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

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 Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine.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

Links

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  • Authors+Show Affiliations

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    Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

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    Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore.

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    Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Cancer Science Institute of Singapore, National University of Singapore, Singapore.

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    Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

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    Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

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    Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

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    Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

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    Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

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    Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

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    Cancer Science Institute of Singapore, National University of Singapore, Singapore.

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    Cancer Science Institute of Singapore, National University of Singapore, Singapore.

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    Cancer Science Institute of Singapore, National University of Singapore, Singapore.

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    Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

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    Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

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    Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research, Singapore. Department of Epidemiology and Biostatistics of the School of Public Health, Imperial College London, London, United Kingdom.

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    Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

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    Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

    Cancer Science Institute of Singapore, National University of Singapore, Singapore. Department of Pathology, National University of Singapore, Singapore.

    Source

    JAMA oncology 3:11 2017 Nov 01 pg 1538-1545

    MeSH

    Adult
    Aged
    Aged, 80 and over
    Antimetabolites, Antineoplastic
    Asian Continental Ancestry Group
    Capecitabine
    Chi-Square Distribution
    Dihydrouracil Dehydrogenase (NADP)
    Double-Blind Method
    Drug Administration Schedule
    Female
    Folic Acid
    Genetic Predisposition to Disease
    Genome-Wide Association Study
    Hand-Foot Syndrome
    Humans
    Incidence
    Intracellular Signaling Peptides and Proteins
    Kaplan-Meier Estimate
    Logistic Models
    Male
    Membrane Proteins
    Microfilament Proteins
    Middle Aged
    Multivariate Analysis
    Neoplasms
    Odds Ratio
    Pharmacogenomic Variants
    Polymorphism, Single Nucleotide
    Predictive Value of Tests
    Pyridoxine
    Risk Assessment
    Risk Factors
    Severity of Illness Index
    Singapore
    Time Factors
    Treatment Outcome

    Pub Type(s)

    Clinical Trial, Phase III
    Journal Article
    Randomized Controlled Trial

    Language

    eng

    PubMed ID

    28715540

    Citation

    Yap, Yoon-Sim, et al. "Predictors of Hand-Foot Syndrome and Pyridoxine for Prevention of Capecitabine-Induced Hand-Foot Syndrome: a Randomized Clinical Trial." JAMA Oncology, vol. 3, no. 11, 2017, pp. 1538-1545.
    Yap YS, Kwok LL, Syn N, et al. Predictors of Hand-Foot Syndrome and Pyridoxine for Prevention of Capecitabine-Induced Hand-Foot Syndrome: A Randomized Clinical Trial. JAMA Oncol. 2017;3(11):1538-1545.
    Yap, Y. S., Kwok, L. L., Syn, N., Chay, W. Y., Chia, J. W. K., Tham, C. K., ... Soong, R. C. T. (2017). Predictors of Hand-Foot Syndrome and Pyridoxine for Prevention of Capecitabine-Induced Hand-Foot Syndrome: A Randomized Clinical Trial. JAMA Oncology, 3(11), pp. 1538-1545. doi:10.1001/jamaoncol.2017.1269.
    Yap YS, et al. 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. PubMed PMID: 28715540.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Predictors of Hand-Foot Syndrome and Pyridoxine for Prevention of Capecitabine-Induced Hand-Foot Syndrome: A Randomized Clinical Trial. AU - Yap,Yoon-Sim, AU - Kwok,Li-Lian, AU - Syn,Nicholas, AU - Chay,Wen Yee, AU - Chia,John Whay Kuang, AU - Tham,Chee Kian, AU - Wong,Nan Soon, AU - Lo,Soo Kien, AU - Dent,Rebecca Alexandra, AU - Tan,Sili, AU - Mok,Zuan Yu, AU - Koh,King Xin, AU - Toh,Han Chong, AU - Koo,Wen Hsin, AU - Loh,Marie, AU - Ng,Raymond Chee Hui, AU - Choo,Su Pin, AU - Soong,Richie Chuan Teck, PY - 2017/7/18/pubmed PY - 2017/11/29/medline PY - 2017/7/18/entrez SP - 1538 EP - 1545 JF - JAMA oncology JO - JAMA Oncol VL - 3 IS - 11 N2 - 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. SN - 2374-2445 UR - https://www.unboundmedicine.com/medline/citation/28715540/Predictors_of_Hand-Foot_Syndrome_and_Pyridoxine_for_Prevention_of_Capecitabine-Induced_Hand-Foot_Syndrome:_A_Randomized_Clinical_Trial L2 - https://jamanetwork.com/journals/jamaoncology/fullarticle/10.1001/jamaoncol.2017.1269 DB - PRIME DP - Unbound Medicine ER -