VEGF G-1 154A is predictive of severe acute toxicities during chemoradiotherapy for esophageal squamous cell carcinoma in Japanese patients

This study was conducted to evaluate the association between systemic exposure to 5-fluorouracil (5-FU) and genetic polymorphisms of vascular endothelial growth factor (VEGF) with clinical outcomes to a 5-FU/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma (ESCC). Forty-nine patients with ESCC (I/II/III/IVa = 11/9/17/7, with 5 post-operative recurrences) were enrolled into this study. One course of treatment consisted of protracted venous infusions of 5-FU (400 mg/m(2)/24 hr for day 1-5 and 8-12) and cisplatin (40 mg/m(2)/3 hr on day I and 8), and radiation (2 Gy/day on day 1-5, 8-12, and 15-19); a second course was repeated after a 2 week interval. A total of eight measurements of the plasma concentration of 5-FU were made per patient to evaluate its systemic exposure as area under the concentration time curve for 480 hours (AUC(480h)), and VEGF genotypes of T-1498C, G-1154A, C-634G, C-7T, C936T, and G1612A were evaluated. The mean value of AUC(480h) in the patients with a complete response was 58.7 +/- 16.8 mg*h/L, which was higher than that in the others, 49.0 +/- 10.9 mg*h/L (P = 0.029), whereas no such association was found for severe acute toxicities. VEGF genotype was not associated with the clinical response, whereas VEGF G-1154A resulted in severe acute leukopenia (P = 0.042) and severe acute cheilitis (P = 0.025). In conclusion, VEGF G-1154A was a predictor of severe acute toxicities during 5-FU/cisplatin-based chemoradiotherapy in Japanese ESCC patients, whereas the AUC(480h), value of 5-FU was predictive of the clinical response.