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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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 (Ktrans), 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.

Original languageEnglish
Pages (from-to)206-212
Number of pages7
JournalClinical Cancer Research
Volume26
Issue number1
DOIs
StatePublished - 1 Jan 2020
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by K23CA169021 (to E.R. Gerstner), 1R01CA129371 (to T. Batchelor), the European Research Council (ERC) grant 758657, the South-Eastern Norway Regional Health Authority grants 2017073 and 2013069, and the Research Council of Norway grant 261984 (to K.E. Emblem). This work was also supported by grants S10RR023043 and P41RR14075.

Funding Information:
K.E. Emblem reports intellectual property rights at NordicNeuroLab AS in Bergen, Norway. D.G. Duda is an employee/paid consultant for Bayer, Tilos, twoXAR, and BMS, and reports receiving commercial research grants from Bayer, Exelixis, BMS, Leap, and Merrimack. R.K. Jain is an employee/paid consultant for Chugai, holds ownership interest (including patents) at Enlight and SynDevRx, and is an advisory board member/unpaid consultant for Ophthotech, SPARC, SynDevRx, XTuit, Merck, the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund. T. Batchelor is an employee/paid consultant for Geno-micare, and reports receiving other commercial research support from UpToDate, Inc., Oakstone Publishing, Oncology Audio Digest, Champions Biotechnology, Amgen, NXDC, Upsher Smith, and Merck. All other authors declare no potential conflicts of interest by the other authors.

Publisher Copyright:
©2019 American Association for Cancer Research.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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