Real-World Effectiveness of Topical Diclofenac for Prophylaxis of Capecitabine-Induced Hand–Foot Syndrome: A Retrospective Cohort Study

Background and Objectives: Topical diclofenac has demonstrated efficacy in reducing capecitabine-induced hand–foot syndrome (HFS) in randomized controlled trials. However, evidence regarding its effectiveness in routine clinical practice remains limited. This study evaluated the real-world effectiveness of topical diclofenac prophylaxis for preventing grade 2–3 HFS among patients receiving capecitabine-based chemotherapy. Materials and Methods: A retrospective cohort study was conducted among adults receiving capecitabine between January 2018 and December 2024. Patients receiving prophylactic topical diclofenac were compared with those receiving standard preventive care with topical urea cream. The primary outcome was grade 2–3 HFS. Propensity score adjustment was used to balance baseline characteristics. Time-to-event analyses accounting for competing events included a time-varying competing-risk model and RMST analysis. Results: Among 596 eligible patients, 83 received prophylactic topical diclofenac and 513 received standard preventive care with topical urea cream. Grade 2–3 HFS occurred in 24 patients (28.9%) and 108 patients (21.1%), respectively. After propensity score adjustment, prophylactic topical diclofenac was not associated with a significant reduction in the cumulative incidence of grade 2–3 HFS compared with standard preventive care (adjusted absolute risk difference, 0.04; 95% confidence interval [CI] −0.06 to 0.14; p = 0.467). In time-to-event analyses, topical diclofenac was associated with a lower subdistribution hazard of grade 2–3 HFS at the beginning of follow-up (adjusted sHR, 0.27; 95% CI 0.10 to 0.78; p = 0.015), with a significant time-varying coefficient (sHR, 1.02 per day; 95% CI 1.01 to 1.03; p = 0.003), indicating attenuation of the association over time. The adjusted RMST difference was +0.85 days (95% CI 0.12 to 1.58; p = 0.022) at 60 days and −0.57 days (95% CI −9.34 to 8.20; p = 0.899) at 180 days. Conclusions: In this real-world retrospective cohort study, prophylactic topical diclofenac was not associated with a significant reduction in grade 2–3 HFS compared with standard care using urea cream. Competing-risk analyses did not demonstrate a clear or clinically meaningful benefit. Further prospective studies with larger sample sizes or meta-analyses are warranted to confirm these findings.