Michelle M Kim1, Madhava P Aryal1, Yilun Sun1,2, Hemant A Parmar3, Pin Li2, Matthew Schipper2, Daniel R Wahl1, Theodore S Lawrence1, Yue Cao1,3,4. 1. Department of Radiation Oncology, The University of Michigan, Ann Arbor, Michigan, USA. 2. Department of Biostatistics, The University of Michigan, Ann Arbor, Michigan, USA. 3. Department of Radiology, The University of Michigan, Ann Arbor, Michigan, USA. 4. Department of Biomedical Engineering, The University of Michigan, Ann Arbor, Michigan, USA.
Abstract
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.
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.
Authors: Paul J Keall; Caterina Brighi; Carri Glide-Hurst; Gary Liney; Paul Z Y Liu; Suzanne Lydiard; Chiara Paganelli; Trang Pham; Shanshan Shan; Alison C Tree; Uulke A van der Heide; David E J Waddington; Brendan Whelan Journal: Nat Rev Clin Oncol Date: 2022-04-19 Impact factor: 65.011
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Authors: Caterina Brighi; Paul J Keall; Lois C Holloway; Amy Walker; Brendan Whelan; Philip C de Witt Hamer; Niels Verburg; Farhannah Aly; Cathy Chen; Eng-Siew Koh; David E J Waddington Journal: Neurooncol Adv Date: 2022-08-19