title: MR Perfusion-derived Hemodynamic Parametric Response Mapping of Bevacizumab Efficacy in Recurrent Glioblastoma.
abstract: OBJECTIVE
  To better understand the effect of bevacizumab therapy on tumor blood flow and oxygenation status in patients with recurrent glioblastoma.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: From the Departments of Neuroradiology (P.K., A.R., S.B., S.H., M.B., D.B.) and Neurology Clinic (A.W., W.W.), University of Heidelberg Medical Center, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (A.R., H.P.S.); and German Cancer Consortium (DKTK), Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany (W.W.).
authors.forename: Philipp
authors.initials: P
authors.lastname: Kickingereder
authors.affiliation: From the Departments of Neuroradiology (P.K., A.R., S.B., S.H., M.B., D.B.) and Neurology Clinic (A.W., W.W.), University of Heidelberg Medical Center, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (A.R., H.P.S.); and German Cancer Consortium (DKTK), Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany (W.W.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Radbruch
authors.affiliation: From the Departments of Neuroradiology (P.K., A.R., S.B., S.H., M.B., D.B.) and Neurology Clinic (A.W., W.W.), University of Heidelberg Medical Center, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (A.R., H.P.S.); and German Cancer Consortium (DKTK), Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany (W.W.).
authors.forename: Sina
authors.initials: S
authors.lastname: Burth
authors.affiliation: From the Departments of Neuroradiology (P.K., A.R., S.B., S.H., M.B., D.B.) and Neurology Clinic (A.W., W.W.), University of Heidelberg Medical Center, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (A.R., H.P.S.); and German Cancer Consortium (DKTK), Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany (W.W.).
authors.forename: Antje
authors.initials: A
authors.lastname: Wick
authors.affiliation: From the Departments of Neuroradiology (P.K., A.R., S.B., S.H., M.B., D.B.) and Neurology Clinic (A.W., W.W.), University of Heidelberg Medical Center, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (A.R., H.P.S.); and German Cancer Consortium (DKTK), Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany (W.W.).
authors.forename: Sabine
authors.initials: S
authors.lastname: Heiland
authors.affiliation: From the Departments of Neuroradiology (P.K., A.R., S.B., S.H., M.B., D.B.) and Neurology Clinic (A.W., W.W.), University of Heidelberg Medical Center, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (A.R., H.P.S.); and German Cancer Consortium (DKTK), Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany (W.W.).
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schlemmer
authors.affiliation: From the Departments of Neuroradiology (P.K., A.R., S.B., S.H., M.B., D.B.) and Neurology Clinic (A.W., W.W.), University of Heidelberg Medical Center, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (A.R., H.P.S.); and German Cancer Consortium (DKTK), Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany (W.W.).
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: From the Departments of Neuroradiology (P.K., A.R., S.B., S.H., M.B., D.B.) and Neurology Clinic (A.W., W.W.), University of Heidelberg Medical Center, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (A.R., H.P.S.); and German Cancer Consortium (DKTK), Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany (W.W.).
authors.forename: Martin
authors.initials: M
authors.lastname: Bendszus
authors.affiliation: From the Departments of Neuroradiology (P.K., A.R., S.B., S.H., M.B., D.B.) and Neurology Clinic (A.W., W.W.), University of Heidelberg Medical Center, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (A.R., H.P.S.); and German Cancer Consortium (DKTK), Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany (W.W.).
authors.forename: David
authors.initials: D
authors.lastname: Bonekamp
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002560:Cerebrovascular Circulation; D003287:Contrast Media; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006439:Hemodynamics; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D018810:Magnetic Resonance Angiography / Q000379:methods*; D008297:Male; D008536:Meglumine; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009942:Organometallic Compounds; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D003287:Contrast Media; D009942:Organometallic Compounds; D000068258:Bevacizumab; D008536:Meglumine; C072417:gadoterate meglumine