Cancer-related fatigue during treatment with neoadjuvant and/or adjuvant immune checkpoint inhibitors: a systematic review and meta-analysis

Purpose: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet cancer-related fatigue (CRF) remains a frequent but poorly characterized adverse effect. We evaluated CRF incidence during ICI treatment in neoadjuvant and adjuvant settings. Methods: We conducted a systematic review of prospective cohort studies and phase 2 or higher trials investigating FDA-approved ICIs in adjuvant or neoadjuvant settings, reporting fatigue as an adverse event or via patient-reported outcomes (PROs). Searches conducted across four databases and ClinicalTrials.gov through September 2024 followed PRISMA guidelines using Covidence software. Studies not in English, lacking full text, or insufficient for meta-analysis were excluded. Data on fatigue incidence and quality of life were extracted. Risk of bias was assessed using the Cochrane tool, and certainty of evidence was graded using GRADEPro. Meta-analysis was performed on all included studies. Results: Forty-three studies met inclusion criteria, primarily involving melanoma, breast, lung, renal, and gastroesophageal cancers. Common ICIs included nivolumab, pembrolizumab, ipilimumab, and durvalumab. Fatigue was more frequent with ICIs versus placebo (risk ratio [RR] 1.21, 95% CI 1.08–1.35), and PROs indicated higher fatigue levels (standardized mean difference 0.12, 95% CI 0.01–0.23). No significant difference was observed between ICIs and chemotherapy (RR 0.81, 95% CI 0.36–1.82). Risk of bias was high due to allocation concealment and open-label designs. Conclusions: ICI monotherapy is associated with modestly increased CRF compared with placebo, as reported by clinicians and patients. These findings underscore the need for patient counseling and further research on the severity and trajectory of ICI-related CRF.