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Tumor growth patterns of MGMT-non-methylated glioblastoma in the randomized GLARIUS trial

  • Original Article – Clinical Oncology
  • Published:
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Abstract

Background

We evaluated patterns of tumor growth in patients with newly diagnosed MGMT-non-methylated glioblastoma who were assigned to undergo radiotherapy in conjunction with bevacizumab/irinotecan (BEV/IRI) or standard temozolomide (TMZ) within the randomized phase II GLARIUS trial.

Methods

In 142 patients (94 BEV/IRI, 48 TMZ), we reviewed magnetic resonance imaging scans at baseline and first tumor recurrence. Based on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery images, we assessed tumor growth patterns and tumor invasiveness. Tumor growth patterns were classified as either multifocal or local at baseline and recurrence; at first recurrence, we additionally assessed whether distant lesions appeared. Invasiveness was determined as either diffuse or non-diffuse. Associations with treatment arms were calculated using Fisher’s exact test.

Results

At baseline, 115 of 142 evaluable patients (81%) had a locally confined tumor. Between treatment arms, there was no significant difference in the fraction of tumors that changed from an initially local tumor growth pattern to a multifocal pattern (12 and 13%, p = 0.55). Distant lesions appeared in 17% (BEV/IRI) and 13% (TMZ) of patients (p = 0.69). 15% of patients in the BEV/IRI arm and 8% in the TMZ arm developed a diffuse growth pattern from an initially non-diffuse pattern (p = 0.42).

Conclusions

The tumor growth and invasiveness patterns do not differ between BEV/IRI and TMZ-treated MGMT-non-methylated glioblastoma patients in the GLARIUS trial. BEV/IRI was not associated with an increased rate of multifocal, distant, or highly invasive tumors at the time of recurrence.

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Funding

Christina Schaub, no relationship to disclose. Sied Kebir, no relationship to disclose. Nina Junold, no relationship to disclose. Elke Hattingen, no relationship to disclose. Niklas Schäfer, Honoraria: Roche Travel, Accommodations, Expenses: Roche. Joachim P. Steinbach, Honoraria: Medac. Consulting or Advisory Role: Roche, Mundipharma, Speakers’ Bureau: Medac. Research Funding: Merck, Travel, Accommodations, Expenses: Roche, Medac,. Astrid Weyerbrock. Research Funding: Roche Pharma AG, Expert Testimony: Roche Pharma AG. Peter Hau, Honoraria: Roche, Consulting or Advisory Role: Roche, BMS, Novocure, Speakers’ Bureau: Roche, Novocure, Medac. Travel, Accommodations, Expenses: Roche, Novocure, Medac. Roland Goldbrunner. Consulting or Advisory Role: Magforce, Roche. Travel, Accommodations, Expenses: Magforce, Roche. Michael Niessen, no relationship to disclose. Frederic Mack, Honoraria: Roche, Consulting or Advisory Role: Roche, Research Funding: Roche. Moritz Stuplich, no relationship to disclose. Theophilos Tzaridis, no relationship to disclose. Oliver Bähr, no relationship to disclose. Rolf-Dieter Kortmann, no relationship to disclose. Uwe Schlegel, Honoraria: Roche, GlaxoSmithKline, Medac, Consulting or Advisory Role: Roche, Travel, Accommodations, Expenses: Roche, GlaxoSmithKline, Medac. Friederike Schmidt-Graf, no relationship to disclose. Veit Rohde, no relationship to disclose. Christian Braun, no relationship to disclose. Mathias Hänel, no relationship to disclose. Michael Sabel, no relationship to disclose. Rüdiger Gerlach. Honoraria: CSL Behring, Bayer, Medtronic. Consulting or Advisory Role: Bayer. Dietmar Krex Honoraria: Northwest Biotherapeutics. Consulting or Advisory Role: Baxter. Consulting or Advisory Role: Novocure. Claus Belka, no relationship to disclose Hartmut Vatter, no relationship to disclose. Martin Proescholdt. Employment: Roche, Consulting or Advisory Role: Roche Pharma AG. Travel, Accommodations, Expenses: Roche, Ulrich Herrlinger. Honoraria: Roche Pharma AG, Mundipharma. Consulting or Advisory Role: Roche Pharma AG, Mundipharma. Speakers’ Bureau: Roche Pharma AG, Mundipharma, Medac. Research Funding: Roche Pharma AG, Medac. Travel, Accommodations, Expenses: Roche Pharma AG. Martin Glas. Honoraria: Roche Pharma AG, Mundipharma. Consulting or Advisory Role: Novartis AG, Roche Pharma AG, Mundipharma. Travel, Accommodations, Expenses: Medac.

