Hand–foot skin reaction as a positive prognostic factor in vascular endothelial growth factor receptor‐tyrosine kinase inhibitor treatment

Hand-foot skin reaction (HFSR) is a common adverse effect of vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), but its prognostic value remained disputable. In this study, we aimed to assess the association between HFSR and survival outcomes in cancer patients receiving VEGFR-TKIs. MEDLINE, Embase and the Cochrane Central Register of Controlled Trials were searched from inception to 29 June 2025. Two authors independently selected cohort studies, extracted data and appraised the risk of bias of included studies using the Quality In Prognosis Studies checklist. The outcomes were overall survival (OS) and progression-free survival (PFS). A random-effects model meta-analysis was performed to calculate pooled hazard ratio (HR) with 95% confidence intervals (CIs). Subgroup analyses based on various cancer types and VEGFR-TKIs types were also conducted. Thirty-two observational studies involving 6543 patients receiving VEGFR-TKIs were included, of whom 2671 experienced HFSR. Patients who developed VEGFR-TKI-induced HFSR showed better OS (HR 0.54, 95% CI 0.49-0.60) and PFS (HR 0.59, 95% CI 0.53-0.65) compared with those who did not. Subgroup analysis revealed significantly improved OS and PFS in patients with hepatocellular carcinoma, colorectal cancer or non-small cell lung cancer who developed VEGFR-TKI-induced HFSR. HFSR was also a positive prognostic factor for OS and PFS in patients receiving sorafenib, regorafenib, fruquintinib, anlotinib and cabozantinib. In conclusion, VEGFR-TKI-induced HFSR may serve as a positive surrogate marker for survival. Early detection and optimal management for HFSR in patients receiving VEGFR-TKI therapy is needed to maintain treatment efficacy and life quality. SYSTEMATIC REVIEW PROTOCOL REGISTRATION: PROSPERO CRD42024598845.