title: VEGF G-1154A is predictive of severe acute toxicities during chemoradiotherapy for esophageal squamous cell carcinoma in Japanese patients.
abstract: 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 postoperative recurrences) were enrolled into this study. One course of treatment consisted of protracted venous infusions of 5-FU (400 mg/m2/24 hr for day 1-5 and 8-12) and cisplatin (40 mg/m2/3 hr on day 1 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 (AUC480h), and VEGF genotypes of T-1498C, G-1154A, C-634G, C-7T, C936T, and G1612A were evaluated. The mean value of AUC480h 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 AUC480h value of 5-FU was predictive of the clinical response.
authors.affiliation: Center for Integrative Education of Pharmacy Frontier (Frontier Education Center), Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan. sakaedat@pharm.kyoto-u.ac.jp
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaeda
authors.forename: Motohiro
authors.initials: M
authors.lastname: Yamamori
authors.forename: Akiko
authors.initials: A
authors.lastname: Kuwahara
authors.forename: Satoko
authors.initials: S
authors.lastname: Hiroe
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Okumura
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Okuno
authors.forename: Ikuya
authors.initials: I
authors.lastname: Miki
authors.forename: Naoko
authors.initials: N
authors.lastname: Chayahara
authors.forename: Noboru
authors.initials: N
authors.lastname: Okamura
authors.forename: Takao
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000628:therapy*; D002945:Cisplatin / Q000008:administration & dosage; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000628:therapy*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011110:Polymorphism, Genetic / Q000235:genetics; D011237:Predictive Value of Tests; D011878:Radiotherapy / Q000009:adverse effects*; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D002945:Cisplatin; D005472:Fluorouracil