Predictors of Hand-Foot Syndrome and Pyridoxine for Prevention of Capecitabine-Induced Hand-Foot Syndrome: A Randomized Clinical Trial

• Published in: JAMA oncology Vol. 3; no. 11; p. 1538
• Main Authors: Yap, Yoon-Sim, Kwok, Li-Lian, Syn, Nicholas, Chay, Wen Yee, Chia, John Whay Kuang, Tham, Chee Kian, Wong, Nan Soon, Lo, Soo Kien, Dent, Rebecca Alexandra, Tan, Sili, Mok, Zuan Yu, Koh, King Xin, Toh, Han Chong, Koo, Wen Hsin, Loh, Marie, Ng, Raymond Chee Hui, Choo, Su Pin, Soong, Richie Chuan Teck
• Format: Journal Article
• Language: English
• Published: United States 01.11.2017
• Subjects: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic - adverse effects; Asians - genetics; Capecitabine - adverse effects; Chi-Square Distribution; Dihydrouracil Dehydrogenase (NADP) - genetics; Double-Blind Method; Drug Administration Schedule; Female; Folic Acid - blood; Genetic Predisposition to Disease; Genome-Wide Association Study; Hand-Foot Syndrome - blood; Hand-Foot Syndrome - ethnology; Hand-Foot Syndrome - genetics; Hand-Foot Syndrome - prevention & control; Humans; Incidence; Intracellular Signaling Peptides and Proteins - genetics; Kaplan-Meier Estimate; Logistic Models; Male; Membrane Proteins - genetics; Microfilament Proteins - genetics; Middle Aged; Multivariate Analysis; Neoplasms - blood; Neoplasms - drug therapy; Neoplasms - ethnology; Odds Ratio; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Predictive Value of Tests; Pyridoxine - administration & dosage; Risk Assessment; Risk Factors; Severity of Illness Index; Singapore - epidemiology; Time Factors; Treatment Outcome; Singapore
• ISSN: 2374-2445
• DOI: 10.1001/jamaoncol.2017.1269

Hand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment. 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. 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. 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 Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine. 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. 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. 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. clinicaltrials.gov Identifier: NCT00486213.