Risk Factors Exacerbating Hand-Foot Skin Reaction Induced by Capecitabine plus Oxaliplatin with or without Bevacizumab Therapy

Background: Capecitabine plus oxaliplatin (CapeOx) ± bevacizumab therapy is associated with a high incidence of hand-foot skin reaction (HFSR), hindering treatment. However, timing of onset and risk factors remain unclear. Objective: This study examined the development of HFSR and risk factors for its exacerbation to a serious condition in CapeOx ± bevacizumab therapy. Methods: We retrospectively examined patients with colorectal cancer receiving CapeOx ± bevacizumab therapy between October 1, 2009, and March 31, 2012. The observation period was defined as lasting until completion of 8 cycles. The relationship between cumulative dose of capecitabine and cumulative proportion of patients developing HFSR was evaluated by Kaplan-Meier methods. Risk factors for exacerbation of HFSR to a serious condition were assessed by multiple logistic regression. Results: Data for 203 patients were analyzed. For patients treated at cumulative capecitabine doses of 100 000 mg/m² and 200 000 mg/m², Grade 1 HFSR occurred in ≥80% and ≥90%, respectively, and moderate-to-severe HFSR (Grade 2+) occurred in ≥10% and ≥20%, respectively. Multivariate analysis showed significant associations with diabetes (odds ratio [OR] = 4.79; 95% confidence interval [CI] = 1.86-12.34; P = 0.001), concomitant use of bevacizumab (OR = 6.01; 95% CI = 2.20-16.41; P = 0.001), history of fluorinated pyrimidine administration (OR = 2.42; 95% CI = 1.10-5.33; P = 0.027), and early onset (within 21 days) of Grade 1 HFSR (OR = 3.78; 95% CI = 1.64-8.70; P = 0.001). Conclusions: HFSR in CapeOx therapy is a cumulative toxicity and risk of exacerbation to a serious condition increases with diabetes, concomitant use of bevacizumab, history of fluorinated pyrimidine administration, and onset of Grade 1 HFSR within 21 days.