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Data from: Effect of methylcobalamin on capecitabine-induced hand-foot syndrome in patients with HER2-negative early breast cancer: A multicentre, double-blind, randomised, placebo-controlled, phase 3 trial

Xia, Yuan1; Zhu, Yingying1; Ling, Li2; Xu, Fei3; Yang, Yaping1; Ye, Jinhui4; Tan, Weige5; Chen, Zouxiang1; Liu, Qiang1; Wei, Wei6; Zhang, Jun7; Zhang, Ailing8; Zhang, Lehong9; Song, Erwei1; Gong, Chang1

Research facility: Sun Yat-sen Memorial Hospital
Published Aug 19, 2025 on Dryad. https://doi.org/10.5061/dryad.gmsbcc31k

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Abstract

Our objective was to evaluate whether methylcobalamin could effectively and safely prevent hand-foot syndrome (HFS) in human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (EBC) patients receiving adjuvant capecitabine treatment. We conducted a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. The trials were conducted across seven hospitals in China between January 2022 and February 2024. Study participants were women aged 18 to 75 years with pathologically confirmed HER2-negative EBC who were scheduled to receive adjuvant capecitabine therapy. Eligible patients were randomly assigned in a 1:1 ratio to receive methylcobalamin at a dose of 0.5mg orally, three times daily, or a placebo for a maximum of 24 weeks. The primary endpoint was the incidence of grade ≥2 HFS at any time of the first occurrence during capecitabine treatment in the intention-to-treat analysis. 234 patients were randomly assigned to receive methylcobalamin (n=117) or placebo (n=117), who were included in the intention-to-treat analysis and safety analysis. The grade ≥2 HFS occurred in 17 (14.5%) of 117 patients with methylcobalamin versus 34 (29.1%) of 117 patients with placebo (risk difference −14.5%, 95% confidence interval −24.9% to −4.1%; one-side P=0.003). The rate of HFS-related reduction or discontinuation of capecitabine was 7.7% (9 of 117) in the methylcobalamin group and 13.7% (16 of 117) in the placebo group (risk difference −6.0%, 95% confidence interval −13.9% to 1.9%). Two groups showed similar incidence of any other adverse events (88 [75.2%] in the methylcobalamin group and 95 [81.2%] in the placebo group). No methylcobalamin-specific adverse events were observed. Oral methylcobalamin, compared to placebo, significantly lowered the severity of HFS by reducing the incidence of grade ≥2 HFS without unexpected safety concerns in women with HER2-negative EBC receiving adjuvant capecitabine treatment. The findings support the use of methylcobalamin to prevent capecitabine-associated severe HFS in this patient population. Trial is registered with ClinicalTrials.gov as NCT05165069.