Efficacy of Melatonin in Alleviating Radiotherapy-Induced Fatigue, Anxiety, and Depression in Breast Cancer Patients: A Systematic Review and Meta-Analysis

Abstract

Background

Breast cancer (BRCA) remains the most diagnosed malignancy among women globally and is predominantly managed through multimodal therapy. Radiotherapy, an essential component of BRCA management, often causes fatigue, anxiety, and depression that compromise the quality of life (QoL) of patients. Melatonin, an endogenous hormone with antioxidant, anti-inflammatory, and circadian rhythm–modulating properties, has shown potential for preventing radiotherapy-associated toxicities. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of melatonin in alleviating radiotherapy-induced fatigue, anxiety, and depression among breast cancer patients.

Methods

Following PRISMA guidelines (PROSPERO: CRD420251144916), a comprehensive search was conducted across PubMed, Scopus, Cochrane Library, Embase, and Google Scholar up to August 2025. RCTSs comparing melatonin with placebo in adult female patients with non-metastatic breast cancer undergoing adjuvant radiotherapy were included. The Cochrane RoB-2 tool was employed for quality assessment. Pooled standardized mean differences (SMDs) and mean differences (MDs) were calculated using a random-effects model in RevMan 5.4 software.

Results

Five RCTs encompassing 561 patients were analyzed. Melatonin significantly reduced fatigue severity (SMD = –0.43; 95% CI –0.65 to –0.20; p = 0.0002) and improved cognitive functioning (MD = 1.16; 95% CI 0.95 to 1.36; p < 0.00001) and global health status (MD = 2.47; 95% CI 2.07 to 2.87; p < 0.00001). No significant effects were observed for emotional, social, or physical functioning, nor for gastrointestinal, pain, or sleep-related domains.

Conclusion

Based on limited number of studies, melatonin supplementation appears to be a safe, well-tolerated, and low-cost adjunct to radiotherapy, capable of improving fatigue, cognitive performance, and overall QoL in breast cancer patients. However, small sample sizes and heterogeneous dosing regimens require further large-scale RCTs to establish optimal dosing and long-term efficacy.

Introduction

Breast cancer (BRCA) is the most commonly diagnosed malignancy among women. ¹ In 2022, approximately 2.3 million new BRCA cases and around 670,000 deaths were reported worldwide, making it the leading cause of cancer-related disability-adjusted life years (DALYs). ² One in eight women is likely to develop BRCA over the course of life. ³ Histopathologically, BRCA is heterogeneous, comprising more than 20 diagnostic subtypes, most of which originate from epithelial tissue. Prognosis is primarily determined by tumor size and lymph node involvement. ⁴ BRCA is characterized by uncontrolled cellular proliferation, with the potential of local invasion and distant metastases. ⁵ Advances in surgery, systemic therapy, and screening have substantially improved early detection and survival. ² Currently, five standard therapeutic modalities are involved in BRCA management: surgery, chemotherapy, hormonal therapy, targeted therapy, and radiotherapy. ⁶ Radiotherapy, an essential component of treatment, is administered to more than 90 % of patients to reduce locoregional recurrence and improve overall survival.^7,8 However, the global incidence of BRCA continues to rise. ⁴

Radiotherapy effectively eradicates residual malignant cells to lower the risk of distant dissemination, but it is associated with both immediate and long-term toxic effects. Fatigue is one of the most prevalent adverse effects, reported in up to 79–81 % of patients undergoing treatment. ⁷ It is a multidimensional symptom, encompassing physical, cognitive, and emotional domains, and significantly compromises social functioning and self-esteem. ³ Anxiety and depression are also common during radiotherapy, with prevalence rates ranging from 21–54 % for anxiety and 12–31 % for depression. ⁹ These conditions frequently coexist among cancer patients. ³ They are associated with treatment non-compliance, reduced quality of life (QoL), prolonged hospitalization, and increased cancer-related mortality. ⁸ In addition, persistent concerns about disease progression and treatment-related adverse effects further intensify psychological distress. ⁹ Standardized assessment tools are frequently used in clinical research to evaluate these symptoms. Fatigue severity is commonly measured with the Multidimensional Fatigue Inventory (MFI), whereas anxiety and depression are assessed using the Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI). ⁴ The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-30) is a 30-item cancer-specific questionnaire, widely used in international clinical trials to assess the QoL of cancer patients. ¹⁰

