Favorable genetic polymorphisms predictive of clinical outcome of chemoradiotherapy for stage II/III esophageal squamous cell carcinoma in Japanese

Abstract

15088 Background: A 5-fluorouracil (5-FU)/cisplatin (CDDP)-based chemoradiotherapy (CRT) was proposed for esophageal cancer patients. Currently, there is an urgent need to establish a methodology to decide which is preferable for a patient, i.e., surgical treatment or CRT, especially for Stage II to III tumors defined as resectable. This study was performed to find the genetic factors predictive of clinical outcome to a 5-FU/ CDDP-based CRT in Japanese patients with locally advanced esophageal squamous cell carcinoma (ESCC). Methods: Thirty-one patients with Stage I-IVa ESCC (I/II/III/IVa = 7/7/14/3) were enrolled in this study. One course of treatment consisted of protracted venous infusions of 5-FU (400 mg/m2/24 h for day 1–5 and 8–12), CDDP (40 mg/m2/3 h on day 1 and 8) and radiation (2 Gy/day on day 1–5, 8–12 and 15–19), and a 2nd course was successively repeated after a 2-week interval. A total of 8 measurements of the plasma concentration of 5-FU were made using high performance liquid chromatography. Genetic polymorphisms examined herein included those in the genes coding thymidylate synthase (TS), glutathione S-transferase P1 (GSTP1) and multi-drug resistant transporter MDR1/P-glycoprotein. Results: The complete response rate depended on Stage (p = 0.001), but the analysis was not sufficiently powered to reach a level of statistical significance for the 2-year survival rate (p = 0.061). For Stage II/III patients, to have 2 or 3 polymorphisms of 3R/3R of 5’-TSER, a 6bp of 3’-TSUTR, and GSTP1-Leu105Val resulted in an extensively longer survival (p =0.0197), although no difference was found between 2 groups, with respect to the plasma concentrations of 5-FU and clinical or pathological characteristics. Conclusions: The genetic prognostic index may allow predictions of the clinical outcome of a 5- FU/CDDP-based CRT in Stage II/III ESCC patients. Now, we are analyzing the contribution of genetic polymorphisms of cytokines, including tumor necrosis factor a. No significant financial relationships to disclose.