Transforming a Roadblock into a Roadmap: Evolving HFSR Management From Adverse Event to Efficacy Biomarker.

opinion statementHand-foot skin reaction (HFSR) is one of the most common adverse events associated with multi-target tyrosine kinase inhibitors (mTKIs), particularly vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), and has traditionally been regarded as a dose-limiting toxicity. However, a growing body of evidence suggests that the occurrence of HFSR may be associated with improved clinical efficacy, prompting a reevaluation of its clinical significance. This review aims to systematically synthesize the literature on the pathogenesis of HFSR, clinical efficacy data from randomized controlled trials (RCTs), and emerging therapeutic concepts in the evolution of management strategies. We found that the occurrence of HFSR exhibits a clear dose-dependent pattern, and the development of high-grade HFSR may be closely associated with favorable clinical efficacy. Therefore, we propose that HFSR could serve as a predictive biomarker for the efficacy of mTKIs-based cancer targeted therapy. HFSR is undergoing a fundamental paradigm shift from a “roadblock to dose adjustment” to a “roadmap for efficacy guidance”, which may intend to provide a comprehensive reference for clinical practice and future research, and facilitate the innovative development of HFSR management strategies in cancer therapy.