Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice

Patients with recurrent malignant glioma treated with bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), alone or in combination with irinotecan have had Impressive reductions in Mill contrast enhancement and vasogenic edema. Responses to this regimen, as defined by a decrease in contrast enhancement, have led to significant Improvements In progression-free survival rates but not in overall survival duration. Some patients for whom this treatment regimen fails have all uncharacteristic pattern Of tumor progression, which call be observed radiographically as all increase in hyperintensity oil T2-weighted or fluid-attenuated inverse recovery (FLAIR) Mill. To date. there have been no reports of paired correlations between radiographic results and histopathologic findings describing the features of this aggressive tumor phenotype. In this study, we correlate such findings for 3 Illustrative cases of gliomas that demonstrated all apparent phenotypic shift to a predominantly infiltrative pattern Of tumor progression after treatment with bevacizumab. Pathologic examination of abnormal FLAIR areas oil Mill revealed infiltrative tumor with areas of thin-walled blood vessels, suggesting vascular "normalization," which was uncharacteristically adjacent to regions of necrosis. High levels Of insuline-like growth factor binding protein-2 and matrix metalloprotease-2 expression were seen within the infiltrating tumor. In all attempt to better understand this infiltrative phenotype associated with anti-VEGF therapy, we forced a highly angtogenic, noninvasive orthotopic U87 xenograft tumor to become infiltrative by treating the mice with bevacizumab. This model mimicked many of the histopathologic findings from the human cases and will augment the discovery of alternative or additive therapies to prevent this type of tumor recurrence in clinical practice.