnant or breastfeeding. They recruited and randomized a total of 709 patients (356 melatonin group, 353 placebo group) from 8 centers. The 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% in the placebo group. In the melatonin group, 13.2% were current smokers and 14.6% of the placebo group were current smokers. In the melatonin group, 78.6% were former smokers and 73.9% of the placebo group were former smokers.
Study parameters assessed
The 2 groups of lung cancer patients, those who took melatonin and those who did not take melatonin, were compared using numerous statistical tests to determine whether melatonin delayed cancer progression or increased patients' survival time. The primary endpoint was disease-free survival (DFS) at 2 years. DFS up to 5 years after surgery was also compared with Kaplan-Meier curves.
Primary outcome measures
The primary endpoint was 2-year DFS, assessing the incidence of recurrence or mortality 2 years after surgical resection. The study used clinical examination by the thoracic surgeon and radiographic evidence of disease as markers of recurrence. In most centers, physicians performed annual computed tomography (CT) scans and clinical examinations. However, they also used a range of other imaging studies for evaluation, depending on the doctor's preferences.
Key insights
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 achieved a 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 group (III and IV). The early-stage group did not achieve 5-year median DFS. There was no difference in median DFS in the late-stage group (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 with the use of melatonin on chemotherapy and radiation side effects, quality of life, fatigue, sleep, depression, anxiety and pain at a dose of 20 mg in this population.
Practice implications
Melatonin has long been a popular substance used in the world of naturopathic and allopathic medicine for its notable benefits in treating insomnia and circadian regulation.1
The relevance of this study goes beyond improving sleep as it suggests the potential for improving survival, particularly for patients with late-stage lung cancer.
Lung cancer remains the second highest incidence cancer in both sexes, behind prostate cancer in men and breast cancer in women; It also has the highest mortality rate among all cancers for both genders around the world.2In addition, there has been a trend of new cancer diagnoses in non-smokers, who tend to be women with adenocarcinoma detected at a later and more advanced stage.3All these factors lead us to look for further ways to improve treatment with less impact on quality of life.
Studies examining the benefits of melatonin in NSCLC patients undergoing chemotherapy show favorable results, particularly in improving the effectiveness of chemotherapy and reducing toxicity.4There have been fewer studies addressing outcomes after surgical resection, making this current study significant.
Melatonin continues to be studied, with recent articles pointing to its numerous benefits.5There is a lot of therapeutic potential for this substance in lung cancer, but also in a variety of other tumor types. Gurunathan et al. specifically mention in their review that “the combination of melatonin with conventional drugs improves the drug sensitivity of cancers, including solid and liquid tumors.”5
Studies examining the benefits of melatonin in NSCLC patients undergoing chemotherapy show favorable results, particularly in improving the effectiveness of chemotherapy and reducing toxicity.
Further studies should ideally also look at combining melatonin with some of the more novel oral targeted drugs, such as erlotinib and osimertinib, that clinicians are using as first-line treatment for late-stage disease.
As clinicians, we are constantly looking for methods to improve our patients' quality of life and prolong survival. Although the number of late-stage patients in this trial was small, the implications are very positive and will likely help initiate similar trials.
This study will likely encourage more physicians to supplement their stage III and IV NSCLC patients with 20 mg of melatonin, especially after surgical resection. However, given the wealth of data on benefit even during chemotherapy, there is a greater likelihood that the majority of late-stage patients would benefit from the addition of melatonin.