Leif Østergaard

Noninvasive Characterization of Tumor Angiogenesis and Oxygenation in Bevacizumab-treated Recurrent Glioblastoma by Using Dynamic Susceptibility MRI: Secondary Analysis of the European Organization for Research and Treatment of Cancer 26101 Trial

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Philipp Kickingereder, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Gianluca Brugnara, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Mikkel Bo Hansen
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  • Martha Nowosielski, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Irada Pflüger, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Marianne Schell, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Fabian Isensee, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Martha Foltyn, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Ulf Neuberger, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Tobias Kessler, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Felix Sahm, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Antje Wick, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Sabine Heiland, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Michael Weller, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Michael Platten, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Andreas von Deimling, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Klaus H Maier-Hein, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
  • ,
  • Leif Østergaard
  • Martin J van den Bent, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Thierry Gorlia, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Wolfgang Wick, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Martin Bendszus, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg

Background Relevance of antiangiogenic treatment with bevacizumab in patients with glioblastoma is controversial because progression-free survival benefit did not translate into an overall survival (OS) benefit in randomized phase III trials. Purpose To perform longitudinal characterization of intratumoral angiogenesis and oxygenation by using dynamic susceptibility contrast agent-enhanced (DSC) MRI and evaluate its potential for predicting outcome from administration of bevacizumab. Materials and Methods In this secondary analysis of the prospective randomized phase II/III European Organization for Research and Treatment of Cancer 26101 trial conducted between October 2011 and December 2015 in 596 patients with first recurrence of glioblastoma, the subset of patients with availability of anatomic MRI and DSC MRI at baseline and first follow-up was analyzed. Patients were allocated into those administered bevacizumab (hereafter, the BEV group; either bevacizumab monotherapy or bevacizumab with lomustine) and those not administered bevacizumab (hereafter, the non-BEV group with lomustine monotherapy). Contrast-enhanced tumor volume, noncontrast-enhanced T2 fluid-attenuated inversion recovery (FLAIR) signal abnormality volume, Gaussian-normalized relative cerebral blood volume (nrCBV), Gaussian-normalized relative blood flow (nrCBF), and tumor metabolic rate of oxygen (nTMRO2) was quantified. The predictive ability of these imaging parameters was assessed with multivariable Cox regression and formal interaction testing. Results A total of 254 of 596 patients were evaluated (mean age, 57 years ± 11; 155 men; 161 in the BEV group and 93 in non-BEV group). Progression-free survival was longer in the BEV group (3.7 months; 95% confidence interval [CI]: 3.0, 4.2) compared with the non-BEV group (2.5 months; 95% CI: 1.5, 2.9; P = .01), whereas OS was not different (P = .15). The nrCBV decreased for the BEV group (-16.3%; interquartile range [IQR], -39.5% to 12.0%; P = .01), but not for the non-BEV group (1.2%; IQR, -17.9% to 23.3%; P = .19) between baseline and first follow-up. An identical pattern was observed for both nrCBF and nTMRO2 values. Contrast-enhanced tumor and noncontrast-enhanced T2 FLAIR signal abnormality volumes decreased for the BEV group (-66% [IQR, -83% to -35%] and -33% [IQR, -71% to -5%], respectively; P < .001 for both), whereas they increased for the non-BEV group (30% [IQR, -17% to 98%], P = .001; and 10% [IQR, -13% to 82%], P = .02, respectively) between baseline and first follow-up. None of the assessed MRI parameters were predictive for OS in the BEV group. Conclusion Bevacizumab treatment decreased tumor volumes, angiogenesis, and oxygenation, thereby reflecting its effectiveness for extending progression-free survival; however, these parameters were not predictive of overall survival (OS), which highlighted the challenges of identifying patients that derive an OS benefit from bevacizumab. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Dillon in this issue.

Original languageEnglish
Article number200978
JournalRadiology
Volume297
Issue1
Number of pages12
ISSN0033-8419
DOIs
Publication statusPublished - 2020

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