title: Voxel-based evidence of perfusion normalization in glioblastoma patients included in a phase I-II trial of radiotherapy/tipifarnib combination.
abstract: 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_CBVTUMOR according to the distribution of CBV in the contralateral normal tissue. These three categories of CBVTUMOR voxels were color-coded over anatomical MRI. Variations of median rCBV were significantly different for two groups of patients (P < 0.013): rCBV decreased when initial rCBV was ≥ 1.0 (Group_rCBV_M0 > 1) and rCBV increased when initial rCBV was < 1.0 (Group_rCBV_M0 < 1). Mapping of color-coded voxels provided additional spatial and quantitative information about tumor perfusion: Group_rCBV_M0 > 1 presented a significant decrease of High_CBVTUMOR volume (P = 0.015) simultaneously with a significant increase of Normal_CBVTUMOR volume (P = 0.009) after treatment. Group_rCBV_M0 < 1 presented a decrease of Low_CBVTUMOR 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.
authors.affiliation: Department of Radiotherapy, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopôle, 1, avenue Irene Joliot-Curie, 31059, Toulouse, France. ken.soleakhena@iuct-oncopole.fr.|Department of Medical Physics, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopôle, 1, avenue Irene Joliot-Curie, 31059, Toulouse, France. ken.soleakhena@iuct-oncopole.fr.|INSERM UMR 825 Imagerie Cérébrale et Handicaps Neurologiques, CHU Purpan - Pavillon Baudot, 31024, Toulouse, France. ken.soleakhena@iuct-oncopole.fr.
authors.forename: Soléakhéna
authors.initials: S
authors.lastname: Ken
authors.affiliation: Department of Radiotherapy, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopôle, 1, avenue Irene Joliot-Curie, 31059, Toulouse, France.|INSERM UMR 825 Imagerie Cérébrale et Handicaps Neurologiques, CHU Purpan - Pavillon Baudot, 31024, Toulouse, France.|Université Paul Sabatier, Toulouse III, 118, route de Narbonne, 31062, Toulouse, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Deviers
authors.affiliation: Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopôle, Bureau des Essais Cliniques, 1, avenue Irene Joliot-Curie, 31059, Toulouse, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Filleron
authors.affiliation: Centre Hospitalier Universitaire de Purpan, 31059, Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Catalaa
authors.affiliation: INSERM UMR 825 Imagerie Cérébrale et Handicaps Neurologiques, CHU Purpan - Pavillon Baudot, 31024, Toulouse, France.|Centre Hospitalier Universitaire de Rangueil, 31059, Toulouse, France.
authors.forename: Jean-Albert
authors.initials: JA
authors.lastname: Lotterie
authors.affiliation: Department of Radiotherapy, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopôle, 1, avenue Irene Joliot-Curie, 31059, Toulouse, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Khalifa
authors.affiliation: INSERM UMR 825 Imagerie Cérébrale et Handicaps Neurologiques, CHU Purpan - Pavillon Baudot, 31024, Toulouse, France.|Centre Hospitalier Universitaire de Rangueil, 31059, Toulouse, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lubrano
authors.affiliation: INSERM UMR 825 Imagerie Cérébrale et Handicaps Neurologiques, CHU Purpan - Pavillon Baudot, 31024, Toulouse, France.|Centre Hospitalier Universitaire de Rangueil, 31059, Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Berry
authors.affiliation: INSERM UMR 825 Imagerie Cérébrale et Handicaps Neurologiques, CHU Purpan - Pavillon Baudot, 31024, Toulouse, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Péran
authors.affiliation: INSERM UMR 825 Imagerie Cérébrale et Handicaps Neurologiques, CHU Purpan - Pavillon Baudot, 31024, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Celsis
authors.affiliation: Department of Radiotherapy, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopôle, 1, avenue Irene Joliot-Curie, 31059, Toulouse, France.|Université Paul Sabatier, Toulouse III, 118, route de Narbonne, 31062, Toulouse, France.|INSERM, UMR 1037, CRCT, 1, avenue Irene Joliot-Curie, 31000, Toulouse, France.
authors.forename: Elizabeth Cohen-Jonathan
authors.initials: EC
authors.lastname: Moyal
authors.affiliation: Department of Radiotherapy, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopôle, 1, avenue Irene Joliot-Curie, 31059, Toulouse, France.|INSERM UMR 825 Imagerie Cérébrale et Handicaps Neurologiques, CHU Purpan - Pavillon Baudot, 31024, Toulouse, France.|Université Paul Sabatier, Toulouse III, 118, route de Narbonne, 31062, Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Laprie
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000628:therapy*; D002560:Cerebrovascular Circulation; D003287:Contrast Media; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000628:therapy*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D015363:Quinolones / Q000627:therapeutic use*; D011878:Radiotherapy / Q000379:methods*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D003287:Contrast Media; D015363:Quinolones; C402769:tipifarnib
keywords: Antiangiogenic therapy; Clinical Trial; Dynamic susceptibility-weighted contrast-enhanced MRI; Glioblastoma; Radiotherapy; Tumor Perfusion