Diffusion MRI Phenotypes Predict Overall Survival Benefit from Anti-VEGF Monotherapy in Recurrent Glioblastoma: Converging Evidence from Phase II Trials
Benjamin M Ellingson, Elizabeth R Gerstner, Marion Smits, Raymond Y Huang, Rivka Colen, Lauren E Abrey, Dana T Aftab, Gisela M Schwab, Colin Hessel, Robert J Harris, Ararat Chakhoyan, Renske Gahrmann, Whitney B Pope, Kevin Leu, Catalina Raymond, Davis C Woodworth, John de Groot, Patrick Y Wen, Tracy T Batchelor, Martin J van den Bent, Timothy F Cloughesy, Benjamin M Ellingson, Elizabeth R Gerstner, Marion Smits, Raymond Y Huang, Rivka Colen, Lauren E Abrey, Dana T Aftab, Gisela M Schwab, Colin Hessel, Robert J Harris, Ararat Chakhoyan, Renske Gahrmann, Whitney B Pope, Kevin Leu, Catalina Raymond, Davis C Woodworth, John de Groot, Patrick Y Wen, Tracy T Batchelor, Martin J van den Bent, Timothy F Cloughesy
Abstract
Purpose: Anti-VEGF therapies remain controversial in the treatment of recurrent glioblastoma (GBM). In the current study, we demonstrate that recurrent GBM patients with a specific diffusion MR imaging signature have an overall survival (OS) advantage when treated with cediranib, bevacizumab, cabozantinib, or aflibercept monotherapy at first or second recurrence. These findings were validated using a separate trial comparing bevacizumab with lomustine.Experimental Design: Patients with recurrent GBM and diffusion MRI from the monotherapy arms of 5 separate phase II clinical trials were included: (i) cediranib (NCT00035656); (ii) bevacizumab (BRAIN Trial, AVF3708g; NCT00345163); (iii) cabozantinib (XL184-201; NCT00704288); (iv) aflibercept (VEGF Trap; NCT00369590); and (v) bevacizumab or lomustine (BELOB; NTR1929). Apparent diffusion coefficient (ADC) histogram analysis was performed prior to therapy to estimate "ADCL," the mean of the lower ADC distribution. Pretreatment ADCL, enhancing volume, and clinical variables were tested as independent prognostic factors for OS.Results: The coefficient of variance (COV) in double baseline ADCL measurements was 2.5% and did not significantly differ (P = 0.4537). An ADCL threshold of 1.24 μm2/ms produced the largest OS differences between patients (HR ∼ 0.5), and patients with an ADCL > 1.24 μm2/ms had close to double the OS in all anti-VEGF therapeutic scenarios tested. Training and validation data confirmed that baseline ADCL was an independent predictive biomarker for OS in anti-VEGF therapies, but not in lomustine, after accounting for age and baseline enhancing tumor volume.Conclusions: Pretreatment diffusion MRI is a predictive imaging biomarker for OS in patients with recurrent GBM treated with anti-VEGF monotherapy at first or second relapse. Clin Cancer Res; 23(19); 5745-56. ©2017 AACR.
Conflict of interest statement
Conflicts of Interest related to this Manuscript: Benjamin M. Ellingson, Albert Lai, Tracy Batchelor, and Timothy F. Cloughesy are paid consultants, members of the advisory board, and are research grant recipients from Roche/Genentech. Lauren E Abrey is an employee for Roche/Genentech. Dana T. Aftab, Gisela M. Schwab, and Colin Hessel are paid employees and stockholders for Exelixis. Tracy Batchelor is a consultant for Merck, Proximagen/Upsher, Oxigene, Cavion, and Accerta and has research support from Pfizer. Martin van den Bent has received research support from Roche. Marion Smits is a paid independent reviewer for Parexel.
©2017 American Association for Cancer Research.
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Source: PubMed