Management of radiotherapy-induced fatigue, anxiety, and depression incorporates non-pharmacological and pharmacological approaches. Non-pharmacologic interventions include physical and occupational therapy, exercise, yoga, and cognitive-behavioral strategies, whereas pharmacologic measures may involve psychostimulants such as methylphenidate and modafinil. Nevertheless, radiotherapy-induced fatigue remains underreported, underdiagnosed, and undertreated. Randomized studies investigating relaxation therapy, group psychotherapy, exercise, and sleep management have demonstrated promising outcomes; however, no single approach has been established as standard of care.^8,10

Given these limitations, melatonin has gained increasing attention owing to its potential anti-cancer effects. ¹¹ Evidence indicates that it may mitigate radiotherapy-associated adverse effects. ⁴ Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous hormone secreted by the pineal gland that protects cells from radiation-induced oxidative damage by neutralizing reactive oxygen and nitrogen species and enhancing antioxidant enzyme activity. In addition to its role in circadian rhythms, melatonin exhibits radioprotective and radiosensitizing properties, as well as anti-inflammatory and anti-apoptotic effects.^12,13 Several studies have also demonstrated that melatonin inhibits tumor growth. ¹⁴ Randomized clinical trials have reported that melatonin supplementation at bedtime significantly reduces fatigue severity, improves QoL, and sleep outcomes in patients with BRCA. ¹⁵

The current evidence on melatonin as an adjuvant in BRCA radiotherapy remains inconclusive, with small sample sizes, variable dosages, treatment durations, and outcome measures limiting the applicability of results. Most investigations have evaluated participants only during radiotherapy, leaving the efficacy and safety of melatonin in hypofractionated regimens and over longer follow-up periods still uncertain. ⁴ The optimal dose and mode of administration remain undefined, underscoring the need for further clinical trials to establish its therapeutic value. ¹³

The current evidence on melatonin as an adjuvant in radiotherapy for BRCA is limited and varies across studies in terms of sample size, dosage, treatment duration, and outcome measures. In addition, most studies have focused primarily on outcomes during radiotherapy, with limited evidence available on longer-term effects and across different radiotherapy regimens. ⁴ Therefore, this study was conducted as a systematic review and meta-analysis to evaluate the efficacy and safety of melatonin in reducing radiotherapy-induced fatigue, anxiety, and depression in BRCA patients.

Methodology

This systematic review and meta-analysis were conducted in accordance with the PRISMA guidelines. ¹⁶ The registration in the International Prospective Register of Systematic Reviews (PROSPERO) was accepted under the registration number (CRD420251144916).

Data Sources and Search Strategy

We systematically conducted a comprehensive literature search across PubMed, Google Scholar, Scopus, Cochrane Library and Embase to identify all relevant records up to August 2025. Additionally, Clinicaltrials.gov was searched for published or unpublished clinical trials. The research question was structured using the PICO strategy design (Population, Intervention, Control, Outcomes). The following search terms were used: (“breast neoplasms” OR “breast cancer”) AND (“radiotherapy” OR “adjuvant radiotherapy”) AND (“melatonin”) AND (“fatigue” OR “anxiety” OR “depression” OR “treatment-related symptoms” OR “quality of life”). Two authors conducted the search without any limitations or conflicts of interest. Supplementary Table 1 shows the Search strategy.

Study Selection

The title and abstract of the articles were reviewed individually by three independent authors. Full texts of the articles deemed relevant were then read thoroughly to confirm whether they met the eligibility criteria. This was done to ensure that only articles meeting specified criteria were selected for the final analysis. Any discrepancy was resolved through discussion with another author.

Inclusion Criteria

The eligibility criteria included randomized controlled trials (RCTs) comparing melatonin with placebo to evaluate its efficacy in alleviating radiotherapy-induced fatigue, anxiety, and depression in BRCA patients, enrolling adult women (≥18 years) with histologically confirmed, non-metastatic BRCA scheduled for adjuvant radiotherapy with or without chemotherapy.

Exclusion Criteria

Exclusion criteria comprised pregnancy or lactation, previous breast or chest irradiation, and serious uncontrolled medical or psychiatric conditions. Single-arm studies and studies without relevant outcomes or original data were excluded. The research screening excluded non-English literature. Additionally, Studies were excluded if they lacked relevant efficacy outcomes or original data. Cross-sectional studies, letters, case reports, case series, reviews, and editorials were also excluded.

Study Outcomes

Across the included studies, the primary outcomes comprised mean fatigue score, physical functioning, social functioning, emotional functioning, and global health status. The secondary outcomes included functional well-being (FWB) and additional QLQ-C30 domains such as role functioning, cognitive functioning, nausea/vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties.

