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Original Investigation
July 13, 2017

Predictors of Hand-Foot Syndrome and Pyridoxine for Prevention of Capecitabine–Induced Hand-Foot SyndromeA Randomized Clinical Trial

Author Affiliations
  • 1Division of Medical Oncology, National Cancer Centre Singapore, Singapore
  • 2Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore
  • 3Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  • 4Cancer Science Institute of Singapore, National University of Singapore, Singapore
  • 5Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research, Singapore
  • 6Department of Epidemiology and Biostatistics of the School of Public Health, Imperial College London, London, United Kingdom
  • 7Department of Pathology, National University of Singapore, Singapore
JAMA Oncol. Published online July 13, 2017. doi:10.1001/jamaoncol.2017.1269
Key Points

Questions  Can pyridoxine prevent capecitabine-induced hand-foot syndrome (HFS), and what are the predictors of HFS?

Findings  The incidence of grade 2 or higher HFS and median time to onset of grade 2 or higher HFS were not significantly different with prophylactic pyridoxine compared with placebo. Increase in serum folate and red blood cell folate levels, as well as genomic variants linked to wound healing and cytoskeletal anchoring, were associated with increased risk of HFS.

Meaning  Pyridoxine is not effective in preventing or delaying the onset of grade 2 or higher HFS; serum and red blood cell folate levels are independent determinants of capecitabine-induced HFS.

Abstract

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.

Trial Registration  clinicaltrials.gov Identifier: NCT00486213

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