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.
Costa et al. (Fri,) studied this question.