Data Extraction

Two independent reviewers extracted the data, and discrepancies were resolved through consensus after discussion. An online Microsoft Excel spreadsheet was created using data from the included studies for baseline characteristics and outcomes. Baseline parameters are as follows: total population, age, body mass index (BMI), breast volume, race, and number of patients.

Study Quality Assessment

The risk of bias was assessed using the Cochrane Risk of Bias Tool (RoB-2). ¹⁷ Two independent reviewers evaluated the studies based on predefined criteria. The factors evaluated were measurement of the outcome, randomization process, selective reporting, missing data, and overall bias. Based on these factors, each trial was categorized as having either high risk, low risk, or some concerns. Any disagreements were initially addressed through discussion. In cases where consensus could not be reached, a third reviewer resolved the final decision.

Statistical Analysis

Statistical analyses were conducted using RevMan (Review Manager, version 5.4, Cochrane Collaboration, London, UK. Relative risk (RR) with 95% confidence intervals (CIs) was used to analyze dichotomous data. In contrast, for continuous outcomes, either the weighted mean difference (WMD) or the SMD with 95% CIs was applied. A two-sided p-value of <0.05 was considered statistically significant. Heterogeneity among studies was assessed using the I² values. The values between 50-75% were considered as moderate heterogeneity, while values > 75% were indicative of severe heterogeneity. Sensitivity analysis was performed for studies exhibiting high heterogeneity to identify the impact of potential sources of variation. Forest plots were generated to display pooled effect sizes and CIs for each outcome, enabling comparison across studies. These plots also illustrated both heterogeneity and the overall summary estimate under the random-effects model. Meta-regression was performed using Comprehensive Meta-Analysis (version 4), and results were reported as regression coefficients (Coeff) and P-values.

Results

Study Selection

Initially, a total of 81 studies were identified through comprehensive searches on various databases. After removing 29 duplicate entries, 52 records were screened by title and abstract. Of these, 42 were excluded because they did not meet the eligibility criteria. Subsequently, a full text assessment was conducted on the remaining 10 articles, resulting in the exclusion of five reports because of an ineligible population, non-relevant outcomes and wrong study design. Consequently, five RCTs^18-22 satisfied all inclusion criteria and were incorporated into the final qualitative synthesis. Publication dates ranged from 2022 to 2024. The detailed study selection process is presented in Figure 1.

Figure 1.

PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only

Baseline Characteristics

The five included RCTs included a total of 561 BRCA patients with sample sizes ranging from 48 to 203 patients in each study. The average age in the studies was mostly between 50 and 60, with most patients in their late 40s to early 60s. BMI was not reported consistently; however, in the two RCTs that did report it, the mean BMI in the intervention groups ranged from 26.4(8.1) to 29.5(6.5), and in the placebo groups from 26(5.3) to 44.0(14.2), indicating that participants were generally overweight. Some studies reported baseline comorbidities, including diabetes mellitus in 32.7% of participants in the intervention group and 26.4% in the control group, hypertension in 18.5% and 20.7%, and hypothyroidism in 8.54% and 7.86%, respectively. Most participants had received doxorubicin-based chemotherapy and conventional radiotherapy, while hypofractionated regimens were less common. Before starting adjuvant therapy, surgical options included both radical mastectomy and breast-conserving surgery, with no significant differences between the groups. Overall, baseline characteristics were well balanced between melatonin and placebo groups across the included trials, supporting the comparability of study populations. Detailed baseline characteristics of included studies are summarized in Table 1.

Table 1.

Baseline Characteristics of Included Studies

​	Comorbidities						Tamoxifen				HER2. enriched
	DM		HTN		Hypothyroidism		Yes		No		Yes		No
	Melatonin	Placebo	Melatonin	Placebo	Melatonin	Placebo	Melatonin	Placebo	Melatonin	Placebo	Melatonin	Placebo	Melatonin	Placebo
Amlashi 2024	32	28	26	30	8	10	78	84	23	18	51	40	50	62
Mukhopadhyay 2023	-	-	-	-	-	-	-	-	-	-	-	-	-	-
Nimee 2024	-	-	-	-	-	-	-	-	-	-	-	-	-	-
Pashaki 2023	60	46	26	28	16	12	72	78	19	14	13	9	-	-
Zetner 2022	-	-	-	-	-	-	-	-	-	-	-	-	-	-

Quality Assessment

Supplementary Figure 1 contains the Cochrane risk of bias and Supplementary Figure 2 contains the Risk of bias graph for randomized controlled trials. Overall, the studies included were mostly of good or fair quality, as demonstrated by low and uncertain risk of bias according to the Cochrane tool.

