MR Perfusion-derived Hemodynamic Parametric Response Mapping of Bevacizumab Efficacy in Recurrent Glioblastoma

Abstract

Purpose: To better understand the effect of bevacizumab therapy on tumor blood flow and oxygenation status in patients with recurrent glioblastoma.

Materials and methods: Retrospective data evaluation was approved by the local ethics committee of the University of Heidelberg (ethics approval number, S-320/2012), and informed consent was waived. A total of 71 patients who received a diagnosis of recurrent glioblastoma underwent conventional anatomic magnetic resonance (MR) imaging and dynamic susceptibility contrast material-enhanced MR imaging at baseline and at the first follow-up examination after initiation of bevacizumab therapy. Parametric response maps (PRMs) were created with multistep (nonlinear) registration of patients' post- to pretreatment images and voxel-wise subtraction between Gaussian-normalized relative cerebral blood volume (nrCBV) and Gaussian-normalized relative cerebral blood flow (nrCBF) maps. Intratumor voxels were stratified as being increased (PRM[+]) or decreased (PRM[-]) if they exceeded a threshold that represented the 95% confidence interval in the normal-appearing brain. Correlation with progression-free and overall survival was performed with Cox proportional hazards models.

Results: The risks for disease progression and death significantly increased with (a) higher baseline nrCBV (hazard ratio [HR] = 1.86, P < .01; HR = 1.52, P < .01) and nrCBF (HR = 1.78, P < .01; HR = 1.86, P < .01) values and (b) higher PRM(-) of nrCBV (HR = 1.03, P = .01; HR = 1.02, P = .03) and nrCBF (HR = 1.04, P < .01; HR = 1.03, P < .01), but not with higher PRM(+) of nrCBV and nrCBF, and not for the relative change in mean nrCBV and nrCBF, confirming the superiority of the PRM approach. The magnitude of PRM(-) for both nrCBV and nrCBF significantly increased for higher baseline values (P < .01).

Conclusion: Pretreatment hemodynamic parameters are the principal determinant of response to bevacizumab therapy in patients with recurrent glioblastoma. Although the magnitude of PRM(-) is a function of the corresponding pretreatment parameter, the finding of higher PRM(-) and a lack of change in PRM(+) in nonresponders to bevacizumab therapy implies that tumors with a high degree of angiogenesis before bevacizumab therapy retain a higher level of angiogenesis during therapy, despite a greater antiangiogenic effect of bevacizumab, such that a reversal of the biologic behavior and relative prognosis of these tumors does not occur.