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

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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.

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Acknowledgments

The authors thank Benjamin Rowland (Brigham and Women’s Hospital, Radiology Department, Boston, MA, USA) for proofreading the manuscript.

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    Authors and Affiliations

    1. Department of Radiotherapy, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopôle, 1, avenue Irene Joliot-Curie, 31059, Toulouse, France

      Soléakhéna Ken, Alexandra Deviers, Jonathan Khalifa, Elizabeth Cohen-Jonathan Moyal & Anne Laprie

    2. Department of Medical Physics, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopôle, 1, avenue Irene Joliot-Curie, 31059, Toulouse, France

      Soléakhéna Ken

    3. INSERM UMR 825 Imagerie Cérébrale et Handicaps Neurologiques, CHU Purpan - Pavillon Baudot, 31024, Toulouse, France

      Soléakhéna Ken, Alexandra Deviers, Jean-Albert Lotterie, Vincent Lubrano, Isabelle Berry, Patrice Péran, Pierre Celsis & Anne Laprie

    4. Université Paul Sabatier, Toulouse III, 118, route de Narbonne, 31062, Toulouse, France

      Alexandra Deviers, Elizabeth Cohen-Jonathan Moyal & Anne Laprie

    5. Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopôle, Bureau des Essais Cliniques, 1, avenue Irene Joliot-Curie, 31059, Toulouse, France

      Thomas Filleron

    6. Centre Hospitalier Universitaire de Purpan, 31059, Toulouse, France

      Isabelle Catalaa

    7. Centre Hospitalier Universitaire de Rangueil, 31059, Toulouse, France

      Jean-Albert Lotterie, Vincent Lubrano & Isabelle Berry

    8. INSERM, UMR 1037, CRCT, 1, avenue Irene Joliot-Curie, 31000, Toulouse, France

      Elizabeth Cohen-Jonathan Moyal

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    Correspondence to Soléakhéna Ken.

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    Elizabeth Cohen-Jonathan Moyal and Anne Laprie are co-last authors and have contributed equally to this work.

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    Ken, S., Deviers, A., Filleron, T. et al. Voxel-based evidence of perfusion normalization in glioblastoma patients included in a phase I–II trial of radiotherapy/tipifarnib combination. J Neurooncol 124, 465–473 (2015). https://doi.org/10.1007/s11060-015-1860-8

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