title: Bevacizumab-induced diffusion-restricted lesions in malignant glioma patients.
abstract: Bevacizumab is an anti-vascular endothelial growth factor (VEGF) antibody with activity against recurrent malignant glioma inducing high rates of objective responses as assessed by magnetic resonance imaging (MRI). However, the mechanisms of the anti-tumor action of bevacizumab are controversial. In particular, it is unclear whether and when bevacizumab induces hypoxia in gliomas. Vascular normalization with hyperperfusion and enhanced oxygen delivery to the tumor has been suggested as an alternative mechanism. We analyzed diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps in 18 consecutive patients with recurrent malignant glioma before and after exposure to bevacizumab. Stroke-like lesions with diffusion restriction on DWI and corresponding ADC decrease were induced by bevacizumab within the previously enhancing tumor area in 13 of 18 patients. These lesions were detectable as early as 4 weeks after initiation of therapy and were maintained for up to 80 weeks. In one patient, an ADC-decreased lesion was biopsied, and histology showed atypical necrosis and nuclear hypoxia-inducible factor 1alpha upregulation but no tumor recurrence. Normalized regional cerebral blood flow (rCBF) and regional cerebral blood volume (rCBV) were analyzed in selected patients. Both parameters were decreased in responders with diffusion-restricted lesions. Within the tumor bed, bevacizumab induces diffusion-restricted lesions in the presence of reduced rCBF and rCBV. The cause of these alterations is unclear but may involve atypical necrosis and chronic hypoxia.
authors.affiliation: Dr. Senckenberg Institute of Neurooncology, Goethe-University Frankfurt, Schleusenweg 2-16, 60528 Frankfurt, Germany. johannes.rieger@med.uni-frankfurt.de
authors.forename: Johannes
authors.initials: J
authors.lastname: Rieger
authors.forename: Oliver
authors.initials: O
authors.lastname: Bähr
authors.forename: Klaus
authors.initials: K
authors.lastname: Müller
authors.forename: Kea
authors.initials: K
authors.lastname: Franz
authors.forename: Joachim
authors.initials: J
authors.lastname: Steinbach
authors.forename: Elke
authors.initials: E
authors.lastname: Hattingen
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002560:Cerebrovascular Circulation / Q000502:physiology; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D013997:Time Factors; D000097382:CD68 Molecule
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000068258:Bevacizumab; D005904:Glial Fibrillary Acidic Protein; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C489788:MAP2 protein, human