Outcomes

The outcomes were divided into primary and secondary categories. Supplementary Table 2 shows the overall outcomes of Efficacy.

Primary Outcomes

Mean Fatigue Score

Mean fatigue scores were assessed by all included clinical trials.^18-22 Figure 2 shows a forest plot comparing the impact of melatonin versus placebo on mean fatigue scores. The pooled analysis shows SMD of -0.43 (95% CI -0.65, -0.20, p=0.0002). This suggests statistically significant reductions in fatigue severity among patients treated with melatonin. Heterogeneity was moderate (I² = 36%) indicating some variability between studies.

Figure 2.

Forest plot for the outcome of patients with severe fatigue

FACIT/QLQ Score (Physical Functioning/PWB)

PWB were reported in three RCTs,^18,21,22 including a total of 300 patients. Figure 3 shows a forest plot comparing the effect of melatonin versus placebo on PWB. The pooled SMD was -0.30(95% CI -0.66, 0.06, p=0.10). This indicates that patients in the melatonin group had slightly lower physical well-being scores compared to controls, but the effect was not statistically significant. Moderate heterogeneity was observed (I²=46%). These same studies also provided social and emotional components, allowing for cross comparison between QoL results.

Figure 3.

Forest plot for the outcome of mean fatigue Score

FACIT (SFWB/Social Function)

The forest plot in Figure 4 illustrates the effect of melatonin versus placebo on SFWB. The results of three studies demonstrated a combined SMD of 0.11(95% CI -0.11, 0.34, p=0.33), showing no significant difference in social or family well-being in patients taking melatonin compared to the controls. There was no evidence of heterogeneity across the studies (I²=0%), indicating consistent results.

Figure 4.

Forest plot for the outcome of FACIT/QLQ score (physical functioning/PWB)

FACIT (EWB/Emotional Function)

The impact of melatonin on EWB, relative to placebo, is summarized in the forest plot shown in Figure 5. A combined SMD of 0.04 (95% CI -0.19, 0.27, p=0.72). This was not statistically significant, suggesting that melatonin was not demonstrated to have any detectable effect on EWB. There was no evidence of heterogeneity across the studies (I²=0%), indicating consistent results.

Figure 5.

Forest plot for the outcome of FACIT (SFWB/social function)

Secondary Outcomes

Patients With Severe Fatigue

Two RCTs^19,20 including 261 patients reported severe fatigue. The results showed a risk ratio of 0.56 (90% CI 0.26, 1.24) which indicates a possible reduction in severe fatigue in the intervention group compared to control. However, the results were not statistically significant since the confidence interval crossed 1 and the p value was 0.16. However, heterogeneity was (I²=0%). Overall, melatonin may lessen severe fatigue, but current evidence is not enough to support a discernible impact. Figure 6.

Figure 6.

Forest plot for the outcome of FACIT (EWB/emotional function)

FACIT (FWB/Functional)

FWB was reported in two out of five RCTs,^21,22 involving 252 patients. The analysis in Figure 7 showed no significant difference in FWB between both arms, with a SMD of -0.07 (90% CI -0.78, 0.64), a p value of 0.85 and high heterogeneity (I²=80%), suggesting inconsistency between results.

Figure 7.

Forest plot for the outcome of FACIT (FWB/functional)

Role Functioning (QLQ C30)

Role functioning was reported by two trials^18,22 comprising 251 patients. A slight but statistically significant difference favouring the control group was seen by the pooled mean difference (MD) for role functioning, which was -0.22 (95% CI -0.42, -0.02 p=0.03). This implies that in comparison to controls, patients in the experimental group had somewhat lower role functioning. Importantly, there was no heterogeneity (I²=0%) Figure 8. These same trials also reported the following.

Figure 8.

Forest plot for the outcome of role functioning (QLQ C30)

Cognitive Functioning (QLQ C30)

The analysis showed a substantial improvement in cognitive functioning following the intervention with MD of 1.16 (95% CI 0.95, 1.36 p <0.00001). This suggests that in comparison to patients in the control group those treated with melatonin exhibited noticeably improved cognitive performance. The robustness of the findings was supported by absence of heterogeneity (I²=0%). Figure 9.

Figure 9.

Forest plot for the outcome of cognitive functioning (QLQ C30)

Global Health Status (QLQ C30)

The analysis revealed that patients in the experimental group had a markedly improved global health status, with a MD of 2.47 (95% CI 2.07, 2.87 p <0.00001).This indicates that patients’ perceptions of their general health improved significantly as the result of intervention. There was no evidence of heterogeneity across the studies (I²=0%), indicating consistent results. Figure 10.

