Effects of gene polymorphisms on the risk of severe hyponatremia during DCF chemotherapy for patients with esophageal squamous cell carcinoma.

Combination chemotherapy using docetaxel, cisplatin and 5-fluorouracil (DCF) is a promising treatment option for patients with advanced esophageal squamous cell carcinoma (ESCC), although its clinical application is limited by severe systemic toxicities. There are no validated markers for predicting the adverse effects caused by this regimen. This pharmacogenetic study enrolled 57 patients with chemotherapy-naive advanced ESCC between July 2012 and March 2016 (UMIN000008462). All patients received at least one course of DCF chemotherapy (docetaxel, 60 mg/m2 on day 1; cisplatin, 70 mg/m2 on day 1; 5-fluorouracil, 600 mg/m2 on days 1-5). The associations between four gene polymorphisms (ERCC1 rs11615, GSTP1 rs1695, TYMS rs151264360 and XPD rs13181) and the development of grade 3/4 adverse events during the first course of chemotherapy were prospectively investigated. The patients had a median age of 66 years (range, 45-77 years) and the majority were male (51 males vs. 6 females). The treatment settings were neoadjuvant (47 patients), adjuvant (1 patient) and salvage (9 patients), with dose intensities of 100% (51 patients) or 80% (6 patients). The severe adverse events were leukopenia (70.2%), neutropenia (86.0%), febrile neutropenia (36.8%), acute kidney injury (29.1%) and hyponatremia (43.9%). Two polymorphisms were independently associated with the development of severe hyponatremia among patients carrying the minor allele (vs. patients with major homozygote genotype): TYMS 3'-UTR rs151264360 (odds ratio, 3.64; 95% confidence interval, 1.11-11.9) and XPD Lys751Gln rs13181 (odds ratio, 10.1; 95% confidence interval, 1.10-93.3). Therefore, the presence of the TYMS and XPD polymorphisms may aid in identifying patients with a high risk of developing severe hyponatremia during DCF chemotherapy.