Oxaliplatin, irinotecan and capecitabine as first-line therapy in metastatic colorectal cancer (mCRC): a dose-finding study and pharmacogenomic analysis

Abstract

BACKGROUND: 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-naïve 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 À2 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 Kö hne 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 ¼ 0.004). CONCLUSION: First-line therapy with oxaliplatin, irinotecan and capecitabine is efficient and well-tolerated. The GSTP1 polymorphism A4G status was significantly associated with ORR and PFS in mCRC treated with this triplet therapy.

Genetic variants in the glutathione S-transferase genes and survival in colorectal cancer patients after chemotherapy and differences according to treatment with oxaliplatin

“…However, our observation of a nonsignificantly increased OS in carriers of the valine is in accordance with previous reports of an association of the GSTP1 valine allele with increased survival (progression-free survival or OS) in CRC patients in general [7], as well as in patients with metastatic CRC treated with different chemotherapeutic regimens [8--11,13], although the results were significant only in two studies [8,11]. Other studies either found no association overall or decreased survival after chemotherapy in carriers of the GSTP1 valine carriers [7,8,13,15].…”

“…Genetic variants in three GST classes have been investigated for their influence on CRC survival, but the results have been inconclusive and often nonsignificant. The GSTP1 ile105val polymorphism has been associated with an increased overall survival (OS) in White CRC patients carrying the valine allele in six studies [7][8][9][10][11][12], but two other studies found no association at all [12][13][14] or even a decreased survival [15]. In patients receiving second-line oxaliplatin treatment, the GSTP1 polymorphism has been associated with prolonged survival [8], which is biologically plausible as the GSTP1 enzyme can prevent the formation of platinum DNA adducts [3].…”

Polymorphisms of GSTP1, ERCC2 and TS-3′UTR are associated with the clinical outcome of mFOLFOX6 in colorectal cancer patients

“…GSTP1 , GSTT1 and GSTM1 genotypes have been extensively studied for drug response, including oxaliplatin-based treatment (21–23). A single nucleotide polymorphism at codon 105 (A>G: Ile>Val) of GSTP1 affects enzyme activity (24).…”

“…A single nucleotide polymorphism at codon 105 (A>G: Ile>Val) of GSTP1 affects enzyme activity (24). Several studies have demonstrated that among MCRC patients receiving oxaliplatin-based treatment, patients with GSTP1 -105 A/G and G/G genotypes have a more favorable outcome compared with patients with the GSTP1 -105 A/A genotype (21–23). …”

Effects of MTHFR Genetic Polymorphisms on Toxicity and Clinical Response of Irinotecan-Based Chemotherapy in Patients with Colorectal Cancer

“…It is widely accepted that genetic variants in the MTHFR gene may modify the activity of the MTHFR enzyme, which in turn reduces the activity of MTHFR and causes an altered metabolism of folates (Stankova et al, 2008). Therefore, it was postulated that MTHFR genetic polymorphisms might influence the toxicity and clinical response of irinotecan-based chemotherapy in human cancers (Zarate et al, 2010). Currently, common polymorphisms (1298 A > C and 677 C/T) in the MTHFR gene have been reported to be closely associated with the toxicity and clinical responses of irinotecan-based chemotherapy in CRC patients (Glimelius et al, 2011;van HuisTanja et al, 2013).…”