Morgane Caulet1,2, Thierry Lecomte1,2, Olivier Bouché3, Jérôme Rollin2,4, Valérie Gouilleux-Gruart2,5, Nicolas Azzopardi2, Julie Léger6, Christophe Borg7, Jean-Yves Douillard8, Sylvain Manfredi9, Denis Smith10, Olivier Capitain11, Aurélie Ferru12, Driffa Moussata2, Eric Terrebone13, Gilles Paintaud1,14, David Ternant15,16. 1. Université François-Rabelais de Tours, CNRS, GICC UMR 7292, Tours, France. 2. Department of Gastroenterology, CHRU de Tours, Tours, France. 3. Department of Gastroenterology and Digestive Oncology, CHU de Reims, Reims, France. 4. Laboratory of Haematology-Haemostasis, CHU de Tours, Tours, France. 5. Laboratory of Immunology, CHU de Tours, Tours, France. 6. INSERM CIC 1415, CHU de Tours, Tours, France. 7. Department of Oncology, CHU Besançon, Besançon, France. 8. Centre René Gauducheau, Institut de Cancerologie, Nantes, France. 9. Department of Gastroenterology, CHU de Rennes, Rennes, France. 10. Department of Oncology, CHU de Bordeaux, Bordeaux, France. 11. Department of Medical Oncology, ICO, Angers, France. 12. Department of Medical Oncology, CHU de Poitiers, Poitiers, France. 13. Department of Gastroenterology, CHU de Bordeaux, Bordeaux, France. 14. Laboratoire de pharmacologie-toxicologie, CHU de Tours, 2 boulevard Tonnellé, 37044, Tours Cedex, France. 15. Université François-Rabelais de Tours, CNRS, GICC UMR 7292, Tours, France. david.ternant@univ-tours.fr. 16. Laboratoire de pharmacologie-toxicologie, CHU de Tours, 2 boulevard Tonnellé, 37044, Tours Cedex, France. david.ternant@univ-tours.fr.
Abstract
OBJECTIVE: Clinical response to bevacizumab varies between patients treated for metastatic colorectal cancer (mCRC). The aim of this study was to quantify individual factors affecting bevacizumab pharmacokinetic variability and assess the relationship between bevacizumab concentrations and clinical outcomes. METHODS: Bevacizumab pharmacokinetics were assessed in 130 mCRC patients using a two-compartment pharmacokinetic population model. Overall and progression-free survival (PFS) were analyzed using Cox models. RESULTS: The bevacizumab volume of distribution increased with height (p = 10-10) and was higher in patients with a 3/3 variable number tandem repeat of the FCGRT (Fc fragment of IgG receptor and transporter) gene (p = 0.039). The elimination rate constant increased with baseline carcinoembryonic antigen (CEA) and vascular endothelial growth factor (VEGF) concentrations, and was higher in patients with extra-hepatic metastases (p = 0.00029, 0.011, and 0.014). A bevacizumab trough concentration ≤15.5 mg/L was associated with both shorter overall survival and PFS (hazard ratio [95 % CI] 1.90 [1.20-2.99] and 1.76 [1.20-2.58], respectively). CONCLUSION: High tumour burden is associated with low bevacizumab concentrations, and high bevacizumab concentration are associated with both decreased overall and progression-free survivals.
OBJECTIVE: Clinical response to bevacizumab varies between patients treated for metastatic colorectal cancer (mCRC). The aim of this study was to quantify individual factors affecting bevacizumab pharmacokinetic variability and assess the relationship between bevacizumab concentrations and clinical outcomes. METHODS:Bevacizumab pharmacokinetics were assessed in 130 mCRC patients using a two-compartment pharmacokinetic population model. Overall and progression-free survival (PFS) were analyzed using Cox models. RESULTS: The bevacizumab volume of distribution increased with height (p = 10-10) and was higher in patients with a 3/3 variable number tandem repeat of the FCGRT (Fc fragment of IgG receptor and transporter) gene (p = 0.039). The elimination rate constant increased with baseline carcinoembryonic antigen (CEA) and vascular endothelial growth factor (VEGF) concentrations, and was higher in patients with extra-hepatic metastases (p = 0.00029, 0.011, and 0.014). A bevacizumab trough concentration ≤15.5 mg/L was associated with both shorter overall survival and PFS (hazard ratio [95 % CI] 1.90 [1.20-2.99] and 1.76 [1.20-2.58], respectively). CONCLUSION: High tumour burden is associated with low bevacizumab concentrations, and high bevacizumab concentration are associated with both decreased overall and progression-free survivals.
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