BACKGROUND Cancer-related fatigue is highly prevalent and significantly impairs quality of life and treatment adherence. Methylphenidate is commonly prescribed, but its efficacy remains uncertain. OBJECTIVE To evaluate the efficacy of methylphenidate for cancer-related fatigue, accounting for the timing of fatigue assessment and the certainty of the available evidence. METHODS A systematic review and meta-analysis of randomized controlled trials was conducted. PubMed, Embase, CINAHL, Cochrane CENTRAL, and SPORTDiscus were systematically searched from inception to February 2026, without language or date restrictions. Adult patients with cancer-related fatigue were included, and methylphenidate was compared with placebo. Fatigue outcomes were analyzed separately during treatment, immediately post-treatment, and at follow-up. The time-specific meta-analyses, subgroup analyses, and sensitivity analyses were conducted post hoc. The review was registered in PROSPERO (CRD42023429827). RESULTS Fourteen randomized controlled trials, involving 1,155 patients, were included. Methylphenidate was associated with a small but statistically significant improvement in fatigue during treatment (SMD 0.26, 95% CI 0.04 to 0.47; I2=30%). No statistically significant benefit was observed immediately post-treatment (SMD 0.27, 95% CI 0.00 to 0.53; I2=63%) or at follow-up (SMD 0.36, 95% CI -0.13 to 0.84; I²=23%). Sensitivity analyses generally supported the during-treatment finding, while subgroup analyses showed statistically significant effects in studies with treatment durations of at least two weeks, among patients with advanced cancer and/or receiving palliative care, and in studies evaluating racemic methylphenidate. No statistically significant improvement in quality of life was observed. The certainty of evidence ranged from very low to low. CONCLUSIONS Current randomized evidence suggests a small benefit of methylphenidate for cancer-related fatigue during treatment, although its clinical relevance and persistence after treatment remain uncertain. The low to very low certainty of the evidence and exploratory nature of subgroup analyses limit conclusions regarding which patients may benefit from treatment.
