title: Modified FOLFOX-6 chemotherapy in advanced gastric cancer: Results of phase II study and comprehensive analysis of polymorphisms as a predictive and prognostic marker.
abstract: BACKGROUND
  The objective of this study was to evaluate the efficacy and toxicity of infusional 5-fluorouracil (5-FU), folinic acid and oxaliplatin (modified FOLFOX-6) in patients with advanced gastric cancer (AGC), as first-line palliative combination chemotherapy. We also analyzed the predictive or prognostic value of germline polymorphisms of candidate genes associated with 5-FU and oxaliplatin.
  
  
  METHODS
  Seventy-three patients were administered a 2 hour infusion of oxaliplatin (100 mg/m2) and folinic acid (100 mg/m2) followed by a 46 hour continuous infusion of 5-FU (2,400 mg/m2). Genomic DNA from the patients' peripheral blood mononuclear cells was extracted. Ten polymorphisms within five genes were investigated including TS, GSTP, ERCC, XPD and XRCC.
  
  
  RESULTS
  The overall response rate (RR) was 43.8%. Median time to progression (TTP) and overall survival (OS) were 6.0 months and 12.6 months, respectively. Toxicities were generally tolerable and manageable. The RR was significantly higher in patients with a 6-bp deletion homozygote (-6 bp/-6 bp) in TS-3'UTR (55.0% vs. 30.3% in +6 bp/+6 bp or +6 bp/-6 bp, p = 0.034), and C/A or A/A in XPD156 (52.0% vs. 26.1% in C/C, p = 0.038). The -6 bp/-6 bp in TS-3'UTR was significantly associated with a prolonged TTP and OS. In a multivariate analysis, the 6-bp deletion in TS-3'UTR was identified as an independent prognostic marker of TTP (hazard ratio = 0.561, p = 0.032).
  
  
  CONCLUSIONS
  Modified FOLFOX-6 chemotherapy appears to be active and well tolerated as first line chemotherapy in AGC patients. The 6-bp deletion in TS-3'UTR might be a candidate to select patients who are likely to benefit from 5-FU based modified FOLFOX-6 in future large scale trial.
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. bhumsuk@medimail.co.kr
authors.forename: Bhumsuk
authors.initials: B
authors.lastname: Keam
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Han
authors.forename: Hye Seon
authors.initials: HS
authors.lastname: Ham
authors.forename: Min A
authors.initials: MA
authors.lastname: Kim
authors.forename: Do-Youn
authors.initials: DY
authors.lastname: Oh
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.forename: Tae-You
authors.initials: TY
authors.lastname: Kim
authors.forename: Dae Seog
authors.initials: DS
authors.lastname: Heo
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
mesh_terms: D020413:3' Untranslated Regions; D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D005838:Genotype; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D013274:Stomach Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D004273:DNA, Neoplasm; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil