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

Abstract

<div>AbstractPurpose:<p>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.</p>Experimental Design:<p><i>N</i> = 276 patients in two phase II trials were used as training data, including bevacizumab ± irinotecan (NCT00345163) and cabozantinib (NCT00704288), and <i>N</i> = 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 (<i>g</i>) and regression (<i>d</i>) rates, time to tumor regrowth (<i>TTG</i>), and the depth of response (<i>DpR</i>). Response characteristics were compared to diffusion MR phenotypes previously shown to predict survival.</p>Results:<p>Optimized thresholds occurred at <i>g</i> = 0.07 months<sup>−1</sup> (phase II: HR = 0.2579, <i>P</i> = 5 × 10<sup>−20</sup>; phase III: HR = 0.2197, <i>P</i> = 5 × 10<sup>−5</sup>); d = 0.11 months<sup>−1</sup> (HR = 0.3365, <i>P</i> < 0.0001; HR = 0.3675, <i>P</i> = 0.0113); <i>TTG</i> = 3.8 months (HR = 0.2702, <i>P</i> = 6 × 10<sup>−17</sup>; HR = 0.2061, <i>P</i> = 2 × 10<sup>−5</sup>); and <i>DpR</i> = 11.3% (HR = 0.6326, <i>P</i> = 0.0028; HR = 0.4785, <i>P</i> = 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 <i>TTG</i> and slower regrowth.</p>Conclusions:<p>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.</p></div>