Bevacizumab-induced diffusion-restricted lesions in malignant glioma patients
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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.
KeywordsADC Glioma Bevacizumab Irinotecan Perfusion
Apparent diffusion coefficient
Regional cerebral blood flow
Regional cerebral blood volume
Vascular endothelial growth factor
The Dr. Senckenberg Institute of Neurooncology is supported by the Dr. Senckenberg Foundation and the Hertie Foundation. J.S. is “Hertie Professor of Neurooncology”.
Prof. Steinbach has served as a consultant for Roche, the European distributor of bevacizumab (Avastin). The other authors report no disclosures.
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