Efficacy of Vitamin E Treatment for Hand-Foot Syndrome in Patients Receiving Capecitabine

Capecitabine is a novel oral fluoropyrimidine that is converted within tumor cells to fluorouracil by thymidine phosphorylase [1]. Hand-foot syndrome (HFS) is the most frequent side effect of capecitabine and has been reported in up to 71% of patients receiving a starting dose of 1,250 mg/m² twice daily [2, 3, 4, 5, 6, 7]. Grade 3 HFS was reported in up to 10–24% of patients. Treatment interruption and, if required, dose reduction usually ameliorate symptoms without compromising efficacy [8, 9]. Supportive treatments such as topical wound care, elevation, and cold compresses may help to relieve pain [10, 11]. Use of systemic corticosteroids, pyridoxine (vitamin B6), and cox-2 inhibitors have been used in patients developing HFS with cytotoxic agents including capecitabine and pegylated liposomal doxorubicin with varying success [11, 12, 13]. Kara et al. [13] from Turkey reported apparent benefit of vitamin E in managing HFS. Therefore we conducted this study to examine the efficacy of vitamin E in managing capecitabine-induced HFS.

This retrospective, multicenter study was undertaken between 2005 and 2009 in HER2-negative patients with breast cancer treated with oral capecitabine 828 mg/m² twice daily on days 1–21 every 4 weeks. Patients with symptoms of grade 2 HFS received oral vitamin E (Tocopherol Acetate, Eisai Pharmaceuticals, Tokyo, Japan) 100 mg/day without chemotherapy dose modification. Patient and treatment-related data, e.g. chemotherapy-related toxicities, dose of vitamin E, severity of symptoms, and tumor response to therapy, were recorded every 4 weeks. Patients underwent a complete der-matological examination at every visit. HFS including pain was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI-CT-CAE v3.0). Wilcoxon signed rank test was used to examine patient demographics and treatment information. Median time to onset of grade 2 HFS was estimated. Severity of HFS was compared before and after vitamin E administration. We identified 32 patients developing grade 2 HFS during capecitabine therapy between January 2005 and February 2009, who subsequently received vitamin E with or without capecitabine treatment modification. The median time to first onset of HFS was 7.3 months (range 4.1–9.6). The initial starting dose of vitamin E for treatment of HFS was 100 mg/day, and the median dose of vitamin E was 200 mg (range 100–400 mg/day). Vitamin E application had a marked effect on dermatological complications within 7 days of initiation. The effect lasted throughout administration. Desquamation and pain reduced gradually (figs. 1] and 2), and the comfort level of the patients improved. Fifteen of 32 patients (46.9%) with HFS experienced symptom improvement with vitamin E (100 mg/day) (p < 0.05; before vs. after 2 months vitamin E administration). Neurological symptoms improved. Thirteen patients still had pain, but this decreased after vitamin E dose escalation to 400 mg/day. The remaining 4 patients had considerable pain interfering with function after vitamin E 100 mg/day, but this reduced after vitamin E dose escalation to 400 mg/day and dose reduction of capecitabine as described previously [14]. Among all 32 patients included, the overall response rate to capecitabine was 37.5%, comprising 2 complete and 10 partial responses. Patients receiving capecitabine and vitamin E (100–400 mg) had longer time to progression than did patients receiving dose reduction of capecitabine (median 10.2 months vs. 6.1 months).

Fig. 1.

Hand-foot syndrome (HFS) began to disappear after 1 month of vitamin E treatment; 15 of 32 patients (47%) with HFS experienced symptom improvement with vitamin E (100 mg/day) (p < 0.05).

Fig. 2.

Clinical presentation of hand-foot syndrome. After vitamin E without dose reduction of capecitabine, the skin lesions had disappeared.

In this retrospective study, 15 of 32 patients with HFS improved with vitamin E 100 mg/day, suggesting a beneficial effect of vitamin E therapy. Vitamin E is a widely used skin care product and functions as the major lipophilic antioxidant, preventing peroxidation of lipids and resulting in more stable cell membranes. The antioxidant membrane stabilizing effect of vitamin E also includes stabilization of the lysomal membrane, a function shared with glucocorticoids [13]. Systemic vitamin E and glucocorticoids inhibit the inflammatory response and collagen synthesis, thereby possibly impeding the

Conflict of Interest

The authors declare no conflict of interests.