A “Vascular Normalization Index” as Potential Mechanistic Biomarker to Predict Survival after a Single Dose of Cediranib in Recurrent Glioblastoma Patients

Abstract

Early imaging or blood biomarkers of tumor response are desperately needed to customize antiangiogenic therapy for cancer patients. Anti-vascular endothelial growth factor (VEGF) therapy can ''normalize'' brain tumor vasculature by decreasing vessel diameter and permeability, and thinning the abnormally thick basement membrane. We hypothesized that the extent of vascular normalization will be predictive of outcome of anti-VEGF therapy in glioblastoma. We used advanced magnetic resonance imaging methods to monitor vascular parameters and treatment response in 31 recurrent glioblastoma patients enrolled in a phase II trial of cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor. We evaluated the correlation between clinical outcome and magnetic resonance imaging-measured changes in vascular permeability/flow (i.e., K trans ) and in microvessel volume, and the change of circulating collagen IV levels, all after a single dose of cediranib. Here, we show that evaluation of biomarkers as early as after one day of anti-VEGF therapy with cediranib is predictive of response in patients with recurrent glioblastoma. Changes in K trans , microvessel volume, and circulating collagen IV correlated with duration of overall survival and/or progression-free survival (P < 0.05). When we combined these three parameters into a ''vascular normalization index,'' we found that it closely associated with overall survival (R = 0.54; P = 0.004) and progression-free survival (R = 0.6; P = 0.001). The vascular normalization index described here should be validated in randomized clinical trials. [Cancer Res 2009;69(13):5296-300]

Role of vascular normalization in benefit from metronomic chemotherapy

“…In a clinical situation, the optimal dose can be determined by the changes that chemotherapy induces in tumor vessel permeability and perfusion. Both vessel permeability and perfusion can be measured clinically with magnetic resonance imaging (MRI) (42,43); thus, the optimal dose and schedule to reduce vessel permeability and improve perfusion can be inferred using MRI. Given the continuously evolving nature of each cancer, as well as differences among tumor types, among tumors of the same type, and between a primary tumor and its metastases, the selection of an optimal dosage schedule must be patient-specific.…”

Pixel-by-Pixel Comparison of Volume Transfer Constant and Estimates of Cerebral Blood Volume from Dynamic Contrast-Enhanced and Dynamic Susceptibility Contrast-Enhanced MR Imaging in High-Grade Gliomas

“…A deep understanding of the physiologic significance of the parameters obtained with DCE and DSC perfusion is very important because both techniques are used in the assessment of antiangiogenic therapies 17,18 and in the differentiation between posttreatment changes and recurrent tumor. [19][20][21][22] The assessment of the bloodbrain barrier has also gained importance because it provides valuable information regarding brain drug penetration.…”

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

“…These parameters can be used to generate a "vascular normalization index" to help identify rGBM patients most likely to benefit from antiangiogenic therapy (17,18). However, whether tumor perfusion and oxygenation increase during combined antiangiogenic and cytotoxic treatments and whether this increased perfusion improves overall survival are not known.…”