title: Evaluation of the lactate-to-N-acetyl-aspartate ratio defined with magnetic resonance spectroscopic imaging before radiation therapy as a new predictive marker of the site of relapse in patients with glioblastoma multiforme.
abstract: OBJECTIVE
  Because lactate accumulation is considered a surrogate for hypoxia and tumor radiation resistance, we studied the spatial distribution of the lactate-to-N-acetyl-aspartate ratio (LNR) before radiation therapy (RT) with 3D proton magnetic resonance spectroscopic imaging (3D-(1)H-MRSI) and assessed its impact on local tumor control in glioblastoma (GBM).
  
  
  METHODS
  Fourteen patients with newly diagnosed GBM included in a phase 2 chemoradiation therapy trial constituted our database. Magnetic resonance imaging (MRI) and MRSI data before RT were evaluated and correlated to MRI data at relapse. The optimal threshold for tumor-associated LNR was determined with receiver-operating-characteristic (ROC) curve analysis of the pre-RT LNR values and MRI characteristics of the tumor. This threshold was used to segment pre-RT normalized LNR maps. Two spatial analyses were performed: (1) a pre-RT volumetric comparison of abnormal LNR areas with regions of MRI-defined lesions and a choline (Cho)-to- N-acetyl-aspartate (NAA) ratio ≥ 2 (CNR2); and (2) a voxel-by-voxel spatial analysis of 4,186,185 voxels with the intention of evaluating whether pre-RT abnormal LNR areas were predictive of the site of local recurrence.
  
  
  RESULTS
  A LNR of ≥ 0.4 (LNR-0.4) discriminated between tumor-associated and normal LNR values with 88.8% sensitivity and 97.6% specificity. LNR-0.4 voxels were spatially different from those of MRI-defined lesions, representing 44% of contrast enhancement, 64% of central necrosis, and 26% of fluid-attenuated inversion recovery (FLAIR) abnormality volumes before RT. They extended beyond the overlap with CNR2 for most patients (median: 20 cm(3); range: 6-49 cm(3)). LNR-0.4 voxels were significantly predictive of local recurrence, regarded as contrast enhancement at relapse: 71% of voxels with a LNR-0.4 before RT were contrast enhanced at relapse versus 10% of voxels with a normal LNR (P<.01).
  
  
  CONCLUSIONS
  Pre-RT LNR-0.4 in GBM indicates tumor areas that are likely to relapse. Further investigations are needed to confirm lactate imaging as a tool to define additional biological target volumes for dose painting.
authors.affiliation: Département de Radiothérapie, Institut Claudius Regaud, Toulouse, France; UMR (Unité Mixte de Recherche) 825, Institut National de la Santé et de la Recherche Médicale, Toulouse, France; INP (Institut National Polytechnique), ENVT (Ecole Nationale Vétérinaire de Toulouse), Unité d'Anatomie-Imagerie-Embryologie, Université de Toulouse, Toulouse, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Deviers
authors.affiliation: Département de Radiothérapie, Institut Claudius Regaud, Toulouse, France; UMR (Unité Mixte de Recherche) 825, Institut National de la Santé et de la Recherche Médicale, Toulouse, France.
authors.forename: Soléakhéna
authors.initials: S
authors.lastname: Ken
authors.affiliation: Bureau des Etudes Cliniques, Institut Claudius Regaud, Toulouse, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Filleron
authors.affiliation: Département de Radiothérapie, Institut Claudius Regaud, Toulouse, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rowland
authors.affiliation: Département de Radiothérapie, Institut Claudius Regaud, Toulouse, France.
authors.forename: Andrea
authors.initials: A
authors.lastname: Laruelo
authors.affiliation: UMR (Unité Mixte de Recherche) 825, Institut National de la Santé et de la Recherche Médicale, Toulouse, France; Hôpital de Rangueil, CHU (Centre Hospitalier Universitaire) de Toulouse, Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Catalaa
authors.affiliation: UMR (Unité Mixte de Recherche) 825, Institut National de la Santé et de la Recherche Médicale, Toulouse, France; Hôpital de Rangueil, CHU (Centre Hospitalier Universitaire) de Toulouse, Toulouse, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lubrano
authors.affiliation: UMR (Unité Mixte de Recherche) 825, Institut National de la Santé et de la Recherche Médicale, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Celsis
authors.affiliation: UMR (Unité Mixte de Recherche) 825, Institut National de la Santé et de la Recherche Médicale, Toulouse, France; Hôpital de Rangueil, CHU (Centre Hospitalier Universitaire) de Toulouse, Toulouse, France; Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Berry
authors.affiliation: UMR (Unité Mixte de Recherche) 825, Institut National de la Santé et de la Recherche Médicale, Toulouse, France; INP (Institut National Polytechnique), ENVT (Ecole Nationale Vétérinaire de Toulouse), Unité d'Anatomie-Imagerie-Embryologie, Université de Toulouse, Toulouse, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Mogicato
authors.affiliation: Département de Radiothérapie, Institut Claudius Regaud, Toulouse, France; UMR1037, CRCT, Institut National de la Santé et de la Recherche Médicale, Toulouse, France; Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cohen-Jonathan Moyal
authors.affiliation: Département de Radiothérapie, Institut Claudius Regaud, Toulouse, France; UMR (Unité Mixte de Recherche) 825, Institut National de la Santé et de la Recherche Médicale, Toulouse, France. Electronic address: laprie.anne@iuct-oncopole.fr.
authors.forename: Anne
authors.initials: A
authors.lastname: Laprie
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000532:radiotherapy; D002794:Choline / Q000378:metabolism; D003401:Creatine / Q000378:metabolism; D005260:Female; D005909:Glioblastoma / Q000378:metabolism* / Q000401:mortality / Q000532:radiotherapy; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000401:mortality; D015363:Quinolones / Q000627:therapeutic use; D020266:Radiotherapy, Conformal; D012680:Sensitivity and Specificity
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D015363:Quinolones; D001224:Aspartic Acid; D019344:Lactic Acid; C000179:N-acetylaspartate; C402769:tipifarnib; D003401:Creatine; D002794:Choline