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

Abajo A, Rodriguez J, Bitarte N, Zarate R, Boni V, Ponz M, Chopitea A, Bandres E, Garcia-Foncillas J - Br. J. Cancer (2010)

Bottom Line: Diarrhoea and neutropenia were the DLT.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Pharmacogenomics, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.

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.

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Related in: MedlinePlus

Kaplan–Meier curves for time to progression (TTP) (A) and overall survival (OS) (B) according to circulating vascular endothelial growth factor (VEGF) serum levels and according to the number of VEGF favourable genotypes (C) TTP outcome stratified on basis of the number of favourable clinical and molecular factors (D).
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fig1: Kaplan–Meier curves for time to progression (TTP) (A) and overall survival (OS) (B) according to circulating vascular endothelial growth factor (VEGF) serum levels and according to the number of VEGF favourable genotypes (C) TTP outcome stratified on basis of the number of favourable clinical and molecular factors (D).

Mentions: VEGF levels were dichotomised into two categories around the median value (platelet-normalised VEGF baseline levels > or <3) to better describe its association with survival times. A significant relationship was found between platelet-normalised VEGF baseline levels and TTP (P=0.02; Breslow test) (Figure 1A), with a median TTP of 2.4 (0.83–3.89) months and 8.2 (5.1–11.2) months for patients with high and low VEGF baseline levels, respectively. A significant association was also found between platelet-normalised VEGF baseline levels and OS (P=0.034; log-rank test) (Figure 1B), with a median OS of 5.2 (0.27–10.1) months and 21.3 (0.3–47.3) months for patients with high and low VEGF baseline levels, respectively.


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

Abajo A, Rodriguez J, Bitarte N, Zarate R, Boni V, Ponz M, Chopitea A, Bandres E, Garcia-Foncillas J - Br. J. Cancer (2010)

Kaplan–Meier curves for time to progression (TTP) (A) and overall survival (OS) (B) according to circulating vascular endothelial growth factor (VEGF) serum levels and according to the number of VEGF favourable genotypes (C) TTP outcome stratified on basis of the number of favourable clinical and molecular factors (D).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2990573&req=5

fig1: Kaplan–Meier curves for time to progression (TTP) (A) and overall survival (OS) (B) according to circulating vascular endothelial growth factor (VEGF) serum levels and according to the number of VEGF favourable genotypes (C) TTP outcome stratified on basis of the number of favourable clinical and molecular factors (D).
Mentions: VEGF levels were dichotomised into two categories around the median value (platelet-normalised VEGF baseline levels > or <3) to better describe its association with survival times. A significant relationship was found between platelet-normalised VEGF baseline levels and TTP (P=0.02; Breslow test) (Figure 1A), with a median TTP of 2.4 (0.83–3.89) months and 8.2 (5.1–11.2) months for patients with high and low VEGF baseline levels, respectively. A significant association was also found between platelet-normalised VEGF baseline levels and OS (P=0.034; log-rank test) (Figure 1B), with a median OS of 5.2 (0.27–10.1) months and 21.3 (0.3–47.3) months for patients with high and low VEGF baseline levels, respectively.

Bottom Line: Diarrhoea and neutropenia were the DLT.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Pharmacogenomics, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.

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.

Show MeSH
Related in: MedlinePlus