Predictors of Hand-Foot Syndrome and Pyridoxine for Prevention of Capecitabine-Induced Hand-Foot Syndrome: A Randomized Clinical Trial

JAMA Oncol. 2017 Nov 1;3(11):1538-1545. doi: 10.1001/jamaoncol.2017.1269.

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 Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine.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.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antimetabolites, Antineoplastic / adverse effects*
  • Asian People / genetics
  • Capecitabine / adverse effects*
  • Chi-Square Distribution
  • Dihydrouracil Dehydrogenase (NADP) / genetics
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Folic Acid / blood
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Hand-Foot Syndrome / blood
  • Hand-Foot Syndrome / ethnology
  • Hand-Foot Syndrome / genetics
  • Hand-Foot Syndrome / prevention & control*
  • Humans
  • Incidence
  • Intracellular Signaling Peptides and Proteins / genetics
  • Kaplan-Meier Estimate
  • Logistic Models
  • Male
  • Membrane Proteins / genetics
  • Microfilament Proteins / genetics
  • Middle Aged
  • Multivariate Analysis
  • Neoplasms / blood
  • Neoplasms / drug therapy*
  • Neoplasms / ethnology
  • Odds Ratio
  • Pharmacogenomic Variants
  • Polymorphism, Single Nucleotide
  • Predictive Value of Tests
  • Pyridoxine / administration & dosage*
  • Risk Assessment
  • Risk Factors
  • Severity of Illness Index
  • Singapore / epidemiology
  • Time Factors
  • Treatment Outcome

Substances

  • Antimetabolites, Antineoplastic
  • Intracellular Signaling Peptides and Proteins
  • MACF1 protein, human
  • Membrane Proteins
  • Microfilament Proteins
  • SPRY2 protein, human
  • Capecitabine
  • Folic Acid
  • Dihydrouracil Dehydrogenase (NADP)
  • Pyridoxine

Associated data

  • ClinicalTrials.gov/NCT00486213