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. 2020 Jan 1;26(1):206-212.
doi: 10.1158/1078-0432.CCR-19-1739. Epub 2019 Sep 26.

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

Elizabeth R Gerstner  1   2 , Kyrre E Emblem  3 , Ken Chang  4 , Bella Vakulenko-Lagun  5 , Yi-Fen Yen  4 , Andrew L Beers  4 , Jorg Dietrich  6   2 , Scott R Plotkin  6   2 , Ciprian Catana  4 , Jacob M Hooker  4 , Dan G Duda  2   7 , Bruce Rosen  2   4 , Jayashree Kalpathy-Cramer  2   4 , Rakesh K Jain  2   7 , Tracy Batchelor  2   8
Affiliations

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

Elizabeth R Gerstner et al. Clin Cancer Res. .

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.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

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 Genomicare, 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.

Figures

Figure 1.
Figure 1.
MRI and PET scans from 1 patient prior to start of bevacizumab (visit 01) and 1 month later (visit 01) showing decrease in contrast enhancement (MPRAGE), SUV, cerebral blood flow (CBF), and Ktrans (vascular permeability).
Figure 2.
Figure 2.
Longitudinal changes within the contrast-enhancing tumor. A, Percent change in contrast-enhancing tumor volume. B, Absolute change in median tumor Ktrans values. C, Absolute change in median CBF. D, Absolute change in median tumor SUV. Patient 11 had 2 tumors, which are shown separately. Visit 1, baseline; visit 2, 1 day after bevacizumab; visit 3, 1 month after bevacizumab.
Figure 3.
Figure 3.
Spearman correlation between median tumor SUV (temozolomide uptake) and median Ktrans (vascular permeability) or median CBF at each visit. Visit 1, baseline; visit 2, 1 day after bevacizumab; visit 3, 1 month after bevacizumab.
Figure 4.
Figure 4.
A, Change in CBF or Ktrans within tumor and peritumoral regions that experienced a decrease in SUV. B, Change in CBF or Ktrans within tumor and peritumoral regions that experienced an increase in SUV. Legends to the right apply to all panels. Visit 1, baseline; visit 2, 1 day after bevacizumab; visit 3, 1 month after bevacizumab.
Figure 5.
Figure 5.
Spearman correlation between SUV and CBF at each visit within the tumor regions with low permeability. None of the P values were significant after adjusting for multiple testing.
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References

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