Oral methylcobalamin eases hand-foot syndrome in breast cancer patients

The use of oral methylcobalamin is effective in lessening the severity of hand-foot syndrome, without any serious safety concerns, among women with HER2 negative early breast cancer who are treated with adjuvant capecitabine, a study has shown.

“These findings support the use of methylcobalamin to prevent capecitabine-associated severe hand-foot syndrome in women with HER2 negative early breast cancer,” the investigators said.

This multicentre, double-blind, randomized, placebo-controlled phase III trial was conducted in seven hospitals in China between January 2022 and February 2024. Women with pathologically confirmed HER2 negative early breast cancer who were scheduled to receive adjuvant capecitabine treatment were included in the study.

The investigators randomized 234 eligible patients to receive methylcobalamin (n=117) at a dose of 0.5 mg orally, three times daily, or placebo (n=117) for a maximum of 24 weeks. They included these participants in the intention-to-treat and safety analyses.

Grade ≥2 hand-foot syndrome, the primary outcome, occurred less in the methylcobalamin group than in the placebo group (17 [14.5 percent] vs 34 [29.1 percent]; risk difference, –14.5 percent, 95 percent confidence interval [CI], –24.9 to –4.1; p=0.003). [BMJ 2025;390:e084290]

Moreover, the rate of reduction or discontinuation of capecitabine treatment because of hand-foot syndrome was lower in the methylcobalamin group (7.7 percent vs 13.7 percent; risk difference, –6.0 percent, 95 percent CI, –13.9 to 1.9).

The safety profile of oral methylcobalamin was satisfactory, showing a similar incidence of any other adverse events when compared with placebo (88 [75.2 percent] vs 95 [81.2 percent]). In addition, adverse events specific to methylcobalamin did not occur.

“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 investigators said.

Potential causes

Based on existing literature, capecitabine-induced hand-foot syndrome is potentially caused by raised levels of thymidine phosphorylase in the palms and soles, upregulation of the cyclooxygenase 2 enzyme, and small fibre neuropathy. [J Clin Neuromuscul Dis 2006;7:128-132; Br J Clin Pharmacol 2008;66:88-95; Oncology (Williston Park) 2002;16(Suppl 14):31-37]

“Of these, small fibre neuropathy is considered a probable cause of the neuropathic pain, dysesthesias, paraesthesia, and temperature intolerance associated with capecitabine-induced hand-foot syndrome,” according to the investigators.

In line with this, methylcobalamin was found to enhance Erk 1/2 and Akt activities through the methylation cycle to promote nerve regeneration and reduce symptoms of neuropathic pain, paraesthesia, and heaviness. [Neural Plast 2013;2013:424651; Exp Neurol 2010;222:191-203; Nutr Cancer 2023;75:33-47]

“The precise underlying mechanism of methylcobalamin preventing capecitabine-induced hand-foot syndrome requires further confirmation,” the investigators said.

Topical treatment

Urea-based cream is another effective treatment for hand-foot syndrome. An open-label trial of 152 patients showed that urea-based cream reduced the incidence of any-grade hand-foot syndrome compared with an antioxidant cream (22.4 percent vs 39.5 percent; p=0.02). [J Clin Oncol 2015;33:2444-2449]

"However, its effectiveness in lowering the risk of grade 2 or 3 hand-foot syndrome is uncertain,” the investigators said. “Furthermore, topical treatments might be inconvenient for patients.”