Demonstration of DCE-MRI as an early pharmacodynamic biomarker of response to VEGF Trap in glioblastoma

Abstract

Glioblastoma (GBM) is an incurable brain tumor characterized by the expression of pro-angiogenic cytokines. A recent phase II clinical trial studied VEGF Trap in adult patients with temozolomide-resistant GBM. We sought to explore changes in [¹⁸F]Fluorodeoxyglucose positron emission tomography (FDG-PET) or magnetic resonance imaging (MRI) in trial participants correlating these changes with disease response. FDG-PET and MRI images obtained before and after the first dose of VEGF Trap were spatially co-registered. Regions of interest on each image slice were combined to produce a volume of interest representative of the entire tumor. Percent and absolute changes in maximum FDG-avidity, mean apparent diffusion coefficient (ADC), K_trans, and Ve were calculated per lesion. Among the 12 participants that underwent dynamic contrast enhanced MRI (DCE-MRI), there were large, statistically significant reductions in K_trans and Ve (median difference = −41.8 %, p < 0.02 and −42.6 %, p < 0.04, respectively). In contrast, there were no significant reductions in ADC or FDG-PET SUVmax values. DCE-MRI is a useful measure of early pharmacodynamic effects of VEGF Trap on tumor vasculature. The absence of significant changes in FDG-PET and DW-MRI suggest that the early pharmacodynamic effects are specific to tumor perfusion and/or permeability and do not directly inhibit metabolism or induce cell death. DCE-MRI in conjunction with standard imaging may be promising for the identification of anti-angiogenic effects in this patient population with this therapeutic target. Further studies are needed to evaluate the relationship between DCE-MRI response and clinical outcome.

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