Figure 10.

Forest plot for the outcome of global health status (QLQ C30)

Nausea Vomiting (QLQ C30)

The analysis showed a MD of –2.08 (95% CI -10.51, 6.35 p= 0.63), suggesting a slight non-significant tendency towards decreased nausea and vomiting in the melatonin group when compared to the controls. The level of heterogeneity was low (I² = 37%), suggesting that the results were fairly consistent across the studies. Figure 11.

Figure 11.

Forest plot for the outcome of nausea vomiting (QLQ C30)

Pain (QLQ C30)

The analysis showed MD of -0.05 (95% CI -0.25, 0.15 P=0.62) suggesting decrease in pain in the intervention group compared to placebo but results were statistically not significant. However, there was no heterogeneity present (I²=0%). Figure 12.

Figure 12.

Forest plot for the outcome of pain (QLQ C30)

Dyspnoea/(QLQ C30)

The results showed MD of 2.90 (95% CI -11.89, 17.70 P=0.70). This wide confidence interval includes both potential harm and benefit, and the result was not statistically significant. Heterogeneity was low (I² = 27%), showing modest variability between studies. Overall, no clear evidence was found that the intervention impacts dyspnoea. Figure 13.

Figure 13.

Forest plot for the outcome of dyspnoea (QLQ C30)

Insomnia (QLQ C30)

The pooled MD was 0.07 (95% CI: –0.10 to 0.24, p = 0.41), showing no significant difference between the experimental and control groups. Both studies provided consistent results, with no heterogeneity (I² = 0%). Thus, the intervention did not significantly affect insomnia levels. Figure 14.

Figure 14.

Forest plot for the outcome of insomnia (QLQ C30)

Appetite Loss (QLQ C30)

The pooled SMD was –0.02 (95% CI: –0.17 to 0.13, p = 0.80), indicating no difference in appetite loss between the groups. The result was not statistically significant, and there was no heterogeneity (I² = 0%), suggesting consistency across the included studies. Figure 15.

Figure 15.

Forest plot for the outcome of appetite loss (QLQ C30)

Constipation (QLQ-C30)

The pooled analysis showed no statistically significant difference between the experimental and control groups (MD = –4.09, 95% CI –21.10 to 12.92, p = 0.64). Although the point estimate slightly favored the intervention, the wide confidence interval crossing zero indicates high uncertainty and a lack of clinical significance. Moderate heterogeneity was observed (I² = 37%), suggesting some variability between studies. Overall, the intervention did not demonstrate a meaningful effect on constipation. (Figure 16).

Figure 16.

Forest plot for the outcome of constipation (QLQ C30)

Diarrhea (QLQ-C30)

The studies revealed no significant difference between the experimental and control groups (MD = –0.04, 95% CI –0.20 to 0.12, p = 0.63). The confidence interval was narrow and crossed zero, indicating a negligible effect size with no evidence of clinical benefit or harm. Heterogeneity was absent (I² = 0%), showing consistency across included studies. These findings suggest that the intervention did not impact diarrhea scores. Figure 17.

Figure 17.

Forest plot for the outcome of diarrhea (QLQ C30)

Financial Difficulties (QLQ-C30)

The pooled results for financial difficulties demonstrated no meaningful difference between the intervention and control groups (MD = 0.01, 95% CI –0.14 to 0.16, p = 0.89). The effect estimate was very close to zero, and the confidence interval indicated no statistical or clinical significance. There was no heterogeneity among studies (I² = 0%), reflecting consistent findings. Overall, the intervention did not influence financial difficulty outcomes. Figure 18.

Figure 18.

Forest plot for the outcome of financial difficulties (QLQ C30)

Discussion

This meta-analysis combined results from RCTs to evaluate whether melatonin provides measurable improvements in QoL outcomes among BRCA receiving radiotherapy.

It is crucial to note that this present meta-analysis was based on a limited data set, with only five studies included. Additionally, a pooled analysis of two or three RCTs was conducted to investigate various secondary outcomes, further limiting the reliability and efficacy of reported findings. Hence, the results from this current dataset offer adequate preliminary assessment but should be interpreted cautiously due to the small number of studies and patients for some outcomes.

