Hrushesky WJM, Lis CG, Levin RD, et al. Daily evening melatonin prolongs survival among patients with advanced non-small-cell lung cancer. Biol Rhythm Res. 2021:1-15. DOI: 10.1080/09291016.2021.1899485.
To evaluate the survival benefit of melatonin in advanced non–small cell lung cancer patients (NSCLC) when given at different times of day compared to placebo
A placebo-controlled, randomized, double-blind, 3-arm clinical trial
Eighty-four advanced (stage IIIB or IV) NSCLC patients receiving identical dosing of standard etoposide/cisplatin therapy, between the ages of 18 and 80 years.
Inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
Patients were randomly assigned to 1 of 3 arms:
- Placebo at 8 a.m. and 8 p.m.
- 20 mg melatonin at 8 a.m. and placebo at 8 p.m.
- Placebo at 8 a.m. and 20 mg melatonin at 8 p.m.
Study Parameters Assessed
Researchers used a Kaplan–Meier survival plot to track the median survival for each of the groups.
They evaluated quality of life using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and Ferrans and Powers Quality of Life Index (QLI).
Researchers also collected and measured data on sleep quality using the Pittsburgh Sleep Quality Index (PSQI).
Primary Outcome Measures
The main outcome measures were overall survival as well as sleep quality. Secondary outcomes measures were objective tumor response and quality of life.
In the nighttime melatonin group, there was a statistically significant (P=0.031) decreased overall survival hazard ratio of 39% compared to the placebo group. The placebo group had a median survival of 10.4 months, whereas the nighttime melatonin group had a median survival of 17.6 months.
Sleep quality and sleep efficiency had a statistically significant impact on survival, and improvement from baseline in sleep quality led to an even larger decrease in overall survival hazard ratio.
Of note, sleep efficiency had a negative impact on hazard ratio, though this is likely due to patients' spending more time resting due to illness, rather than frankly sleeping.
There was no group with notable tumor response, and unfortunately there were no patients who had a complete response; however, the most common response was stable disease, and there was higher prevalence of this in the evening melatonin group.
Sleep is a wondrous thing for our bodies and brains. It is well-proven that proper sleep is essential for overall good health. Sleep also has numerous benefits for risk reduction of a number of cancer types and plays a critical role in tolerance of chemotherapy and radiation treatment for our oncology patients. Early in my residency training, I came across a study that describes how our bodies secrete anti-inflammatory cytokines during sleep. I have come to appreciate that melatonin has a large impact specifically on nuclear factor kappa B (NF-κB), which is considered the emperor of the inflammatory cascade.1 This helps to explain why generalized inflammatory symptoms such as joint pain,2 swelling, fatigue, headache, anxiety/depression, or an upset digestive system are often milder upon waking in the morning when compared to bedtime.
This helps to explain why generalized inflammatory symptoms such as joint pain, swelling, fatigue, headache, anxiety/depression, or an upset digestive system are often milder upon waking in the morning when compared to bedtime
A recent study describes how shift workers can have increased levels of inflammation, which can lead to immune dysregulation and the many adverse consequences of shift work, cancer likely being one of them.3,4 Melatonin is an anti-inflammatory compound and immune system–modulating hormone.5 It’s not surprising that melatonin can help normalize circadian rhythm as well as improve outcomes for patients with cancer.6
In addition to improving quality of life through better sleep, melatonin impacts several intracellular signaling pathways that lead to downregulating growth and enhancing chemosensitivity for non–small cell lung cancer patients receiving chemotherapy.7,8
This particular study focused on the importance of timing of melatonin and found a significant survival advantage for advanced lung cancer patients who supplement with melatonin in the evening. This benefit was not found in those who took melatonin in the morning. This study suggests that night-time dosing of melatonin is a critical part of this hormone’s value.
Melatonin is inexpensive and well-tolerated for the vast majority of patients. Given the accumulation of trial data that suggests benefit to sleep, bone marrow recovery, and overall survival during conventional treatment, the question I am starting to ask myself is what does melatonin not do for our non–small cell lung cancer patients?