title: Assessment of tumor oxygenation and its impact on treatment response in bevacizumab-treated recurrent glioblastoma.
abstract: Antiantiogenic therapy with bevacizumab in recurrent glioblastoma is currently understood to both reduce microvascular density and to prune abnormal tumor microvessels. Microvascular pruning and the resulting vascular normalization are hypothesized to reduce tumor hypoxia and increase supply of systemic therapy to the tumor; however, the underlying pathophysiological changes and their timing after treatment initiation remain controversial. Here, we use a novel dynamic susceptibility contrast MRI-based method, which allows simultaneous assessment of tumor net oxygenation changes reflected by the tumor metabolic rate of oxygen and vascular normalization represented by the capillary transit time heterogeneity. We find that capillary transit time heterogeneity, and hence the oxygen extraction fraction combine with the tumoral blood flow (cerebral blood flow) in such a way that the overall tumor oxygenation appears to be worsened despite vascular normalization. Accordingly, hazards for both progression and death are found elevated in patients with a greater reduction of tumor metabolic rate of oxygen in response to bevacizumab and patients with higher intratumoral tumor metabolic rate of oxygen at baseline. This implies that tumors with a higher degree of angiogenesis prior to bevacizumab-treatment retain a higher level of angiogenesis during therapy despite a greater antiangiogenic effect of bevacizumab, hinting at evasive mechanisms limiting bevacizumab efficacy in that a reversal of their biological behavior and relative prognosis does not occur.
authors: 1 Department of Neuroradiology, University of Heidelberg Medical Center, Heidelberg, Germany.|2 Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: David
authors: D
authors: Bonekamp
authors: 3 Center of Functionally Integrative Neuroscience and MINDLab, Aarhus University Hospital, Aarhus, Denmark.
authors: Kim
authors: K
authors: Mouridsen
authors: 1 Department of Neuroradiology, University of Heidelberg Medical Center, Heidelberg, Germany.|2 Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Alexander
authors: A
authors: Radbruch
authors: 1 Department of Neuroradiology, University of Heidelberg Medical Center, Heidelberg, Germany.
authors: Felix T
authors: FT
authors: Kurz
authors: 1 Department of Neuroradiology, University of Heidelberg Medical Center, Heidelberg, Germany.
authors: Oliver
authors: O
authors: Eidel
authors: 4 Neurology Clinic, University of Heidelberg Medical Center, Heidelberg, Germany.
authors: Antje
authors: A
authors: Wick
authors: 2 Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Heinz-Peter
authors: HP
authors: Schlemmer
authors: 4 Neurology Clinic, University of Heidelberg Medical Center, Heidelberg, Germany.|5 Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Wolfgang
authors: W
authors: Wick
authors: 1 Department of Neuroradiology, University of Heidelberg Medical Center, Heidelberg, Germany.
authors: Martin
authors: M
authors: Bendszus
authors: 3 Center of Functionally Integrative Neuroscience and MINDLab, Aarhus University Hospital, Aarhus, Denmark.|6 Department of Neuroradiology, Aarhus University Hospital, Aarhus, Denmark.
authors: Leif
authors: L
authors: Østergaard
authors: 1 Department of Neuroradiology, University of Heidelberg Medical Center, Heidelberg, Germany.
authors: Philipp
authors: P
authors: Kickingereder
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000627:therapeutic use*; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D001932:Brain Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects; D005909:Glioblastoma / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods; D009364:Neoplasm Recurrence, Local / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D010100:Oxygen / Q000032:analysis / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D010100:Oxygen
keywords: Tumor oxygenation; angiogenesis; bevacizumab; glioblastoma; hypoxia