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Bevacizumab-induced diffusion-restricted lesions in malignant glioma patients

  • Clinical Study - Patient Study
  • Published:
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Abstract

Bevacizumab is an anti-vascular endothelial growth factor (VEGF) antibody with activity against recurrent malignant glioma inducing high rates of objective responses as assessed by magnetic resonance imaging (MRI). However, the mechanisms of the anti-tumor action of bevacizumab are controversial. In particular, it is unclear whether and when bevacizumab induces hypoxia in gliomas. Vascular normalization with hyperperfusion and enhanced oxygen delivery to the tumor has been suggested as an alternative mechanism. We analyzed diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps in 18 consecutive patients with recurrent malignant glioma before and after exposure to bevacizumab. Stroke-like lesions with diffusion restriction on DWI and corresponding ADC decrease were induced by bevacizumab within the previously enhancing tumor area in 13 of 18 patients. These lesions were detectable as early as 4 weeks after initiation of therapy and were maintained for up to 80 weeks. In one patient, an ADC-decreased lesion was biopsied, and histology showed atypical necrosis and nuclear hypoxia-inducible factor 1alpha upregulation but no tumor recurrence. Normalized regional cerebral blood flow (rCBF) and regional cerebral blood volume (rCBV) were analyzed in selected patients. Both parameters were decreased in responders with diffusion-restricted lesions. Within the tumor bed, bevacizumab induces diffusion-restricted lesions in the presence of reduced rCBF and rCBV. The cause of these alterations is unclear but may involve atypical necrosis and chronic hypoxia.

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Abbreviations

ADC:

Apparent diffusion coefficient

CR:

Complete response

DWI:

Diffusion-weighted imaging

HIF-1α:

Hypoxia-inducible factor-1α

MR:

Minor response

PD:

Progressive disease

PFS:

Progression-free survival

PR:

Partial response

rCBF:

Regional cerebral blood flow

rCBV:

Regional cerebral blood volume

SD:

Stable disease

VEGF:

Vascular endothelial growth factor

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Acknowledgments

The Dr. Senckenberg Institute of Neurooncology is supported by the Dr. Senckenberg Foundation and the Hertie Foundation. J.S. is “Hertie Professor of Neurooncology”.

Disclosures

Prof. Steinbach has served as a consultant for Roche, the European distributor of bevacizumab (Avastin). The other authors report no disclosures.

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Authors and Affiliations

  1. Dr. Senckenberg Institute of Neurooncology, Goethe-University Frankfurt, Schleusenweg 2-16, 60528, Frankfurt, Germany

    Johannes Rieger, Oliver Bähr & Joachim Steinbach

  2. Edinger Institute, Goethe-University Frankfurt, Heinrich Hoffmann Strasse 7, 60528, Frankfurt, Germany

    Klaus Müller

  3. Department of Neurosurgery, Goethe-University Frankfurt, Schleusenweg 2-16, 60528, Frankfurt, Germany

    Kea Franz

  4. Institute for Neuroradiology, Goethe-University Frankfurt, Schleusenweg 2-16, 60528, Frankfurt, Germany

    Elke Hattingen

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  1. Johannes Rieger
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Correspondence to Johannes Rieger.

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Rieger, J., Bähr, O., Müller, K. et al. Bevacizumab-induced diffusion-restricted lesions in malignant glioma patients. J Neurooncol 99, 49–56 (2010). https://doi.org/10.1007/s11060-009-0098-8

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  • DOI: https://doi.org/10.1007/s11060-009-0098-8

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