Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation

Abstract

Antiangiogenic therapy has shown clear activity and improved survival benefit for certain tumor types. However, an incomplete understanding of the mechanisms of action of antiangiogenic agents has hindered optimization and broader application of this new therapeutic modality. In particular, the impact of antiangiogenic therapy on tumor blood flow and oxygenation status (i.e., the role of vessel pruning versus normalization) remains controversial. This controversy has become critical as multiple phase III trials of anti-VEGF agents combined with cytotoxics failed to show overall survival benefit in newly diagnosed glioblastoma (nGBM) patients and several other cancers. Here, we shed light on mechanisms of nGBM response to cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, using MRI techniques and blood biomarkers in prospective phase II clinical trials of cediranib with chemoradiation vs. chemoradiation alone in nGBM patients. We demonstrate that improved perfusion occurs only in a subset of patients in cediranib-containing regimens, and is associated with improved overall survival in these nGBM patients. Moreover, an increase in perfusion is associated with improved tumor oxygenation status as well as with pharmacodynamic biomarkers, such as changes in plasma placenta growth factor and sVEGFR2. Finally, treatment resistance was associated with elevated plasma IL-8 and sVEGFR1 posttherapy. In conclusion, tumor perfusion changes after antiangiogenic therapy may distinguish responders vs. nonresponders early in the course of this expensive and potentially toxic form of therapy, and these results may provide new insight into the selection of glioblastoma patients most likely to benefit from anti-VEGF treatments.

Keywords: brain tumor; personalized treatment.

Fig. 1.

MRI changes during treatment with cediranib and chemoradiation in nGBM patients. Combination treatment induces a decrease in contrast enhancing (CE) tumor volume, FLAIR volume, vessel caliber, and permeability measured by MRI. Error bars represent SEM.

Fig. 2.

Increased tumor perfusion. (A) Representative anatomic MRI showing decrease in contrast-enhanced tumor area. (B) Perfusion maps demonstrating increased perfusion. (C) Histogram analysis of enhancing tumor region (red line) showing increased and subsequent normalization of perfusion compared with reference tissue (black line). (D) Perfusion increased in 20 patients, decreased in 10 patients, and remained stable in 10 patients during combination therapy. (E) Kaplan–Meier OS distributions in these groups, after adjustment for MGMT status and Karnofsky performance status (KPS).

Fig. 3.

Relative arteriole-to-venule oxygen saturation (∆SO₂) levels. In patients with increased tumor perfusion, ∆SO₂ decreases suggesting improved oxygenation, whereas ∆SO₂ increased in patients with decreased perfusion suggesting impaired delivery of oxygen to the tumor.

Fig. 4.

Kinetics of VEGF family proteins in nGBM patients treated with cediranib and chemoradiation. (A) Circulating PlGF. (B) Circulating sVEGFR2. Data are shown as median levels (pg/mL) in patients with increased, stable, or decreased perfusion during combination therapy.