Bevacizumab reduces permeability and concurrent temozolomide delivery in a subset of patients with recurrent glioblastoma

Purpose: Targeting tumor blood vessels is an attractive herapy in glioblastoma (GBM), but the mechanism of action f these agents and how they modulate delivery of concomitant hemotherapy are not clear in humans. We sought to elucidate ow bevacizumab modulates tumor vasculature and the impact hose vascular changes have on drug delivery in patients with ecurrent GBM. Experimental Design: Temozolomide was labeled with [11C], nd serial PET-MRI scans were performed in patients with recurent GBM treated with bevacizumab and daily temozolomide. PET-MRI scans were performed prior to the first bevacizumab dose, 1 day fter the first dose, and prior to the third dose of bevacizumab. We alculated tumor volume, vascular permeability (K_trans), perfusion cerebral blood flow), and the standardized uptake values (SUV) of 11C] temozolomide within the tumor. Results: Twelve patients were enrolled, resulting in 23 evaluable scans. Within the entire contrast-enhancing tumor volume, both temozolomide uptake and vascular permeability decreased after initiation of bevacizumab in most patients, whereas change in perfusion was more variable. In subregions of the tumor where permeability was low and the blood–brain barrier not compromised, increased perfusion correlated with increased temozolomide uptake. Conclusions: Bevacizumab led to a decrease in permeability and concomitant delivery of temozolomide. However, in subregions of the tumor where permeability was low, increased perfusion improved delivery of temozolomide, suggesting that perfusion may modulate the delivery of chemotherapy in certain settings. These results support exploring whether lower doses of bevacizumab improve perfusion and concomitant drug delivery.