Methylphenidate-Type Psychostimulants for Cancer-Related Fatigue: Updated Meta-Analysis of Randomized Controlled Trials

BACKGROUND: Nonpharmacologic interventions are the mainstay of management for cancer-related fatigue (CRF), with few pharmacologic options available-notably methylphenidate (MPH) and dexmethylphenidate (d-MPH). Given mixed evidence from randomized controlled trials (RCTs) and newly published phase III data, we conducted an updated systematic review and meta-analysis to clarify the efficacy and safety of these psychostimulants in managing CRF. METHODS: PubMed, Embase, and CENTRAL were searched through January 2025 for placebo-controlled, double-blind RCTs evaluating MPH/d-MPH in adults with advanced cancer or receiving active cancer-directed therapy. Outcomes included between-group differences in fatigue score changes measured by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), self-rated 0-10 scales, or any validated scales, as well as treatment-emergent adverse events (TEAEs). Exploratory subanalyses examined FACIT-F score changes at 2 ± 1, 5 ± 1, and ≥8 weeks after treatment initiation. Pooled estimates were calculated using random-effects models. RESULTS: A total of 9 RCTs met inclusion criteria (n=823; with evaluable sample sizes varying per analysis). Compared with placebo, MPH/d-MPH monotherapy (MPH-equivalent dose range: 5-100 mg/d) produced statistically significant improvements in fatigue scores, as measured by FACIT-F (mean difference [MD], 2.43; 95% CI, 0.90 to 3.96), self-rated 0-10 scales (MD, -1.52; 95% CI, -2.90 to -0.14), and any validated scale (standardized MD, 0.38; 95% CI, 0.17 to 0.60). FACIT-F improvements followed a temporal gradient, exceeding the 3-point threshold for clinical meaningfulness by 5 ± 1 weeks (MD, 3.56; 95% CI, 1.57 to 5.55) and rising further by ≥8 weeks (MD, 3.89; 95% CI, 1.76 to 6.01). No statistically significant differences in the odds of key TEAEs were observed. CONCLUSIONS: MPH-type psychostimulants produce a modest but consistent reduction in CRF, with therapeutic benefits becoming clinically meaningful after 5 weeks and a favorable safety profile in the studied population, thereby meriting consideration for carefully selected individuals living with cancer when nonpharmacologic strategies are insufficient or still taking effect.