BackgroundBreast 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.MethodsFollowing 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.ResultsFive 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.ConclusionBased 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.
