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Clinical Trial
. 2025 Sep 11:390:e084290.
doi: 10.1136/bmj-2025-084290.

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

Yuan Xia  1   2 , Yingying Zhu  3 , Li Ling  3   4 , Fei Xu  5 , Yaping Yang  1   2 , Jinhui Ye  6 , Weige Tan  7 , Zouxiang Chen  3 , Qiang Liu  1   2 , Wei Wei  8 , Jun Zhang  9 , Ailing Zhang  10 , Lehong Zhang  11 , Erwei Song  1   2 , Chang Gong  12   2
Affiliations
Clinical Trial

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

Yuan Xia et al. BMJ. .

Abstract

Objective: To evaluate whether methylcobalamin could effectively and safely prevent hand-foot syndrome in patients with human epidermal growth factor receptor 2 (HER2) negative early breast cancer receiving adjuvant capecitabine treatment.

Design: Multicentre, double blind, randomised, placebo controlled, phase 3 trial.

Setting: Seven hospitals in China between January 2022 and February 2024.

Participants: Women aged 18-75 years with pathologically confirmed HER2 negative early breast cancer who were scheduled to receive adjuvant capecitabine treatment.

Interventions: Eligible patients were randomly assigned in a 1:1 ratio to receive methylcobalamin at a dose of 0.5 mg orally, three times daily, or a placebo for a maximum of 24 weeks.

Main outcome measures: The primary endpoint was the incidence of grade ≥2 hand-foot syndrome occurring for the first time during capecitabine treatment in the intention-to-treat analysis.

Results: 234 patients were randomly assigned to receive methylcobalamin (n=117) or placebo (n=117) and were included in the intention-to-treat and safety analysis. Grade ≥2 hand-foot syndrome occurred in 17 (14.5%) of 117 patients in the methylcobalamin group and 34 (29.1%) of 117 patients in the placebo group (risk difference -14.5%, 95% confidence interval -24.9% to -4.1%; one sided P value=0.003). The rate of reduction or discontinuation of capecitabine treatment because of hand-foot syndrome 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%). The 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.

Conclusions: Oral methylcobalamin significantly lowered the severity of hand-foot syndrome by reducing the incidence of grade ≥2 symptoms without unexpected safety concerns in women with HER2 negative early breast cancer who were receiving adjuvant capecitabine treatment. The findings support the use of methylcobalamin to prevent capecitabine associated severe hand-foot syndrome in this patient population.

Trial registration: ClinicalTrials.gov NCT05165069.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from National Science and Technology Major Project for the Prevention and Treatment of Cancer, Cardiovascular, Respiratory, and Metabolic Diseases, Noncommunicable Chronic Diseases-National Science and Technology Major Project of China, Fundamental Research Funds for the Central Universities, Sun Yat-sen University, Sun Yat-sen University Clinical Research 5010 Program, National Natural Science Foundation of China, Science and Technology Projects in Guangzhou, Guangdong Science and Technology Department, Project of The Beijing Xisike Clinical Oncology Research Foundation, Department of Natural Resources of Guangdong Province, the Science and Technology Planning Project of Guangdong Province, Guangzhou Science and Technology Program, High-tech, Major and Characteristic Technology Projects in Guangzhou Area, Guangdong Provincial Clinical Research Centre for Breast Diseases, and National Key R&D Program of China for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Figures

Fig 1
Fig 1
CONSORT (consolidated standards of reporting trials) diagram of trial
Fig 2
Fig 2
Subgroup analyses of incidence of grade ≥2 hand-foot syndrome. CI=confidence interval; TNM=tumour node metastasis
None
See this image and copyright information in PMC

References

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