Modified FOLFOX-6 chemotherapy in advanced gastric cancer: Results of phase II study and comprehensive analysis of polymorphisms as a predictive and prognostic marker.
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.
Keam
Bhumsuk
B
Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. bhumsuk@medimail.co.kr
Im
Seock-Ah
SA
Han
Sae-Won
SW
Ham
Hye Seon
HS
Kim
Min A
MA
Oh
Do-Youn
DY
Lee
Se-Hoon
SH
Kim
Jee Hyun
JH
Kim
Dong-Wan
DW
Kim
Tae-You
TY
Heo
Dae Seog
DS
Kim
Woo Ho
WH
Bang
Yung-Jue
YJ
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
D020413:3' Untranslated Regions; D004273:DNA, Neoplasm; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil