Response assessment during chemoradiation using a hypercellular/hyperperfused imaging phenotype predicts survival in patients with newly diagnosed glioblastoma

Background. Adversely prognostic hypercellular and hyperperfused regions of glioblastoma (GBM) predict progression-free survival, and are a novel target for dose-intensified chemoradiation (chemoRT) recently implemented in a phase II clinical trial. As a secondary aim, we hypothesized that dose-intensified chemoRT would induce greater mid-treatment response of hypercellular/hyperperfused tumor regions vs standard chemoradiation, and that early response would improve overall survival (OS). Methods. Forty-nine patients with newly diagnosed GBM underwent prospective, multiparametric high b value diffusion-weighted MRI (DW-MRI) and perfusion dynamic contrast-enhanced MRI (DCE-MRI) pre-RT and 3-4 weeks into RT. The hypercellular tumor volume (TVHCV, mean contralateral normal brain + 2SD) and hyperperfused tumor volume (TVCBV, contralateral normal frontal gray matter + 1SD) were generated using automated thresholding. Twenty-six patients were enrolled on a dose-escalation trial targeting TVHCV/TVCBV with 75 Gy in 30 fractions, and 23 non-trial patients comprised the control group. OS was estimated using the Kaplan-Meier method and compared using the log-rank test. The effect of TVHCV/TVCBV and Gd-enhanced tumor volume on OS was assessed using multivariable Cox proportional-hazard regression. Results. Most patients had gross total (47%) or subtotal resection (37%), 25% were MGMT-methylated. Patients treated on the dose-escalation trial had significantly greater reduction in TVHCV/TVCBV (41% reduction, IQR 17%-75%) vs non-trial patients (6% reduction, IQR 6%-22%, P = .002). An increase in TVHCV/TVCBV during chemoRT was associated with worse OS (adjusted hazard ratio [aHR] 1.2, 95%CI 1.0-1.4, P = .02), while pre-treatment tumor volumes (P > .5) and changes in Gd-enhanced volume (P = .9) were not. Conclusions. Multiparametric MRI permits identification of therapeutic resistance during chemoRT and supports adaptive strategies in future trials.