1 research outputs found
Oxaliplatin, irinotecan and capecitabine as first-line therapy in metastatic colorectal cancer (mCRC): a dose-finding study and pharmacogenomic analysis
A dose-finding study was performed to evaluate the dose-limiting
toxicity (DLT), maximum-tolerated dose (MTD) and the recommended dose (RD) of
escalating the doses of capecitabine and fixed doses of irinotecan and
oxaliplatin on a biweekly schedule for metastatic colorectal cancer patients
(mCRC). A pharmacogenomic analysis was performed to investigate the association
between SNPs and treatment outcome. METHODS: Eighty-seven chemotherapy-naive mCRC
patients were recruited through a two-step study design; 27 were included in the
dose-finding study and 60 in the pharmacogenomic analysis. Oxaliplatin (85 mg
m(-2)) and CPT-11 (150 mg m(-2)), both on day 1, and capecitabine doses ranging
from 850 to 1500 mg m(-2) bid on days 1-7 were explored. Peripheral blood samples
were used to genotype 13 SNPs in 10 genes related to drug metabolism or efficacy.
Univariate and multivariate Cox analysis was performed to examine associations
between SNPs, ORR and PFS. RESULTS: The capecitabine RD was 1000 mg m(-2) bid.
Diarrhoea and neutropenia were the DLTs. After a median follow-up of 52.5 months,
the median PFS and OS were 12 (95% CI; 10.6-13.4) and 27 months (95% CI;
17.2-36.8), respectively.The GSTP1-G genotype, the Kohne low-risk category and
use of a consolidation approach strongly correlated with decreased risk of
progression. Patients with all favourable variables showed a median PFS of 42
months vs 3.4 months in the group with all adverse factors. A superior clinical
response was obtained in patients with one GSTP1-G allele as compared with
GSTP1-AA carriers (P=0.004). CONCLUSION: First-line therapy with oxaliplatin,
irinotecan and capecitabine is efficient and well-tolerated. The GSTP1
polymorphism A>G status was significantly associated with ORR and PFS in mCRC
treated with this triplet therapy