Voxel-based evidence of perfusion normalization in glioblastoma patients included in a phase I–II trial of radiotherapy/tipifarnib combination

We previously showed that the farnesyl transferase inihibitor, Tipifarnib induced vascularization normalization, oxygenation and radiosensitization in a pre-clinical glioblastoma (GBM) model. The aim of this study was to assess by dynamic-susceptibility-contrast MRI (DSC-MRI) the effect of radiotherapy (RT) and Tipifarnib combination on tumor perfusion in GBM patients. Eighteen patients with newly diagnosed GBM, enrolled in a phase I-II clinical trial associating RT with Tipifarnib, underwent anatomical MR imaging and DSC-MRI before (M0) and two months after treatment (M2). Anatomic volumes of interest (VOIs) were delineated according to contrast-enhanced and hyper-intense signal areas on T1-Gd and T2 images, respectively. Perfusion variations between M0 and M2 were assessed with median relative cerebral blood volume (rCBV) inside these VOIs. Another voxel by voxel analysis of CBV values classified 405,117 tumor voxels into High_, Normal_ and Low_CBV_TUMOR according to the distribution of CBV in the contralateral normal tissue. These three categories of CBV_TUMOR voxels were color-coded over anatomical MRI. Variations of median rCBV were significantly different for two groups of patients (P  1) and rCBV increased when initial rCBV was  1 presented a significant decrease of High_CBV_TUMOR volume (P = 0.015) simultaneously with a significant increase of Normal_CBV_TUMOR volume (P = 0.009) after treatment. Group_rCBV_M0 TUMOR volume with an increase of Normal_ and High_CBV _TUMOR volume after treatment. Pre and post-treatment CBV measurements with DSC-MRI characterized tumor perfusion evolution in GBM patients treated with RT combined to Tipifarnib; showing variations in favour of tumor perfusion normalization in agreement with our pre-clinical results of vascular normalization.