Depth of Radiographic Response and Time to Tumor Regrowth Predicts Overall Survival Following Anti-VEGF Therapy in Recurrent Glioblastoma

Purpose: Antiangiogenic therapies are known to cause high radiographic response rates due to reduction in vascular permeability resulting in a lower degree of contrast extravasation. In this study, we investigate the prognostic ability for model-derived parameters describing enhancing tumor volumetric dynamics to predict survival in recurrent glioblastoma treated with antiangiogenic therapy. Experimental Design: N ¼ 276 patients in two phase II trials were used as training data, including bevacizumab ± irinotecan (NCT00345163) and cabozantinib (NCT00704288), and N ¼ 74 patients in the bevacizumab arm of a phase III trial (NCT02511405) were used for validation. Enhancing volumes were estimated using T1 subtraction maps, and a biexponential model was used to estimate regrowth (g) and regression (d) rates, time to tumor regrowth (TTG), and the depth of response (DpR). Response characteristics were compared to diffusion MR phenotypes previously shown to predict survival.Results: Optimized thresholds occurred at g ¼ 0.07 months^–1 (phase II: HR ¼ 0.2579, P ¼ 5 × 10^–20; phase III: HR ¼ 0.2197, P ¼ 5 × 10^–5); d ¼ 0.11 months^–1 (HR ¼ 0.3365, P < 0.0001; HR ¼ 0.3675, P ¼ 0.0113); TTG ¼ 3.8 months (HR ¼ 0.2702, P ¼ 6 × 10^–17; HR ¼ 0.2061, P ¼ 2 × 10^–5); and DpR ¼ 11.3% (HR ¼ 0.6326, P ¼ 0.0028; HR ¼ 0.4785, P ¼ 0.0206). Multivariable Cox regression controlling for age and baseline tumor volume confirmed these factors as significant predictors of survival. Patients with a favorable pretreatment diffusion MRI phenotype had a significantly longer TTG and slower regrowth. Conclusions: Recurrent glioblastoma patients with a large, durable radiographic response to antiangiogenic agents have significantly longer survival. This information is useful for interpreting activity of antiangiogenic agents in recurrent glioblastoma.