Bevacizumab dose adjustment to improve clinical outcomes of glioblastoma

N García-Romero,F Pérez-Rodríguez,I Palacín-Aliana,C Fernández-Carballal,B Jiménez,E Calvo,S Esteban-Rubio,A Collazo,J Carrión-Navarro,P Sánchez-Gómez,A Ortiz De Mendivil,A Ayuso-Sacido,R Madurga,R Prat-Acín,J Diamantopoulos-Fernández,S García-Duque,C Belda-Iniesta

doi:10.1186/s12916-020-01610-0

Abstract

BackgroundGlioblastoma (GBM) is one of the most aggressive and vascularized brain tumors in adults, with a median survival of 20.9 months. In newly diagnosed and recurrent GBM, bevacizumab demonstrated an increase in progression-free survival, but not in overall survival.MethodsWe conducted an in silico analysis of VEGF expression, in a cohort of 1082 glioma patients. Then, to determine whether appropriate bevacizumab dose adjustment could increase the anti-angiogenic response, we used in vitro and in vivo GBM models. Additionally, we analyzed VEGFA expression in tissue, serum, and plasma in a cohort of GBM patients before and during bevacizumab treatment.ResultsWe identified that 20% of primary GBM did not express VEGFA suggesting that these patients would probably not respond to bevacizumab therapy as we proved in vitro and in vivo. We found that a specific dose of bevacizumab calculated based on VEGFA expression levels increases the response to treatment in cell culture and serum samples from mice bearing GBM tumors. Additionally, in a cohort of GBM patients, we observed a correlation of VEGFA levels in serum, but not in plasma, with bevacizumab treatment performance.ConclusionsOur data suggest that bevacizumab dose adjustment could improve clinical outcomes in Glioblastoma treatment.

Highlights

Glioblastoma (GBM) is one of the most aggressive and vascularized brain tumors in adults, with a median survival of 20.9 months
VEGFA expression level stratifies human glial tumors To observe the clinical relevance of VEGFA, we first evaluated its mRNA expression in a cohort of 981 low(LGG) and high-grade glioma (HGG) patients [28] (Additional file 1: Tables S2-3)
Our results show that the level of VEGFA expression increased according to the histopathology degree

Summary

Introduction

Glioblastoma (GBM) is one of the most aggressive and vascularized brain tumors in adults, with a median survival of 20.9 months. Glioblastoma (GBM), a grade IV glioma according to the World Health Organization (WHO) classification, is one of the most common, aggressive, and highly vascularized brain tumors in adults, with a median survival of 20.9 months and an incidence rate of 3–4 newly diagnosed patients per 100,000 population [1,2,3]. Some phase II and phase III clinical trials performed with bevacizumab in newly diagnosed (AVAglioB021990 and RTOG-0825) and recurrent GBM patients failed to demonstrate a significant OS advantage, while revealing strong evidence of prolonged progression-free survival in GBM [15,16,17,18,19]. Some predictive biomarkers have been suggested to be measured in plasma [22] and in solid biopsies [23], more robust and efficient biomarkers are needed to identify responder and non-responder patient subpopulations as well as to personalize the bevacizumab doses required to achieve antitumor effectiveness in the responder group

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Conclusion