Research article

Modified FOLFOX-6 chemotherapy in advanced gastric cancer: Results of phase II study and comprehensive analysis of polymorphisms as a predictive and prognostic marker

Bhumsuk Keam¹ , Seock-Ah Im^1,2 , Sae-Won Han¹ , Hye Seon Ham² , Min A Kim^2,3 , Do-Youn Oh^1,2 , Se-Hoon Lee^1,2 , Jee Hyun Kim^1,2 , Dong-Wan Kim^1,2 , Tae-You Kim^1,2 , Dae Seog Heo^1,2 , Woo Ho Kim^2,3 and Yung-Jue Bang^1,2

¹Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea

²Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea

³Department of pathology, Seoul National University Hospital, Seoul, South Korea

author email corresponding author email

BMC Cancer 2008, 8:148doi:10.1186/1471-2407-8-148

Published:	27 May 2008

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).

Conclusion

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.