Importance  Hand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment.

Objective  To compare the incidence and time to onset of grade 2 or greater HFS in patients receiving pyridoxine vs placebo and to identify biomarkers predictive of HFS.

Design, Setting, and Participants  This single-center, randomized double-blind, placebo-controlled phase 3 trial conducted at National Cancer Centre Singapore assessed whether oral pyridoxine could prevent the onset of grade 2 or higher HFS in 210 patients scheduled to receive single-agent capecitabine chemotherapy for breast, colorectal, and other cancers.

Interventions  Patients were randomized to receive concurrent pyridoxine (200 mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by sex and use in adjuvant or neoadjuvant vs palliative setting. Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine.

Main Outcomes and Measures  Primary end point was the incidence of grade 2 or higher HFS in patients receiving pyridoxine. Secondary end points included the time to onset (days) of grade 2 or higher HFS and identification of biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, as well as genetic polymorphisms with genome-wide arrays.

Results  In this cohort of 210 patients (median [range] age, 58 [26-82] years; 162 women) grade 2 or higher HFS occurred in 33 patients (31.4%) in the pyridoxine arm vs 39 patients (37.1%) in the placebo arm (P = .38). The median time to onset of grade 2 or higher HFS was not reached in both arms. In univariate analysis, the starting dose of capecitabine (odds ratio [OR], 1.99; 95% CI, 1.32-3.00; P = .001), serum folate levels (OR, 1.27; 95% CI, 1.10-1.47; P = .001), and red blood cell folate levels (OR, 1.25; 95% CI, 1.08-1.44; P = .003) were associated with increased risk of grade 2 or higher HFS. In multivariate analyses, serum folate (OR, 1.30; 95% CI, 1.12-1.52; P < .001) and red blood cell folate (OR, 1.28; 95% CI, 1.10-1.49; P = .001) were the only significant predictors of grade 2 or higher HFS. Grade 2 or higher HFS was associated with 300 DNA variants at genome-wide significance (P < 5 × 10⁻⁸), including a novel DPYD variant (rs75267292; P = 1.57 × 10⁻¹⁰), and variants in the MACF1 (rs183324967, P = 4.80 × 10⁻¹¹; rs148221738, P = 5.73 × 10⁻¹⁰) and SPRY2 (rs117876855, P < 1.01 × 10⁻⁸; rs139544515, P = 1.30 × 10⁻⁸) genes involved in wound healing.

Conclusions and Relevance  Pyridoxine did not significantly prevent or delay the onset of grade 2 or higher HFS. Serum and red blood cell folate levels are independent predictors of HFS.

Trial Registration  clinicaltrials.gov Identifier: NCT00486213

重要性  手足综合征 (HFS) 是卡培他滨治疗的常见不良反应。

目的  比较接受吡哆醇与安慰剂的患者发生 2 级或更高 HFS 的发生率和时间，并确定预测 HFS 的生物标志物。

设计、设置和参与者  这项在新加坡国家癌症中心进行的单中心、随机双盲、安慰剂对照的 3 期试验评估了口服吡哆醇是否可以预防 210 名计划接受单药治疗的患者发生 2 级或更高的 HFS。用于乳腺癌、结肠直肠癌和其他癌症的药物卡培他滨化学疗法。

干预  患者随机接受每日并发吡哆醇（200 mg）或安慰剂，最多 8 个周期的卡培他滨，按性别分层，用于辅助或新辅助与姑息治疗。患者退出研究发生 2 级或更高 HFS 或停止卡培他滨。

主要结果和措施  主要终点是接受吡哆醇的患者中 2 级或更高 HFS 的发生率。次要终点包括 2 级或更高 HFS 的发病时间（天）和预测 HFS 的生物标志物的鉴定，包括基线叶酸和维生素 B12 水平，以及全基因组阵列的遗传多态性。

结果  在这 210 名患者（中位 [范围] 年龄，58 [26-82] 岁；162 名女性）队列中，吡哆醇组 33 名患者（31.4%）与 39 名患者（37.1%）发生 2 级或更高的 HFS安慰剂组 ( P  = .38)。两组均未达到 2 级或更高 HFS 发作的中位时间。在单变量分析中，卡培他滨的起始剂量（优势比 [OR]，1.99；95% CI，1.32-3.00；P  = .001），血清叶酸水平（OR，1.27；95% CI，1.10-1.47；P  = .001）和红细胞叶酸水平（OR，1.25；95% CI，1.08-1.44；P  = .003）与 2 级或更高 HFS 的风险增加相关。在多变量分析中，血清叶酸（OR，1.30；95% CI，1.12-1.52；P < .001) 和红细胞叶酸 (OR, 1.28; 95% CI, 1.10-1.49; P  = .001) 是 2 级或更高 HFS 的唯一显着预测因子。2 级或更高的 HFS 与全基因组显着性的 300 个 DNA 变体相关 ( P  < 5 × 10 ^-8 )，包括一个新的DPYD变体 ( rs75267292 ; P  = 1.57 × 10 ^-10 ) 和MACF1中的变体( rs183324967 , P  = 4.80 × 10 ^-11 ; rs148221738 , P  = 5.73 × 10 ^-10 ) 和SPRY2 ( rs117876855 , P < 1.01 × 10 ^-8 ; rs139544515 , P  = 1.30 × 10 ^-8 ) 参与伤口愈合的基因。

结论和相关性  吡哆醇没有显着预防或延迟 2 级或更高级别 HFS 的发作。血清和红细胞叶酸水平是 HFS 的独立预测因子。

试验注册  临床试验.gov 标识符：NCT00486213