Impact of Zinc Supplementation and Topical Clobetasol on the Prevention of Regorafenib-Induced Hand-Foot Skin Reaction: The ZINCLO-HAND Study

Purpose Regorafenib-induced hand-foot skin reaction (HFSR) is a common dose-limiting toxicity. We evaluated whether prophylaxis with oral zinc plus topical clobetasol is associated with lower clinically significant HFSR compared with either strategy alone. Methods ZINCLO-HAND was a prospective, multicenter, pragmatic, nonrandomized comparative study across 13 oncology centers in Türkiye. Adults initiating regorafenib were managed at physician discretion with oral zinc, topical clobetasol propionate 0.05%, or the combination for 8 weeks. The primary end point was grade ≥2 HFSR within the prophylaxis period. Secondary end points included grade 3 HFSR, treatment modification, relative dose intensity, and patient-reported outcomes. Results Of 179 enrolled patients, 156 were evaluable: zinc, n = 49; clobetasol, n = 52; combination, n = 55. Grade ≥2 HFSR occurred in 38.8%, 38.5%, and 16.4% of patients, respectively ( P = .016). In multivariable logistic regression adjusted for age, Eastern Cooperative Oncology Group performance status, tumor type, and initial regorafenib dose intensity, zinc monotherapy (adjusted odds ratio [OR], 3.37 [95% CI, 1.30 to 8.71]; P = .012) and clobetasol monotherapy (adjusted OR, 3.15 [95% CI, 1.26 to 7.88]; P = .014) were associated with higher odds of grade ≥2 HFSR versus combination prophylaxis. Median relative dose intensity was comparable across groups. HFSR-attributable treatment modification occurred in 30.6%, 28.8%, and 12.7% of patients, respectively. Conclusion In this nonrandomized prospective cohort, zinc plus topical clobetasol was associated with lower clinically significant regorafenib-induced HFSR and fewer HFSR-attributable treatment modifications. These findings support consideration of combination prophylaxis in routine practice and warrant randomized confirmation.