Abstract

Rationale

Preserving health‐related quality of life is an aspect of care that requires constant attention from the time of cancer diagnosis. Melatonin has been used to diminish treatment‐related side effects and cancer symptoms, and as a medication to regulate circadian rhythm. An up‐to‐date systematic review is needed to investigate the current evidence concerning possible beneficial effects of melatonin on quality of life and sleep in cancer patients.

Objectives

To evaluate the benefits and harms of melatonin for preserving health‐related quality of life and sleep in cancer patients.

Search methods

To identify studies for inclusion in this review, we used CENTRAL, MEDLINE, 10 other databases, and four trial registers, together with reference checking, citation searching, and contact with study authors. The latest search date was 10 September 2024.

Eligibility criteria

We included randomised controlled trials (RCTs) of adults (18 years or over) with histologically proven cancer of any stage that evaluated melatonin (alone or in combination with standard anticancer treatment) versus no treatment or placebo (alone or in combination with standard anticancer treatment), or standard anticancer treatment. Standard anticancer treatment refers to treatments to stop or prevent cancer, including chemotherapy, radiation therapy, surgery, immunotherapy, and hormonal therapies (such as androgen deprivation therapy).

Outcomes

The primary outcomes of interest were quality of life and sleep quality within three months, and melatonin‐related adverse events. Other outcomes included survival, disease‐free survival, progression‐free survival, tumour response, and anticancer treatment‐related harms.

Risk of bias

We used Cochrane's risk of bias tool (RoB 1) to assess the risk of bias in the studies included in the review.

Synthesis methods

We synthesised results for each outcome using random‐effects meta‐analysis. The effect size was presented as risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, with 95% confidence intervals (CI). If this was not possible, due to the nature of the data, we synthesised results in a narrative format. We used GRADE to assess the certainty of evidence for each outcome.

Included studies

We identified 30 RCTs (reported in 49 publications) involving 5093 adult participants with cancer (2470 males, 2228 females, 395 not reported). Studies were conducted in a hospital setting and took place in at least 10 countries. We assessed two studies at low risk of bias and the other 28 at high risk of bias.

Synthesis of results

Melatonin plus standard treatment versus placebo plus standard treatment

The evidence is very uncertain about the effect of melatonin on quality of life score (MD 2.60, 95% CI −14.53 to 19.73; 1 study, 126 participants; very low certainty evidence), and sleep score (MD 2.80, 95% CI 0.18 to 5.42; 1 study, 50 participants; very low certainty evidence) within three months. We are also very uncertain about potential adverse effects of melatonin: headache (RR 2.77, 95% CI 0.33 to 23.14; 1 study, 25 participants; very low certainty evidence); fatigue (RR 1.02, 95% CI 0.90 to 1.17; 2 studies, 170 participants; very low certainty evidence); and nausea (RR 1.01, 95% CI 0.66 to 1.56; 1 study, 146 participants; very low certainty evidence). No data are available relating to dizziness. We downgraded the certainty of the evidence because of high risk of bias, small sample size, the width of the 95% confidence interval, and indirectness due to inadequate reporting of cancer type.

Melatonin plus standard treatment versus standard treatment

No data are available relating to quality of life and sleep within three months. The evidence is very uncertain about headaches (experienced by 15 of 820 participants in melatonin groups, with no data available for control groups; 2 studies, 1640 participants; very low certainty evidence). Melatonin likely reduces the incidence of fatigue (RR 0.46, 95% CI 0.39 to 0.55; 10 studies, 1359 participants; moderate‐certainty evidence) and may reduce nausea (RR 0.85, 95% CI 0.72 to 1.00; 6 studies, 710 participants; low‐certainty evidence). No data are available relating to dizziness. We downgraded the certainty of the evidence because of the high risk of bias and the width of the 95% confidence interval.

Melatonin (topical use) plus standard treatment versus placebo plus standard treatment

The evidence is very uncertain about the effect of melatonin on quality of life (one study reported no difference between groups, both having the same median score of 66.7; 48 participants; very low certainty evidence). No data are available relating to sleep and adverse events (including headache, dizziness, fatigue, and nausea). We downgraded the certainty of the evidence because of the high risk of bias, small sample size, and insufficient data.

Authors' conclusions

The available evidence is of very low certainty, so we are unable to draw conclusions about the effects of melatonin on quality of life and sleep at three months in people receiving treatment for cancer. There may be no difference in adverse events between melatonin plus standard treatment and placebo plus standard treatment, but the evidence is very uncertain. Data were lacking for some outcomes, such as dizziness. Melatonin used alongside standard treatment probably reduces the risk of fatigue and may reduce nausea when compared to standard treatment alone. Since the evidence base for melatonin in people with cancer is limited due to insufficient data and risks of bias in study design, the decision for or against using melatonin as an adjunct to cancer treatment cannot easily be made at the current time.

Funding

This Cochrane Review was partially funded by AG Biologische Krebstherapie, Deutsche Krebshilfe (grant numbers 70‐301 and 109863). The funding agency had no role in the design or conduct of the study.

Registration

The protocol for this review is available via DOI 10.1002/14651858.CD010145.

