TY - JOUR
T1 - Diffusion MRI phenotypes predict overall survival benefit from Anti-VEGF monotherapy in recurrent glioblastoma
T2 - Converging evidence from phase II trials
AU - Ellingson, Benjamin M.
AU - Gerstner, Elizabeth R.
AU - Smits, Marion
AU - Huang, Raymond Y.
AU - Colen, Rivka
AU - Abrey, Lauren E.
AU - Aftab, Dana T.
AU - Schwab, Gisela M.
AU - Hessel, Colin
AU - Harris, Robert J.
AU - Chakhoyan, Ararat
AU - Gahrmann, Renske
AU - Pope, Whitney B.
AU - Leu, Kevin
AU - Raymond, Catalina
AU - Woodworth, Davis C.
AU - De Groot, John
AU - Wen, Patrick Y.
AU - Batchelor, Tracy T.
AU - Van Den Bent, Martin J.
AU - Cloughesy, Timothy F.
N1 - Funding Information:
This study was financially supported by the American Cancer Society (ACS) Research Scholar Grant (RSG-15-003-01-CCE; B.M. Ellingson), the American Brain Tumor Association (ABTA) Research Collaboration Grant supported by Humor to Fight the Tumor (ARC1700002; B.M. Ellingson), the National Brain Tumor Society (NBTS) Research Grant (B.M. Ellingson, T.F. Cloughesy), the Art of the Brain (T.F. Cloughesy), the Ziering Family Foundation in memory of Sigi Ziering (Cloughesy), the Singleton Family Foundation (T.F. Cloughesy), NIHR01CA129371 (T.T. Batchelor), NIHR21CA117079 (T.T. Batchelor), and NIHK24CA125440 (T.T. Batchelor).
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/10/1
Y1 - 2017/10/1
N2 - 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 mm2/ms produced the largest OS differences between patients (HR 0.5), and patients with an ADCL > 1.24 mm2/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.
AB - 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 mm2/ms produced the largest OS differences between patients (HR 0.5), and patients with an ADCL > 1.24 mm2/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.
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U2 - 10.1158/1078-0432.CCR-16-2844
DO - 10.1158/1078-0432.CCR-16-2844
M3 - Article
C2 - 28655794
AN - SCOPUS:85032032062
SN - 1078-0432
VL - 23
SP - 5745
EP - 5756
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -