Elizabeth R Gerstner1,2, Kyrre E Emblem3, Yi-Fen Yen4,2, Jorg Dietrich1,2, Justin T Jordan1,2, Ciprian Catana4,2, Kevin Lou Wenchin4, Jacob M Hooker4,2, Dan G Duda5,2, Bruce R Rosen4,2, Jayashree Kalpathy-Cramer4,2, Rakesh K Jain5,2, Tracy T Batchelor6,2. 1. Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA. 2. Harvard Medical School, Boston, Massachusetts, USA. 3. Department of Diagnostic Physics, Oslo University, Oslo, Norway. 4. Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts, USA. 5. Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA. 6. Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Abstract
BACKGROUND: Hypoxia is a driver of treatment resistance in glioblastoma. Antiangiogenic agents may transiently normalize blood vessels and decrease hypoxia before excessive pruning of vessels increases hypoxia. The time window of normalization is dose and time dependent. We sought to determine how VEGF blockade with bevacizumab modulates tumor vasculature and the impact that those vascular changes have on hypoxia in recurrent glioblastoma patients. METHODS: We measured tumor volume, vascular permeability (Ktrans), perfusion parameters (cerebral blood flow/volume, vessel caliber, and mean transit time), and regions of hypoxia in patients with recurrent glioblastoma before and after treatment with bevacizumab alone or with lomustine using [18F]FMISO PET-MRI. We also examined serial changes in plasma biomarkers of angiogenesis and inflammation. RESULTS: Eleven patients were studied. The magnitude of global tumor hypoxia was variable across these 11 patients prior to treatment and it did not significantly change after bevacizumab. The hypoxic regions had an inefficient vasculature characterized by elevated cerebral blood flow/volume and increased vessel caliber. In a subset of patients, there were tumor subregions with decreased mean transit times and a decrease in hypoxia, suggesting heterogeneous improvement in vascular efficiency. Bevacizumab significantly changed known pharmacodynamic biomarkers such as plasma VEGF and PlGF. CONCLUSIONS: The vascular signature in hypoxic tumor regions indicates a disorganized vasculature which, in most tumors, does not significantly change after bevacizumab treatment. While some tumor regions showed improved vascular efficiency following treatment, bevacizumab did not globally alter hypoxia or normalize tumor vasculature in glioblastoma.
BACKGROUND: Hypoxia is a driver of treatment resistance in glioblastoma. Antiangiogenic agents may transiently normalize blood vessels and decrease hypoxia before excessive pruning of vessels increases hypoxia. The time window of normalization is dose and time dependent. We sought to determine how VEGF blockade with bevacizumab modulates tumor vasculature and the impact that those vascular changes have on hypoxia in recurrent glioblastoma patients. METHODS: We measured tumor volume, vascular permeability (Ktrans), perfusion parameters (cerebral blood flow/volume, vessel caliber, and mean transit time), and regions of hypoxia in patients with recurrent glioblastoma before and after treatment with bevacizumab alone or with lomustine using [18F]FMISO PET-MRI. We also examined serial changes in plasma biomarkers of angiogenesis and inflammation. RESULTS: Eleven patients were studied. The magnitude of global tumor hypoxia was variable across these 11 patients prior to treatment and it did not significantly change after bevacizumab. The hypoxic regions had an inefficient vasculature characterized by elevated cerebral blood flow/volume and increased vessel caliber. In a subset of patients, there were tumor subregions with decreased mean transit times and a decrease in hypoxia, suggesting heterogeneous improvement in vascular efficiency. Bevacizumab significantly changed known pharmacodynamic biomarkers such as plasma VEGF and PlGF. CONCLUSIONS: The vascular signature in hypoxic tumor regions indicates a disorganized vasculature which, in most tumors, does not significantly change after bevacizumab treatment. While some tumor regions showed improved vascular efficiency following treatment, bevacizumab did not globally alter hypoxia or normalize tumor vasculature in glioblastoma.
Authors: Elizabeth R Gerstner; Xiaobu Ye; Dan G Duda; Michael A Levine; Tom Mikkelsen; Thomas J Kaley; Jeffrey J Olson; Burt L Nabors; Manmeet S Ahluwalia; Patrick Y Wen; Rakesh K Jain; Tracy T Batchelor; Stuart Grossman Journal: Neuro Oncol Date: 2015-05-24 Impact factor: 12.300
Authors: Christin Y Sander; Boris Keil; Daniel B Chonde; Bruce R Rosen; Ciprian Catana; Lawrence L Wald Journal: Magn Reson Med Date: 2014-07-07 Impact factor: 4.668
Authors: David Bonekamp; Kim Mouridsen; Alexander Radbruch; Felix T Kurz; Oliver Eidel; Antje Wick; Heinz-Peter Schlemmer; Wolfgang Wick; Martin Bendszus; Leif Østergaard; Philipp Kickingereder Journal: J Cereb Blood Flow Metab Date: 2016-07-21 Impact factor: 6.200
Authors: Elizabeth R Gerstner; Zheng Zhang; James R Fink; Mark Muzi; Lucy Hanna; Erin Greco; Melissa Prah; Kathleen M Schmainda; Akiva Mintz; Lale Kostakoglu; Edward A Eikman; Benjamin M Ellingson; Eva-Maria Ratai; A Gregory Sorensen; Daniel P Barboriak; David A Mankoff Journal: Clin Cancer Res Date: 2016-05-16 Impact factor: 12.531
Authors: Andrew Beers; James Brown; Ken Chang; Katharina Hoebel; Jay Patel; K Ina Ly; Sara M Tolaney; Priscilla Brastianos; Bruce Rosen; Elizabeth R Gerstner; Jayashree Kalpathy-Cramer Journal: Neuroinformatics Date: 2021-01