Cancer-related fatigue (CRF) is among the most prevalent and debilitating symptoms for individuals undergoing cancer treatment. Compared with other cancer-related symptoms, including pain or nausea, CRF is generally considered more distressing and often long-lasting, with a strong impact on daily living, adversely impacting patients’ health-related Quality-of-Life (hrQoL). Depending on the clinical impact of the cancer, prevalence rates range from 59% to nearly 100% of all patients diagnosed with cancer.
Despite its significant impact on hrQoL, progress in developing new treatments for CRF—a condition often unrecognized and under-treated within oncology practice—is hindered by a limited understanding of the intricate biological, clinical, demographic, and lifestyle factors that contribute to it.[1][2][3][4]
The May 2026 issue of the Journal of the National Comprehensive Cancer Network (JNCCN) features a pivotal meta-analysis providing the most comprehensive assessment to date on the efficacy and safety of methylphenidate-type psychostimulants for CRF management. [4]
Understanding Cancer-Related Fatigue
CRF is defined as the feeling of extraordinary exhaustion associated with a high level of distress, disproportionate to the patient’s activity, and is not relieved by sleep or rest. Or, as defined by the National Comprehensive Cancer Network (NCCN), it is ‘a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.’
Its pathophysiology is multifactorial, involving proinflammatory cytokines, hypothalamic-pituitary-adrenal axis alterations, autonomic nervous system dysregulation, circadian rhythm disruption, serotonin imbalance, muscle metabolic dysfunction, and psycho-socio-behavioral factors. The pooled prevalence of CRF is estimated at 49%-71% in oncologic populations, yet it is often underestimated and undertreated by clinicians.
Current guidelines recommend that, beyond correction of reversible causes, first-line interventions for CRF should be nonpharmacologic (exercise, mind–body practices, psychosocial approaches, and integrative therapies). However, pharmacologic options—primarily short-term corticosteroids and psychostimulants such as methylphenidate (MPH) and dexmethylphenidate (d-MPH)—are considered when nonpharmacologic measures are insufficient. Despite nearly 25 years since NCCN’s first CRF guideline, no drug has regulatory approval for this indication, highlighting the need for rigorous evaluation of available pharmacologic strategies.
Study Design and Methods
The featured systematic review and meta-analysis (SRMA) was conducted in accordance with Cochrane and PRISMA guidelines, with the protocol registered on PROSPERO. A comprehensive search of PubMed, Embase, and CENTRAL databases identified nine double-blind, randomized, placebo-controlled, phase 2/3 trials published between May 2006 and July 2024. Participants included 823 adults (410 assigned to MPH/d-MPH; 413 to placebo) with advanced cancer or actively receiving cancer-directed therapy.
Eligible studies evaluated either MPH or d-MPH (any oral formulation, dosage, or duration) as a supportive intervention for CRF. Fatigue was measured primarily using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale—a 13-item patient-reported instrument with a score range of 0–52 (higher scores indicate less fatigue). Secondary measures included the Edmonton Symptom Assessment System-Fatigue (ESAS-F) and other validated fatigue scales.
Efficacy and Temporal Profile
Across six RCTs, supportive treatment with MPH/d-MPH was associated with a statistically significant improvement in FACIT-F scores (pooled mean difference [MD], 2.43; 95% CI, 0.90–3.96; P=.002), though this fell short of established thresholds for clinical meaningfulness in short-term follow-up. When considering all validated fatigue scales, the pooled standardized mean difference (SMD) was 0.38 (95% CI, 0.17–0.60; P<.001), indicating a small-to-moderate benefit. On self-rated 0–10 scales (e.g., ESAS-F), the pooled MD was −1.52 (95% CI, −2.90 to −0.14; P=.03), exceeding the 1-point threshold for a minimal clinically important difference.
Importantly, subgroup analyses revealed a temporal gradient in efficacy: at 2 weeks, improvements did not reach clinically meaningful thresholds, but by 5 weeks, pooled FACIT-F improvements surpassed the 3-point benchmark for probable clinical benefit (MD, 3.56; 95% CI, 1.57–5.55; P<.001), increasing further at 8 weeks (MD, 3.89; 95% CI, 1.76–6.01; P<.001). These findings suggest that the benefit of psychostimulant therapy for CRF becomes most apparent after several weeks, likely reflecting the time needed for dose titration and patient acclimatization.
Clinical Implications
The authors advocate for integrating methylphenidate as an adjunct within a multimodal, patient-centered approach to CRF. While nonpharmacologic interventions such as exercise and cognitive-behavioral therapy remain the gold standard for long-term improvement, these may require 8–12 weeks of consistent engagement. MPH/d-MPH can serve as a bridging strategy to provide earlier symptomatic relief. Careful patient selection and gradual dose titration are vital, with preference for immediate-release MPH over extended-release or d-MPH where flexibility, cost, and tolerability are concerns.
