Publication: Predictors of hand-foot syndrome and pyridoxine for prevention of capecitabine-induced hand-foot syndrome: a randomized clinical trial

Reference
Title	Predictors of hand-foot syndrome and pyridoxine for prevention of capecitabine-induced hand-foot syndrome: a randomized clinical trial
Topic	Vitamin B6
Author	Yap, Y, Kwok, L, Syn, N, Chay, W Y, Chia, J W K, Tham, C K, Wong, N S, Lo, S K, Dent, R A, Tan, S, Mok, Z Y, Koh, K X, Toh, H C, Koo, W H, Loh, M, Ng, R C H, Choo, S P, Soong, R C T
Year	2017
Journal	JAMA Oncology
DOI	https://doi.org/10.1001/jamaoncol.2017.1269

Author's Abstract The abstract and the information and conclusions contained therein were written by the authors of the publication.

Importance: Hand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment. Objective: To compare the incidence and time to onset of grade 2 or greater HFS in patients receiving pyridoxine vs placebo and to identify biomarkers predictive of HFS. Design, Setting, and Participants: This single-center, randomized double-blind, placebo-controlled phase 3 trial conducted at National Cancer Centre Singapore assessed whether oral pyridoxine could prevent the onset of grade 2 or higher HFS in 210 patients scheduled to receive single-agent capecitabine chemotherapy for breast, colorectal, and other cancers. Interventions: Patients were randomized to receive concurrent pyridoxine (200 mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by sex and use in adjuvant or neoadjuvant vs palliative setting. Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine. Main Outcomes and Measures Primary end point was the incidence of grade 2 or higher HFS in patients receiving pyridoxine. Secondary end points included the time to onset (days) of grade 2 or higher HFS and identification of biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, as well as genetic polymorphisms with genome-wide arrays. Results: In this cohort of 210 patients (median (range) age, 58 (26-82) years; 162 women) grade 2 or higher HFS occurred in 33 patients (31.4%) in the pyridoxine arm vs 39 patients (37.1%) in the placebo arm (P  = .38). The median time to onset of grade 2 or higher HFS was not reached in both arms. In univariate analysis, the starting dose of capecitabine (odds ratio (OR), 1.99; 95% CI, 1.32-3.00; P = .001), serum folate levels (OR, 1.27; 95% CI, 1.10-1.47; P = .001), and red blood cell folate levels (OR, 1.25; 95% CI, 1.08-1.44; P  = .003) were associated with increased risk of grade 2 or higher HFS. In multivariate analyses, serum folate (OR, 1.30; 95% CI, 1.12-1.52; P < .001) and red blood cell folate (OR, 1.28; 95% CI, 1.10-1.49; P  = .001) were the only significant predictors of grade 2 or higher HFS. Grade 2 or higher HFS was associated with 300 DNA variants at genome-wide significance (P < 5 × 10−8), including a novel DPYD variant (rs75267292; P = 1.57 × 10−10), and variants in the MACF1 (rs183324967, P = 4.80 × 10−11; rs148221738, P = 5.73 × 10−10) and SPRY2 (rs117876855, P < 1.01 × 10−8; rs139544515, P = 1.30 × 10−8) genes involved in wound healing. Conclusions and Relevance: Pyridoxine did not significantly prevent or delay the onset of grade 2 or higher HFS. Serum and red blood cell folate levels are independent predictors of HFS.

This publication is referenced in the following studies:

1. Yap et al. (2017): Predictors of hand-foot syndrome and pyridoxine for prevention of capecitabine-induced hand-foot syndrome: a randomized clinical trial