Methylphenidate in improving cancer-related fatigue: efficacy and safety – systematic review and meta-analysis of randomised controlled trials with trial sequential analysis

BACKGROUND: Cancer-related fatigue (CRF) affects up to 70.7% of patients with cancer, significantly impairing quality of life and treatment adherence. Methylphenidate (MPH) and its dexmethylphenidate (D-MPH) are commonly used psychostimulants, but evidence regarding their efficacy remains inconsistent. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, we systematically searched PubMed, Cochrane Library, Embase and Web of Science from inception to June 2025. Primary outcomes were CRF improvement and safety. Meta-analysis was performed using R software (V.4.2.1) with random-effects models. Trial sequential analysis (TSA), Bayesian methods for sparse adverse event data and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment were applied. RESULTS: Nine randomised controlled trials (RCTs) involving 668 patients were included. Pooled analysis showed a slight but significant reduction in fatigue for MPH versus placebo (standardised mean difference, SMD=0.23, 95% CI 0.06 to 0.40; I²=0%). Efficacy increased at 6-week follow-up (SMD=0.30, 95% CI 0.08 to 0.52; 3 RCTs). Subgroup analysis indicated that D-MPH significantly improved CRF (SMD=0.29, 95% CI 0.01 to 0.57; 3 RCTs), while racemic MPH did not (SMD=0.19, 95% CI -0.02 to 0.41; 4 RCTs). Safety analysis revealed no significant increase in overall adverse events versus placebo, though non-significant trends towards increased mood changes (OR=3.35) and dizziness (OR=2.66) were observed. TSA indicated insufficient information size to confirm definitive efficacy (cumulative Z-curve crossed traditional boundary but not O'Brien-Fleming boundary). GRADE evidence certainty was moderate for overall MPH and D-MPH efficacy, and low for racemic MPH. CONCLUSIONS: MPH demonstrates a modest improvement in CRF, with enhanced effects at 6 weeks. D-MPH shows superior therapeutic potential compared with racemic MPH. However, current evidence is insufficient to support widespread clinical application due to limitations in sample size and heterogeneity. Higher-quality RCTs are needed to confirm efficacy and safety profiles.