Bevacizumab Reduces Permeability and Concurrent Temozolomide Delivery in a Subset of Patients with Recurrent Glioblastoma.

Abstract

PURPOSE:

Targeting tumor blood vessels is an attractive therapy in glioblastoma (GBM), but the mechanism of action of these agents and how they modulate delivery of concomitant chemotherapy are not clear in humans. We sought to elucidate how bevacizumab modulates tumor vasculature and the impact those vascular changes have on drug delivery in patients with recurrent GBM.

EXPERIMENTAL DESIGN:

Temozolomide was labeled with [11C], and serial PET-MRI scans were performed in patients with recurrent GBM treated with bevacizumab and daily temozolomide. PET-MRI scans were performed prior to the first bevacizumab dose, 1 day after the first dose, and prior to the third dose of bevacizumab. We calculated 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.

• Authors: Elizabeth R Gerstner, Kyrre E Emblem, Ken Chang, Bella Vakulenko-Lagun, Yi-Fen Yen, Andrew L Beers, Jorg Dietrich, Scott R Plotkin, Ciprian Catana, Jacob M Hooker, Dan G Duda, Bruce Rosen, Jayashree Kalpathy-Cramer, Rakesh K Jain, Tracy Batchelor
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 1 Pg. 206-212 (01 01 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 31558474 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Bevacizumab
• Temozolomide

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bevacizumab (administration & dosage)
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Capillary Permeability (drug effects)
• Chemotherapy, Cancer, Regional Perfusion
• Female
• Glioblastoma (drug therapy, metabolism, pathology)
• Humans
• Magnetic Resonance Imaging (methods)
• Male
• Middle Aged
• Neoplasm Recurrence, Local (drug therapy, metabolism, pathology)
• Positron-Emission Tomography (methods)
• Prognosis
• Temozolomide (administration & dosage)