Oral vitamin B12 supplements may offer an additional way to prevent hand-foot syndrome, a common side effect of chemotherapy with capecitabine, a clinical trial suggested.

The phase 3 trial, conducted at seven hospitals in China, found that daily B12 supplements halved the rate of grade 2 or higher hand-foot syndrome among women receiving adjuvant capecitabine for early breast cancer. And there was no indication that the vitamin increased the toxicity of chemotherapy or caused treatment-specific side effects, the researchers reported in BMJ.

The results are “quite impressive,” said Eleonora Teplinsky, MD, head of Breast and Gynecologic Medical Oncology, Valley-Mount Sinai Comprehensive Cancer Care, Paramus, New Jersey, and an American Society of Clinical Oncology expert in breast cancer.

Teplinsky, who was not involved in the research, noted that hand-foot syndrome can be debilitating for patients — affecting quality of life and often requiring capecitabine dose reductions or interruptions.

“Even though [vitamin B12] didn’t eliminate hand-foot syndrome, reducing the severity of grade 2 and up is really clinically meaningful,” Teplinsky told Medscape Medical News.

Hand-foot syndrome affects up to 73% of patients receiving capecitabine, a standard oral chemotherapy drug for colorectal and breast cancers. While grade 1 hand-foot syndrome is self-limiting, causing erythema and tingling or numbness in the palms and soles, more severe cases are painful and can interfere with daily functioning — sometimes progressing to bleeding blisters and ulcers.

The pathophysiology of hand-foot syndrome is unclear, but research suggests it involves small fiber neuropathy. Methylcobalamin, a form of B12, is widely used in Asia as a treatment for peripheral neuropathies. So researchers led by Yuan Xia, of Sun Yat-sen University, Guangzhou, China, hypothesized that the vitamin might help prevent hand-foot syndrome.

To investigate, they recruited 234 patients with early-stage, HER2-negative breast cancer who were scheduled to begin capecitabine treatment. Patients were randomly assigned to take oral methylcobalamin, at a dose of 0.5 mg three times a day, or placebo tablets for a maximum of 24 weeks. That methylcobalamin dose is substantially higher than the daily recommended amount of vitamin B12 for adults — but it is in line with dosages used to treat neuropathies, according to Xia’s team.

Patients were assessed for hand-foot syndrome every 3 weeks until completion of the eighth capecitabine cycle or withdrawal from the study.

Overall, grade 2 or higher hand-foot syndrome occurred in 17 (14.5%) of 117 patients in the vitamin B12 group compared with 34 (29.1%) of 117 patients in the placebo group (risk difference, -14.5%, P = .003). Grade 1 cases, meanwhile, were numerically higher in the vitamin B12 group (36.8% vs 28.2% in the placebo group).

As for safety, the two groups had a similar incidence of other adverse events during chemotherapy (75.2% in the vitamin B12 group and 81.2% in the placebo group), most commonly lymphopenia, leukopenia, and anemia. There was no indication that vitamin B12 increased the toxicity of chemotherapy — an important finding, Teplinsky noted.

Until recently, the only proven intervention for hand-foot syndrome was the oral anti-inflammatory celecoxib (Celebrex). But it was rarely used due to safety concerns.

Two years ago, however, the D-TORCH trial showed that diclofenac gel, a common remedy for osteoarthritis pain, reduced the incidence of hand-foot syndrome by 75%. The finding was hailed as “practice-changing,” given that topical diclofenac has been safely used for years and is widely available as a cheap generic.

According to Teplinsky, vitamin B12 might offer another option that is “easy” for patients to take.

“I think I would definitely consider it,” she said. “We are always looking for supportive interventions that can help.”

The study was funded by government grants and Sun Yat-sen University. Teplinsky disclosed having no disclosures, and the study authors reported having no disclosures.