Our meta-analysis demonstrated that melatonin significantly reduced fatigue severity among BRCA undergoing adjuvant radiotherapy compared with placebo (SMD = −0.43, 95% CI −0.65 to −0.20, p = 0.0002), with moderate heterogeneity (I² = 36%). These findings align with the results of Yazdankhah et al. ⁴ who reported that 20 mg/day of melatonin markedly alleviated fatigue, anxiety, and depression in women receiving radiotherapy for BRCA. Additionally, Innominato et al. ²³ also reported that 5 mg/day led to clinically meaningful decreases in fatigue severity. Melatonin’s neuroprotective properties likely manifest in the cognitive improvements observed in this meta-analysis. At the molecular level, melatonin activates nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of antioxidant defense that upregulates genes involved in neutralizing ROS and suppressing neuroinflammation. Melatonin also acts on MT1 receptors on mitochondrial outer membranes to inhibit stress-mediated cytochrome C release and prevent neuronal apoptosis. ²⁴ Experimental evidence also demonstrates that melatonin administration significantly attenuated radiation-induced oxidative stress in neural tissue, normalizing glutathione levels and reducing lipid peroxidation, reflecting the neuroprotective properties of melatonin. ²⁵ Circadian disruption in breast cancer patients can occur due to suppression of melatonin production. ²⁶ Alterations in the circadian rhythm are also strongly associated with mood, fatigue, and cognition as well as with treatment outcomes. ²⁷ Melatonin use has been associated with improving sleep in patients with circadian disruption thus indicating improved fatigue and cognitive functioning in patients, ²³ suggesting that melatonin’s antioxidant and circadian-regulating properties may play a role in mitigating treatment-related fatigue.

In the present meta-analysis, melatonin did not significantly improve physical well-being (PWB) or physical functioning scores compared with placebo, as reflected by a pooled SMD of –0.30 (95% CI –0.66 to 0.06, p=0.10). Although the melatonin group showed slightly lower mean PWB scores, this difference was not statistically meaningful. Although some individual trials, such as Lund Rasmussen et al. ²⁸ observed a slight improvement in physical functioning scores among melatonin-treated patients compared with placebo, this effect was also not statistically significant. The overall consistency of findings across studies suggests that while melatonin may confer certain symptomatic or psychological benefits, its role in enhancing physical functioning among BRCA undergoing radiotherapy remains limited. Our meta-analysis found no significant improvement in social or family well-being with melatonin (SMD = 0.11, 95% CI −0.11 to 0.34, p = 0.33; I² = 0%). Although an individual study by Innominato et al. ²³ reported improved social and cognitive function in patients with advanced BRCA receiving melatonin, a systematic review and meta-analysis by Fan et al. ²⁹ did not confirm a significant enhancement in overall QoL. These findings collectively suggest that melatonin’s effect on social well-being is not consistently supported across trials.

Our pooled analysis demonstrated no significant difference in emotional well-being between melatonin and placebo groups (SMD = 0.04, 95% CI −0.19 to 0.27, p = 0.72; I² = 0%), indicating consistent findings across studies. This is backed up by Vaziri et al. ³⁰ , which also found no significant change in emotional state of the patients in the intervention group. While Innominato et al. ²³ observed a trend toward improved emotional functioning in advanced BRCA receiving melatonin, these results were also not statistically significant. Together, these findings suggest that while melatonin may reduce fatigue, its effect on emotional well-being remains inconsistent and not clinically significant. The absence of significant melatonin-related improvements in emotional and social well-being likely reflects the predominantly psychosocial rather than biological determinants of these domains. Emotional well-being in breast cancer patients is heavily shaped by fear of cancer recurrence or progression, and has been associated with impaired quality of life, elevated emotional distress, and a range of physical symptoms. This also represents one of the most prevalent and distressing unmet needs reported by breast cancer patients regardless of the treatment received, ³¹ an aspect that falls out of the pharmacological scope of melatonin. Consistent with this, evidence suggests that psychological interventions, like cognitive behavioral therapy, mindfulness-based approaches, and meaning-centered psychotherapy, have demonstrated efficacy in reducing distress and improving quality of life among breast cancer patients. ³²

The pooled analysis revealed a modest but statistically significant decline in role functioning among patients receiving melatonin compared with placebo (MD = –0.22, p = 0.03). Although melatonin has well-recognized physiological and therapeutic benefits, these did not translate into improved ability to perform daily or occupational tasks during adjuvant treatment. This outcome may be influenced by persistent fatigue, treatment-related malaise, or psychological distress that melatonin alone may be insufficient to alleviate. The result is consistent with the findings of Fan et al. ²⁹ who reported no significant improvement in overall QoL among cancer patients receiving melatonin, aligning with our finding that melatonin failed to benefit patients’ functional role capacity.

