Abstract B12: Adding angiotensin-system inhibitors to anti-angiogenic therapy reduces vasogenic edema in newly diagnosed glioblastomas but not in recurrent disease
Authors: Emblem Kyrre E. , Gerstner Elizabeth R. , Sorensen A Gregory , Rosen Bruce R. , Wen Patrick Y. , Batchelor Tracy T. , Jain Rakesh K. 
Published: March 2017

Introduction: Recent theoretical [1], pre-clinical [2] and human tumor data [3] suggest anti-hypertensives with an extracellular matrix-depleting effect improve vascular function by reducing the solid stress that can squeeze tumor vessels shut [4]. This work is contrasted by studies showing that certain matrix-depleting anti-hypertensives (angiotensin-II receptor blockers) are also associated with reduced peri-tumoral edema [5]. We here show that combined matrix-depleting and anti-angiogenic therapy does reduce vasogenic edema in newly diagnosed glioblastomas but not in recurrent disease and that the mechanisms of action are therefore not fully understood.

Methods: We retrospectively assessed data from 40 patients with newly diagnosed glioblastomas (nGBM) and 30 patients with recurrent glioblastomas (rGBM) receiving cediranib, an oral pan-VEGFR inhibitor, with- (NCT00662506) and without (NCT00305656) chemoradiation, respectively. Conventional, perfusion and vessel caliber MRI were performed at baseline and repeated weekly (nGBM) or monthly (rGBM) [6, 7]. Vasogenic edema was measured as the relative volume of peri-tumoral hyper T2-Fluid Attenuated Inversion Recovery (FLAIR) signal on the conventional MRIs. For nGBM, after cediranib onset, 12/40 patients received angiotensin II receptor blockers (Valsartan), β1 receptor antagonists (Atenolol) or angiotensin-converting enzyme inhibitors (Lisinopril), while 8/40 patients received calcium antagonists (Norvasc, Amlodipine) [3]. Similarly, for rGBM, 15/30 patients received Atenolol and 7/30 patients Norvasc.

Results: While angiotensin-system inhibitors (ASIs) significantly improved the perfused vessel fraction (% of tumor values &gt;½ the value of healthy tissue; Wilcoxon P&lt;0.05) and the relative small vessel fraction (&lt;½ the size of healthy tissue; Wilcoxon P&lt;0.01) for both cohorts, reduction of vasogenic edema was only observed in nGBM patients. Here, both cediranib alone and in combination with ASIs reduced the median relative vasogenic edema volume (82% and 54% over study period and compared to baseline values, respectively; Wilcoxon P&lt;0.05), but not for non-ASI calcium antagonists (96%). For rGBMs, cediranib alone reduced the median relative vasogenic edema volume (90%; P&lt;0.05), but not when adding ASIs. Instead, there was a trend towards reduced vasogenic edema with non-ASI calcium antagonists.

Conclusion: The potential anti-edema effect associated with ASI anti-hypertensives is an attractive feature for reduced administration of steroids in patients with glioblastoma. However, our data indicate that the matrix-depleting activity of some anti-hypertensives improves vascular function in both nGBMs and rGBMs [3], but only reduces vasogenic edema in the newly diagnosed setting [5]. Further studies to understand the mechanisms of benefit of ASIs in cancer are warranted.

References:

1: PNAS 2013;110:18632-37

2: Nat Commun 2013; 4, 2516

3: Proc AACR Annual Meeting 2016; p3975

4: PNAS 2012; 109, 15101-8

5: J Neurol. 2016; 263, 524-30

6: PNAS 2013; 110, 19059-64

7: Nat Med 2013; 19, 1178-83

Citation Format: Kyrre E. Emblem, Elizabeth R. Gerstner, A Gregory Sorensen, Bruce R. Rosen, Patrick Y. Wen, Tracy T. Batchelor, Rakesh K. Jain. Adding angiotensin-system inhibitors to anti-angiogenic therapy reduces vasogenic edema in newly diagnosed glioblastomas but not in recurrent disease. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B12.