Capecitabine Dosage as an Independent Prognostic Factor for the Development of Hand-Foot Syndrome: A Competing Risk Analysis

Purpose: Capecitabine, an oral prodrug of 5-fluorouracil, commonly causes hand-foot syndrome (HFS). Although clinical predictors of HFS have been reported, causal evidence supporting dosage as an independent prognostic factor remains limited. Because competing events may preclude HFS, this study evaluated the prognostic role of capecitabine dosage in grade 2-3 HFS using a competing risk analysis. Patients and Methods: A retrospective observational cohort study was conducted. Capecitabine dosage was the exposure of interest. Potential confounders including sex, combination chemotherapy, and estimated glomerular filtration rate (eGFR) were identified using a directed acyclic graph. The primary endpoint was time from treatment initiation to grade 2-3 HFS. A multivariable competing risk analysis was performed using the Lambert model, with loss to follow-up, severe diarrhea, sepsis, and death defined as competing events. Capecitabine dosage was categorized (2000-4000 mg/day) to facilitate clinical interpretability. Results: Among 596 patients, 132 (22.2%) developed grade 2-3 HFS, with a median onset time of 63 days (interquartile range, 42-84). Higher capecitabine dosage was independently associated with an increased risk of HFS, with the greatest effect observed at 4000 mg/day compared with 2000 mg/day (aHR 4.41; 95% CI, 1.31-14.81; p = 0.016), demonstrating a clear dose-dependent increase in risk. In addition, higher dosage was associated with a shorter model-predicted median time to HFS onset. Conclusion: This study confirms capecitabine dosage as an independent prognostic factor for grade 2-3 HFS, with significantly increased risk at 4000 mg/day and a shorter median time to HFS onset as dosage increases. These findings underscore the importance of careful dosing and support the implementation of evidence-based strategies for dose adjustment in high-risk patients.