Cognitive functioning showed a robust and statistically significant improvement, suggesting that melatonin exerted a positive influence on patients’ concentration, memory, and mental clarity. This result is consistent with the findings of Keshtpour Amlashi et al. ²² who observed enhanced cognitive and overall QoL scores following long-term melatonin supplementation in BRCA. Similarly, Sedighi Pashaki et al. ²⁰ reported that 20 mg/day of melatonin improved mental clarity and concentration during adjuvant therapy. Collectively, these studies support the neuroprotective potential of melatonin, likely attributed to its antioxidant, anti-inflammatory, and circadian rhythm–regulating properties that help maintain cognitive performance during radiotherapy.

Global health status showed a marked improvement in the melatonin group, reflecting a significant enhancement in patients’ overall perception of health and QoL. This benefit is likely attributed to melatonin’s multifactorial effects, including improved sleep quality, reduced fatigue, and better mood regulation, all of which contribute to enhanced overall well-being during adjuvant therapy. In line with this, Sedighi Pashaki et al. ²⁰ reported that 6 mg/day of melatonin significantly alleviated fatigue and enhanced overall QoL in BRCA receiving adjuvant chemo-radiotherapy. Likewise, Innominato et al. ²³ demonstrated that 5 mg/day melatonin significantly improved global health status and sleep quality in BRCA. Furthermore, Yazdankhah et al. ⁴ observed that 20 mg/day of melatonin during radiotherapy notably improved fatigue, anxiety, and depression, reinforcing its beneficial influence on patients’ overall well-being and global health perception.

For nausea and vomiting, a slight reduction was observed; however, the difference was not statistically significant. This indicates that melatonin’s potential antiemetic or gastroprotective properties may have limited clinical relevance in patients receiving radiotherapy, likely due to the comparatively lower gastrointestinal toxicity associated with radiation than with chemotherapy. Nonetheless, a systematic review and meta-analysis by Seely et al. ³³ demonstrated that melatonin significantly decreased the incidence of chemotherapy-induced nausea and vomiting when administered as an adjunctive treatment, highlighting its antiemetic efficacy in more emetogenic contexts such as chemotherapy.

Our pooled analysis found no statistically significant difference in pain scores between melatonin and placebo (MD = –0.05, 95% CI –0.25 to 0.15, p = 0.62; I² = 0%). Individual trial data also showed virtually identical mean pain scores between groups. For example, Amlashi (2024) reported 3.01 ± 0.55 versus 3.06 ± 0.87, and Pashaki (2023) observed 27.8 ± 52.32 versus 27.8 ± 52.86. The consistency and absence of heterogeneity across these trials support the reliability of this null finding. These results are in agreement with prior RCTs and meta-analyses that found no analgesic benefit of melatonin in cancer populations. Fan et al. ²⁹ similarly reported no significant improvement in pain outcomes across oncology RCTs, and studies in non-cancer contexts such as neuropathic or postoperative pain have shown comparable findings. Although a few individual trials have suggested modest improvements in overall QoL, pain-specific domains remain largely unaffected. Mechanistically, melatonin’s anti-inflammatory and antioxidant properties could theoretically modulate nociceptive pathways, but clinical evidence remains inconsistent. The lack of measurable benefit in this pooled analysis may reflect variability in pain assessment tools (such as QLQ-C30 versus FACIT-F), dosage formulations, treatment durations, and baseline disease burden. Overall, current evidence does not support melatonin as an effective adjunct for cancer-related pain management, although further high-quality randomized trials are warranted to determine whether specific subgroups might benefit.

Melatonin also failed to demonstrate a significant impact on dyspnoea (MD = 2.90, 95% CI –11.89 to 17.70, p = 0.70; I² = 27%), indicating low heterogeneity and consistent results. The wide confidence interval spanning both potential benefit and harm suggests an absence of effect. Prior research reported no improvements in respiratory or symptom-related QoL domains in cancer patients, ²⁹ supporting the conclusion that melatonin’s therapeutic actions do not extend to respiratory symptoms.

No significant difference was observed in insomnia scores between melatonin and placebo (MD = 0.07, 95% CI –0.10 to 0.24, p = 0.41; I² = 0%). This is consistent with evidence showing limited benefit of melatonin on sleep quality among oncology patients, despite documented improvements in sleep latency in non-cancer populations. ²⁴ Cancer-related insomnia is multifactorial, often influenced by treatment stress, hormonal changes, and psychological distress, which may attenuate melatonin’s chronobiotic and antioxidant effects. Further studies integrating behavioral or cognitive interventions could clarify whether combination strategies yield better outcomes.