Author(s)

Ze Yu Yu, Rong Yan Peng, Nuo Cheng, Rui Ting Wang, Meng Die Nan, Stefania Milazzo, Karen Pilkington, Dugald Seely, Markus Horneber, Jian Ping Liu

Abstract

Plain language summary

For cancer patients, what are the benefits and risks of taking the hormone melatonin?

Key messages

• Due to a lack of robust evidence, the effects of melatonin on quality of life and sleep quality in people receiving treatment for cancer are unclear.
• Melatonin might not increase the risk of adverse events, but the available evidence is not strong enough for us to be certain.
• Well designed studies using melatonin over a period of up to three months are needed to give better estimates of the benefits and risks.

What is melatonin?

Melatonin is a hormone produced in the body to regulate the daily sleep and wakefulness cycle. It has been suggested that melatonin may improve sleep quality and quality of life, which are very important in cancer treatment. Moreover, there is research suggesting that melatonin is effective against solid tumours and may be effective for the treatment of cancer.

What did we want to find out?

We wanted to find out if melatonin can be used in cancer treatment, particularly for preserving the quality of life and sleep quality of cancer patients. We also wanted to find out if melatonin causes any unwanted side effects ('adverse events').

What did we do?

We searched for studies that looked at melatonin used with other standard cancer treatments compared with standard cancer treatments used alone or with placebo (fake treatment).

What did we find?

We found 30 studies that involved 5093 cancer patients, both men and women, with cancer of any type. The studies were conducted in 10 countries around the world.

We focused on the effects of melatonin over a period of three months. When compared to placebo plus standard cancer treatments, it is unclear if melatonin has an effect on quality of life and sleep. Melatonin may have little to no effect on potential adverse events like headache, fatigue, and nausea, but we are very uncertain about these results. No results are available for dizziness.

We found no studies to help us answer our questions about quality of life and sleep quality when melatonin is used with standard cancer treatments compared to the standard treatment alone. However, the studies did evaluate potential adverse events that might be related to melatonin, and they found that melatonin probably reduces the risk of tiredness (fatigue), and may reduce the risk of feeling sick (nausea). It is unclear if melatonin has an effect on headaches. No results are available for dizziness.

When melatonin is used topically, such as in a cream to put on the skin or in a mouth wash, it is unclear if it has an effect on quality of life. We found no studies to help us answer our questions about sleep quality. No data are available for adverse events like headache, fatigue, nausea, and dizziness, as these are not relevant if the melatonin is used topically. It is unclear if melatonin has any other unwanted effects when used topically.

What are the limitations of the evidence?

We are not confident in the evidence because it is possible that people in the studies were aware of which treatment they were getting. The evidence relating to some benefits and risks we are interested in does not cover all cancer types, or it is based on only a few cases.

How up to date is this evidence?

The evidence is up‐to‐date to September 2024.

Author(s)

Ze Yu Yu, Rong Yan Peng, Nuo Cheng, Rui Ting Wang, Meng Die Nan, Stefania Milazzo, Karen Pilkington, Dugald Seely, Markus Horneber, Jian Ping Liu

Reviewer's Conclusions

Authors' conclusions 

Implications for practice

There is evidence that melatonin may have little to no effect on quality of life and sleep compared with placebo or standard treatments when the follow‐up is less than three months, but the evidence is very uncertain. The evidence for melatonin's effect on quality of life in comparison with standard treatment alone is also uncertain because of insufficient data. No data are available relating to sleep quality for melatonin used topically within three months. There may be no difference between melatonin and placebo for suspected melatonin toxicity‐related adverse events, such as fatigue, headache, and nausea, but the evidence is uncertain. No data are available for the outcome of dizziness. However, when compared to standard treatments without placebo, melatonin likely reduces the incidence of fatigue and may reduce the incidence of nausea.

Since the evidence base for melatonin in people with cancer is limited by insufficient data and methodological limitations in the studies, the decision for or against using melatonin as an adjunct to cancer treatment cannot easily be made at the current time.

Implications for research

To establish firm evidence, we look forward to further high‐quality clinical studies on melatonin in different cancer populations and populations with different anticancer treatments, which use standardised and validated measurements and outcomes, and are reported according to guidelines such as CONSORT (www.equator‐network.org/reporting‐guidelines/). We suggest that future research addresses the following aspects.

• Settings: trials should be blinded, especially for self‐report outcomes like quality of life and sleep quality assessed via questionnaires. We recommend that trials include a cost‐effectiveness analysis to assess the cost of melatonin.
• Population: trials should clarify the diagnostic method for cancer. Trials should involve people with cancers other than non‐small cell lung cancer, gastrointestinal, and breast cancer, as few studies on cancers other than these have been carried out. We also recommend that studies involving participants in the early stage of cancer are conducted, as the existing evidence is mainly based on participants with advanced cancers.
• Intervention: trials should study the use of melatonin at varied doses as informed by current guidelines, with full reporting on source, quality control, and adverse events, to discover the relationship of dosage with effects and toxicities.
• Comparison: placebo should be used. The trials should identify which standard treatments the participants will receive or have received.
• Outcome: trials should assess quality of life and sleep with a follow‐up time period of three months.

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