HER2阴性早期乳腺癌大约占全部乳腺癌的80%至85%，化疗后卡培他滨辅助治疗可显著改善此类患者生存结局。不过，手足综合征是限制卡培他滨剂量的常见不良反应，分为1至3级，发生于29%至73%的患者，特征为手掌和足底出现红斑、神经疼痛、水肿和感觉异常，逐渐发展为脱屑、糜烂、溃疡和水疱。虽然不超过3级的手足综合征并不致命，但是严重影响生活质量，并且通常需要减少或停止卡培他滨治疗，这将影响剂量强度和整体治疗效果。虽然维生素B6、塞来昔布、尿素乳膏已被研究用于预防卡培他滨相关手足综合征，但是维生素B6并未显著降低手足综合征风险，尿素乳膏预防2级或3级手足综合征的作用仍不确定，塞来昔布由于心血管安全问题而长期用药受限导致指南推荐级别相对较低。因此，迫切需要更有效、更安全的治疗方案预防HER2阴性早期乳腺癌患者卡培他滨辅助治疗发生2级或3级手足综合征。既往研究表明，小纤维神经病变可能是卡培他滨诱发手足综合征手掌足底神经疼痛和感觉异常的潜在病因。钴胺素（维生素B12）活性形式之一甲钴胺问世于1963年，通过甲基化循环促进神经突生长和神经元存活可缓解神经疼痛和感觉异常，临床常用于治疗维生素B12缺乏所致巨幼红细胞贫血、糖尿病周围神经病变和化疗所致神经毒性反应，已于2018年进入《国家基本药物目录》，目前京东、美团、饿了么的零售价格每盒（0.5毫克×20片）仅几元至几十元。2013年12月至2015年2月，山东大学附属山东省立医院对80例胃癌、结直肠癌或乳腺癌患者大剂量维生素B6±甲钴胺防治卡培他滨所致手足综合征进行随机比较，结果发现可减少发生率、延长发生时间。2017年8月至2018年10月，南方医科大学南方医院51例晚期乳腺癌患者回顾分析表明，甲钴胺对卡培他滨所致手足综合征有防治作用。2018年1月至2020年1月，厦门大学附属妇女儿童医院对176例卡培他滨化疗女性乳腺癌患者维生素B6±甲钴胺防治卡培他滨所致手足综合征进行随机比较，结果发现能够有效降低发生率，提高生活能力及生活质量。那么，甲钴胺能否降低HER2阴性早期乳腺癌卡培他滨辅助治疗患者手足综合征风险？
2025年9月11日，国际四大医学期刊之一、英国医学会官方期刊《英国医学杂志》在线发表中山大学孙逸仙纪念医院、中山大学公共卫生学院、中山大学肿瘤防治中心、肇庆市第一人民医院、广州医科大学第一附属医院、北京大学深圳医院、深圳市前海蛇口自贸区医院、东莞市人民医院、广州医科大学第二附属医院的2020-KY-007研究报告，首次对甲钴胺预防HER2阴性早期乳腺癌卡培他滨辅助治疗患者手足综合征的有效性和安全性进行多中心安慰剂双盲随机对照。这是继北京PHILA研究、上海BCTOP-T-A01研究之后，《英国医学杂志》创刊185年以来第三次发表中国乳腺癌随机对照临床研究，也是第一次发表中国乳腺癌药物不良反应干预研究。
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2020-KY-007 (NCT05165069): The Efficacy and Safety of Mecobalamin in the Prevention of Capecitabine Induced Hand Foot Syndrome
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Official Title: The Efficacy and Safety of Mecobalamin in the Prevention of Capecitabine Induced Hand Foot Syndrome in Breast Cancer Patients: a Multicenter, Phase III, Randomized, Double-blind, Controlled Trial
该研究于2022年1月至2024年2月在中国七家医院入组年龄18～75岁经病理证实为HER2阴性早期乳腺癌计划术后卡培他滨辅助治疗女性234例，按1比1随机分为两组，每天三次口服甲钴胺0.5毫克或安慰剂，疗程最长24周。主要终点为全部患者卡培他滨治疗期间首次≥2级手足综合征发生率。
结果，甲钴胺组（117例）与安慰剂组（117例）相比：
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≥2级手足综合征发生率：14.5%比29.1%（风险差：-14.5%，95%置信区间：-24.9%至-4.1%；单侧P=0.003）
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手足综合征所致卡培他滨减量或停药比例：7.7%比13.7%（风险差：-6.0%，95%置信区间：-13.9%至1.9%）
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其他不良事件发生率：75.2%比81.2%
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未见甲钴胺相关不良事件
根据亚组分析，无论患者年龄、绝经状态、乳腺癌分期、激素受体、既往化疗方案、卡培他滨起始剂量如何，结果都有利于甲钴胺。
因此，该研究结果表明，HER2阴性早期乳腺癌术后卡培他滨辅助治疗女性，口服甲钴胺与安慰剂相比，≥2级手足综合征发生率显著降低14.5%，手足综合征所致卡培他滨减量或停药比例降低6%，其他不良事件发生率相似，而且未见意外安全问题，支持对此类患者用甲钴胺预防卡培他滨相关严重手足综合征。该研究还表明，中国乳腺癌高水平研究已经从生存数量拓展至生存质量。
BMJ. 2025 Sep 11;390:e084290. IF: 42.7
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.
Xia Y, Zhu Y, Ling L, Xu F, Yang Y, Ye J, Tan W, Chen Z, Liu Q, Wei W, Zhang J, Zhang A, Zhang L, Song E, Gong C.
Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; School of Public Health, Sun Yat-sen University, Guangzhou, China; Sun Yat-sen University Cancer Centre, Guangzhou, China; The First People’s Hospital of Zhaoqing, Zhaoqing, China; The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Peking University Shenzhen Hospital, Shenzhen, China; Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, China; Dongguan People’s Hospital, Dongguan, China; The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
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
PMID: 40935571
DOI: 10.1136/bmj-2025-084290