Similarly, melatonin had no significant influence on appetite loss (SMD = –0.02, 95% CI –0.17 to 0.13, p = 0.80; I² = 0%). Del Fabbro et al. ³⁴ reported comparable findings in advanced cancer cachexia, with no improvement in appetite, weight, or QoL. Fan et al. ²⁹ also observed no enhancement of appetite-related QoL domains. Collectively, current evidence suggests melatonin’s potential effects may be confined to fatigue or circadian regulation rather than metabolic or cachexia-related symptoms.

Melatonin showed no measurable benefit for gastrointestinal outcomes. For constipation, the pooled mean difference was –4.09 (95% CI –21.10 to 12.92, p = 0.64; I² = 37%), and for diarrhoea it was –0.04 (95% CI –0.20 to 0.12, p = 0.63; I² = 0%). Although the direction of effect slightly favored melatonin, the wide or null confidence intervals indicate a lack of clinical relevance. Trials by Del Fabbro et al. ²⁸ and the systematic review by Fan et al. ²⁵ similarly reported no meaningful effect on gastrointestinal symptoms, including nausea, constipation, or appetite loss. Overall, melatonin does not appear to mitigate treatment-related bowel toxicity or discomfort in cancer patients.

Financial difficulty scores were comparable between groups (MD = 0.01, 95% CI –0.14 to 0.16, p = 0.89; I² = 0%). As expected, melatonin has no plausible mechanism to influence socioeconomic aspects of QoL, which depend on structural and contextual factors such as treatment costs and employment status. Fan et al. ²⁵ also noted that improvements in symptom control rarely translate into gains in financial well-being or other external QoL domains. When outcomes were measured using the same scale across studies, MD was used to preserve the original units and enhance interpretability. However, when the same outcome was assessed using different measurement scales, SMD was employed to enable comparability across studies, in accordance with recommendations from the Cochrane Handbook for Systematic Reviews of Interventions. ³⁵

Limitations

The comparatively small number of included trials, moderate sample sizes, along with potential publication bias are some limitations reported in this meta-analysis. Heterogeneity across analyses was caused by variations in study design, melatonin dosage (5–20 mg), treatment duration, and outcome assessment instruments (QLQ-C30 vs. FACIT). Subgroup interpretation was further hampered by a number of trials’ insufficient reporting of baseline characteristics like BMI, comorbidities, and preceding therapy. The observed results may also have been affected by the inclusion of studies with different adjuvant regimens and radiotherapy protocols. The use of SMD for pooling outcomes measured on different scales may limit the clinical interpretability of effect sizes and introduce variability related to differences in standard deviations across studies. Publication bias cannot be ruled out, especially given the small number of included trials and the prevalence of small-sample studies. Furthermore, selective reporting of outcomes, where weariness is more frequently reported than psychosocial domains, may contribute to an overestimation of melatonin’s domain-specific benefits. These methodological variations show that in order to better comprehend melatonin’s clinical role in this context, larger, standardized RCTs with harmonized endpoints and long-term follow-up are required.

Conclusion

This meta-analysis suggests that melatonin is generally well tolerated during radiotherapy in patients with breast cancer, although its broader oncologic safety profile has yet to be fully defined. Given its biological activity, the possibility of influencing treatment response cannot be excluded, and current clinical evidence remains insufficient to draw firm conclusions regarding long-term outcomes. Melatonin was associated with significant improvements in fatigue, cognitive functioning, and overall health status, while no meaningful benefits were observed across other quality-of-life domains. These findings suggest its use as a selective adjunct for symptom management rather than a comprehensive therapeutic approach.

Further large-scale, rigorously designed randomized trials with longer follow-up are needed to better characterize its long-term implications, optimize dosing strategies, and define its role alongside standard supportive care.

Appendix.

Abbreviations

BRCA

Breast cancer

QoL

quality of life

SMDs

standardized mean differences

MD

mean differences

WMD

Weighted mean difference

MFI

Multidimensional Fatigue Inventory

BAI

Beck Anxiety Inventory

BDI

Beck Depression Inventory

EORTC QLQ-30

The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire

FWB

functional well-being

BMI

body mass index

CIs

confidence intervals

RCTs

randomized controlled trials

PWB

physical well-being

ORCID iD

Bibek Giri https://orcid.org/0009-0003-0100-9111

Ethical Considerations

No ethical approval was required as this study did not involve human participants or laboratory animals.

Data Availability Statement

Not applicable for this research.*