Patients with greater baseline fatigue, coexisting depression, opioid-induced sedation, or known ADHD may be particularly suitable candidates, whereas those with poorly controlled anxiety, insomnia, or cardiovascular disease should be approached cautiously. Pharmacologic interventions should always complement first-line strategies, not replace them.
Safety and Tolerability
MPH has a long-standing safety record, with no significant increase in adverse events compared with placebo in the meta-analysis. The pooled odds ratios for adverse events such as anorexia, nausea, diarrhea, tachycardia, headaches, dizziness, insomnia, and anxiety-related symptoms were not significantly different. However, higher doses or prolonged use may increase side effect risk, especially in patients with underlying cardiovascular or psychiatric comorbidities, who were mostly excluded from trials. Regular monitoring and individualized risk–benefit assessment remain essential.
Quality of Evidence and Limitations
Most included RCTs were rated as low risk or having some concerns for bias, with one trial identified as high risk due to missing data. Limitations include heterogeneity in drug regimens, populations, and fatigue assessment timing, as well as relatively short trial durations and underrepresentation of younger or early-stage cancer populations. Placebo effects and high dropout rates in palliative care settings may also have affected outcome estimates.
Despite the Society for Integrative Oncology (SIO) and American Society of Clinical Oncology‘s (ASCO) conditional recommendation against routine psychostimulant use for CRF, [5] current NCCN Guidelines® continue to list MPH as an option in selected circumstances, especially when nonpharmacologic measures are insufficient. This meta-analysis offers timely, methodologically rigorous evidence to help reconcile these differing recommendations, highlighting the importance of identifying subpopulations most likely to benefit and of integrating pharmacologic and nonpharmacologic approaches.
This updated systematic review and meta-analysis provide the most robust evidence to date for the modest but clinically meaningful role of MPH/d-MPH in alleviating CRF in carefully selected patients. Benefits become most apparent after 5 weeks of treatment, and the safety profile is reassuring within the studied populations. Integration of psychostimulants with nonpharmacologic strategies offers a practical, patient-centered approach to improving quality of life for people facing cancer-related fatigue.
Based on the study outcomes, the authors believe that future RCTs should prioritize longer follow-up, more homogeneous populations, and strategies to mitigate placebo effects. Adaptive trial designs and patient-centered retention frameworks will further clarify which patients derive the most benefit from psychostimulant therapy.
Note: Acknowledgments Bruno Almeida Costa, MD, acknowledges the mentorship and career development support provided by the American Academy of Hospice and Palliative Medicine (AAHPM).
Reference
[1] Al Maqbali M. Cancer-related fatigue: an overview. Br J Nurs. 2021 Feb 25;30(4):S36-S43. doi: 10.12968/bjon.2021.30.4.S36. PMID: 33641391.
[2] Weis J. Cancer-related fatigue: prevalence, assessment and treatment strategies. Expert Rev Pharmacoecon Outcomes Res. 2011 Aug;11(4):441-6. doi: 10.1586/erp.11.44. PMID: 21831025.
[3] Sleight AG, Crowder SL, Skarbinski J, Coen P, Parker NH, Hoogland AI, Gonzalez BD, Playdon MC, Cole S, Ose J, Murayama Y, Siegel EM, Figueiredo JC, Jim HSL. A New Approach to Understanding Cancer-Related Fatigue: Leveraging the 3P Model to Facilitate Risk Prediction and Clinical Care. Cancers (Basel). 2022 Apr 14;14(8):1982. doi: 10.3390/cancers14081982. PMID: 35454890; PMCID: PMC9027717.
[4] Costa BA, Sheppard R, Coelho HGB, Crowley F, Oliveira D, Costa VA, Chen J, Afezolli D, DeCastro GA, Apoeso O, Popp B, Curseen KA, Quest TE. Methylphenidate-Type Psychostimulants for Cancer-Related Fatigue: Updated Meta-Analysis of Randomized Controlled Trials. J Natl Compr Canc Netw. 2026 May;24(5):163-171. doi: 10.6004/jnccn.2025.7135. PMID: 42140261.[Article]
[5] Gowin K, Muminovic M, Zick SM, Lee RT, Lacchetti C, Mehta A. Integrative Therapies in Cancer Care: An Update on the Guidelines. Am Soc Clin Oncol Educ Book. 2024 Jun;44(3):e431554. doi: 10.1200/EDBK_431554. PMID: 38820485.
Featured image: Cancer Patient: © 2026 photo courtesy: Kateryna Hliznitsova. Licensed under the Unsplash+ License. sed with permission.
DOI
 is among the most prevalent and debilitating symptoms for individuals undergoing cancer treatment. Compared with other cancer-related symptoms, including pain or nausea, CRF is generally considered more distressing and often long-lasting, with a strong impact on daily living, adversely impacting patients' health-related Quality-of-Life (hrQoL). Depending on the clinical impact of the cancer, prevalence rates range from 59% to nearly 100% of all patients diagnosed with cancer.){kind=link}