Effect of melatonin on the fatigue, sleep, and depression symptom cluster in breast cancer according to dosage and treatment phase: A systematic review and meta-analysis.

Abstract

e24112 Background: Patients with breast cancer (BC) frequently experience a debilitating symptom cluster of sleep disturbances, depression, and fatigue, significantly impairing quality of life. While melatonin is a common supportive therapy, clinical trials yield conflicting results due to heterogeneous protocols. This meta-analysis clarifies melatonin’s efficacy by evaluating the pharmacological threshold (High-dose: ≥10mg vs. Low-dose: < 10mg) and clinical treatment phase (Active Treatment vs. Post-Treatment). Methods: Following PRISMA guidelines, a systematic search of PubMed, Embase, and Cochrane identified eight RCTs comparing oral melatonin to placebo in BC patients. Outcomes were sleep quality, depression, and fatigue, measured via Standardized Mean Difference (SMD). Data were pooled using random-effects models. Pre-specified subgroup analyses investigated dosage (≥10mg vs. < 10mg) and treatment phase (Active vs. Post-Treatment). Heterogeneity was assessed using the I 2 statistic and Cochrane Q test to ensure statistical rigor. Results: Eight RCTs involving 675 unique patients were included. For depression, a significant dose-dependent benefit was identified; high-dose melatonin (≥10mg) significantly reduced symptoms (SMD -1.07; 95% CI -1.43 to -0.71; P < 0.00001; I 2 = 0%), whereas low-dose ( < 10mg) had no significant effect (P = 0.83). For fatigue, a robust benefit was observed specifically during radiotherapy (SMD -1.33; 95% CI -1.82 to -0.84; P < 0.00001), while non-radiotherapy fatigue showed no significant improvement (SMD 0.14; P = 0.20; I 2 = 0%). Sleep quality improved significantly during active treatment in high-dose groups (SMD -1.75; 95% CI -2.54 to -0.97; P < 0.0001), though overall sleep results were confounded by extreme heterogeneity (I 2 = 98%) in post-treatment low-dose settings. Conclusions: Melatonin’s therapeutic benefit in BC is strictly dose-dependent and phase-specific. High-dose supplementation (≥10mg) is a robust co-adjuvant for managing depression and treatment-related distress during active chemotherapy and radiotherapy, offering a high-safety-profile intervention. Conversely, low-dose melatonin is ineffective for chronic survivorship symptoms. These findings advocate for implementing standardized high-dose protocols in supportive oncology during active adjuvant therapy to optimize patient-reported outcomes.