Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion

Abstract

The abnormal vasculature of the tumor microenvironment supports progression and resistance to treatment. Judicious application of antiangiogenic therapy may normalize the structure and function of the tumor vasculature, promoting improved blood perfusion. However, direct clinical evidence is lacking for improvements in blood perfusion after antiangiogenic therapy. In this study, we used MRI to assess tumor blood perfusion in 30 recurrent glioblastoma patients who were undergoing treatment with cediranib, a pan-VEGF receptor tyrosine kinase inhibitor. Tumor blood perfusion increased durably for more than 1 month in 7 of 30 patients, in whom it was associated with longer survival. Together, our findings offer direct clinical evidence in support of the hypothesis that vascular normalization can increase tumor perfusion and help improve patient survival.

Trial registration: ClinicalTrials.gov NCT00035656.

Figure 1. Vascular Normalization Hypothesis

Schematic of the effects of anti-angiogenic therapy on tumor vascular structure and blood perfusion. Compared to normal vessels (left), the tumor vasculature (center) is less efficient. After anti-angiogenic therapy, the tumor vasculature might become “normalized”, resulting in increased blood perfusion (top right); or not respond to therapy (center right); or be markedly pruned leading to decreased blood perfusion (bottom right).

Figure 2. Increased Perfusion

Representative example of a patient with perfusion increase. (A) Anatomic MRI showing decrease in the contrast enhanced tumor area with blue ovals indicating tumor region. (B) Blood perfusion maps showing increasing perfusion. (C) Histogram analysis of enhancing tumor showing increase and normalization of perfusion compared to reference tissue.

Figure 3. Perfusion Response to Treatment and Survival analysis

(A) Three types of perfusion response to anti-angiogenic treatment are evident: perfusion increase, stable perfusion or perfusion decrease. Figure show log-scaled averaged values (±SEM) and P-values from Kruskal-Wallis tests (Holm-Bonferroni corrected). Values at day −1 were set as 100%. (B) Kaplan-Meier analysis for progression-free survival. (C) Kaplan-Meier analysis for overall survival. Patients with an increase in tumor perfusion had prolonged PFS compared patients with stable perfusion, and prolonged OS compared to patients with stable and decreased perfusion (Mann-Whitney; P<0.01, Holm-Bonferroni corrected). Differences between PFS and OS may be attributed to the inherent uncertainty of the PFS estimate by the Macdonald criteria – since anti-VEGF agents decrease vascular permeability resulting in decreased contrast in the absence of an anti-tumor effect.

Figure 4. Relationship Between Microvessel Perfusion and a Vascular Normalization Index (VNI)

Patients with an increase in perfusion showed significantly higher VNI values compared to patients with stable or decreased perfusion for PFS and OS (*Mann-Whitney; P<0.05, Holm-Bonferroni corrected). A higher VNI value is also associated with increased PFS and OS. Although perfusion and blood volume are inherently associated, but not identical, the relationship between perfusion changes and VNI indicate that increased perfusion could be a result of decreased vascular permeability.