Dose-finding study and pharmacogenomic analysis of fixed-rate infusion of gemcitabine, irinotecan and bevacizumab in pretreated metastatic colorectal cancer patients

Abstract

Background:To determine the dose-limiting toxicity (DLT), maximum tolerated dose, recommended dose (RD) and preliminary evidence of activity of escalating doses of irinotecan (CPT-11) fixed-dose-rate infusional gemcitabine (FDR-GMB) and bevacizumab in pretreated metastatic colorectal cancer (mCRC) patients. Pharmacogenomic analysis was performed to investigate the association between VEGF single-nucleotide polymorphisms and clinical outcome.Patients and methods:A total of 89 mCRC patients were recruited in a two-step study design; 28 were included in the dose-finding study and 59 in the pharmacogenomic analysis. The FDR-GMB of 1000 mg m–2, bevacizumab 5 mg kg–1 and CPT-11 doses ranging from 100 to 160 mg m–2 were explored. The VEGF protein serum levels were quantified by EIA. Allelic discrimination was performed to genotype polymorphisms in the VEGF gene.Results:CPT-11 RD was 150 mg m–2. Diarrhoea and neutropenia were the DLT. After a median follow-up of 42 months, the median time to progression (TTP) and overall survival were 5.2 and 19.9 months, respectively. VEGF levels were significantly correlated with VEGF-2578AA and VEGF-460CC genotypes, and a trend was observed with VEGF+405GG genotype. The presence of any of these genotypes correlated with a longer median TTP (8.8 vs 4.5 months, P=0.04).Conclusion:The triplet combination tested in this study is effective and well tolerated. A possible predictive role for VEGF gene polymorphisms and baseline VEGF circulating levels is suggested.

Vascular endothelial growth factor polymorphisms and clinical outcome in colorectal cancer patients treated with irinotecan-based chemotherapy and bevacizumab

“…A definitive association between VEGF levels and patients' outcome has not been convincingly demonstrated thus far. In the aforementioned study, which included colorectal cancer patients, 27 significantly longer median survival times were found in patients with low baseline VEGF serum levels. Similarly, in a phase-II study, which investigated the combination of bevacizumab and vinorelbine as treatment for refractory breast cancer, lower levels of baseline plasma VEGF were associated with longer time to progression.…”

“…26 In a recent study including 89 pretreated metastatic colorectal cancer patients treated with irinotecan, gemcitabine and bevacizumab, low VEGF level-associated SNPs were correlated with a better clinical outcome in terms of time to disease progression. 27 Moreover, in the analysis conducted by Schneider et al in breast cancer patients, the VEGFÀ2578 AA and VEGFÀ1154 AA genotypes were associated with a superior OS. These genotypes have been associated with a trend for lower VEGF expression in human breast cancer specimens.…”

“…Thus far, data regarding the potential association between VEGF genotypes and outcome in colorectal cancer patients receiving bevacizumab-based treatment are extremely limited, and based on studies with relatively small number of patients. 27,29 Abbreviations: CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; PS, performance status; VEGF, vascular endothelial growth factor.…”

Angiogenesis as a therapeutic target in breast cancer

“…The VEGF-1154 GG genotype has been correlated with higher production of VEGF [62]. In another study in metastatic colorectal cancer evaluating the administration of irinotecan, gemcitabine and bevacizumab in pretreated patients, low VEGF level-associated single nucleotide polymorphisms (SNPs) were associated with an improved time to disease-progression [63]. Additionally, in the above mentioned study considering breast cancer patients [59], the VEGF-1154 AA and VEGF-2578 AA genotypes were associated with a trend for lower VEGF expression.…”

Tumor characteristics and metastatic sites may predict bevacizumab efficacy in the first-line treatment of metastatic colorectal cancer

“…Numerous markers, including CD133 (11), circulating tumor cell count (12), lactate dehydrogenase level (22), carbonic anhydrase 9 (23), CA 125 (24), CA 19.9 (25), visceral fat area (26), SHMT1 polymorphism (27), VEGF gene polymorphisms and baseline VEGF circulating level (13,28,29), were reported as potential predictors of angiogenesis blockade. Although the biology of tumor angiogenesis is complex, there is a biological rationale to support such observations.…”