Author information

Author notes

  1. Christina Schaub, Sied Kebir, Nina Junold, Ulrich Herrlinger and Martin Glas contributed equally.

Authors and Affiliations

  1. Division of Clinical Neurooncology, Department of Neurology, University of Bonn Medical Center, Bonn, Germany

    Christina Schaub, Sied Kebir, Nina Junold, Niklas Schäfer, Michael Niessen, Frederic Mack, Moritz Stuplich, Theophilos Tzaridis, Ulrich Herrlinger & Martin Glas

  2. West German Cancer Center (WTZ), University Hospital Essen and German Cancer Consortium, Partner Site University Hospital Essen, University Duisburg-Essen, Essen, Germany

    Sied Kebir, Niklas Schäfer & Martin Glas

  3. Neuroradiology; Department of Radiology, University of Bonn Medical Center, Bonn, Germany

    Elke Hattingen

  4. Dr. Senckenberg Institute of Neurooncology, University of Frankfurt, Frankfurt, Germany

    Joachim P. Steinbach & Oliver Bähr

  5. Department of Neurosurgery, University of Freiburg, Freiburg, Germany

    Astrid Weyerbrock

  6. Department of Neurology and Wilhelm Sander NeuroOncology Unit, University of Regensburg, Regensburg, Germany

    Peter Hau

  7. Department of Neurosurgery, University of Cologne, Cologne, Germany

    Roland Goldbrunner

  8. Department of Radiation Oncology, University of Leipzig, Leipzig, Germany

    Rolf-Dieter Kortmann

  9. Department of Neurology, Knappschaftskrankenhaus Klinikum der Ruhr-Universität Bochum, Bochum, Germany

    Uwe Schlegel

  10. Department of Neurology, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany

    Friederike Schmidt-Graf

  11. Department of Neurosurgery, Georg-August-University, Göttingen, Germany

    Veit Rohde

  12. Department of Neurology, University Hospital Tübingen, Tübingen, Germany

    Christian Braun

  13. Department of Internal Medicine III, Klinikum Chemnitz gGmbH, Chemnitz, Germany

    Mathias Hänel

  14. Department of Neurosurgery, Medizinische Fakultät, Heinrich-Heine-Universität, Düsseldorf, Germany

    Michael Sabel

  15. Department of Neurosurgery, HELIOS Klinikum Erfurt, Erfurt, Germany

    Rüdiger Gerlach

  16. Department of Neurosurgery, Technical University Dresden, Dresden, Germany

    Dietmar Krex

  17. Department of Radiation Oncology, LMU Munich, Munich, Germany

    Claus Belka

  18. Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany

    Hartmut Vatter

  19. Department of Neurosurgery, University of Regensburg, Regensburg, Germany

    Martin Proescholdt

  20. Division of Clinical Neurooncology, Department of Neurology, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    Sied Kebir & Martin Glas

Authors
  1. Christina Schaub
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  2. Sied Kebir
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  3. Nina Junold
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  4. Elke Hattingen
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  5. Niklas Schäfer
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  6. Joachim P. Steinbach
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  7. Astrid Weyerbrock
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  8. Peter Hau
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  9. Roland Goldbrunner
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  10. Michael Niessen
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  15. Rolf-Dieter Kortmann
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  16. Uwe Schlegel
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  20. Mathias Hänel
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  21. Michael Sabel
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  27. Ulrich Herrlinger
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  28. Martin Glas
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Contributions

CS acquisition of data, analysis and interpretation of data, manuscript writing. SK cquisition of data, analysis and interpretation of data, manuscript writing. NJ acquisition of data, analysis and interpretation of data. EH acquisition of data, analysis and interpretation of data, critical manuscript revision. NS cquisition of data, analysis and interpretation of data, critical manuscript revision. JPS acquisition of data, analysis and interpretation of data, critical manuscript revision. AW acquisition of data, analysis and interpretation of data, critical manuscript revision. PH acquisition of data, analysis and interpretation of data, critical manuscript revision. RG acquisition of data, analysis and interpretation of data, critical manuscript revision. MN acquisition of data, analysis and interpretation of data, critical manuscript revision. FM acquisition of data, analysis and interpretation of data, critical manuscript revision. MS acquisition of data, analysis and interpretation of data, critical manuscript revision. TT acquisition of data, analysis and interpretation of data, critical manuscript revision. OB acquisition of data, analysis and interpretation of data, critical manuscript revision. RDK acquisition of data, analysis and interpretation of data, critical manuscript revision. US acquisition of data, analysis and interpretation of data, critical manuscript revision. FSG acquisition of data, analysis and interpretation of data, critical manuscript revision. VR acquisition of data, analysis and interpretation of data, critical manuscript revision. CB acquisition of data, analysis and interpretation of data, critical manuscript revision. MH acquisition of data, analysis and interpretation of data, critical manuscript revision. MS acquisition of data, analysis and interpretation of data, critical manuscript revision. RG acquisition of data, analysis and interpretation of data, critical manuscript revision. DK acquisition of data, analysis and interpretation of data, critical manuscript revision. CB acquisition of data, analysis and interpretation of data, critical manuscript revision. HV acquisition of data, analysis and interpretation of data, critical manuscript revision. MP acquisition of data, analysis and interpretation of data, critical manuscript revision. UH acquisition of data, analysis and interpretation of data, critical manuscript revision, study concept and design. MG acquisition of data, analysis and interpretation of data, critical manuscript revision, study concept and design.

Corresponding author

Correspondence to Martin Glas.

Ethics declarations

Conflict of interest

Ulrich Herrlinger has served as a consultant for Roche, Novocure, Mundipharma, Noxxon and Bristol-Myers-Squibb. He has received a scientific grant from Roche and speakers honoraria from Roche, Medac, and Riemser Pharma. Martin Glas has served as a consultant for Roche, Novartis, Mundipharma, sigma tau and UCB Corporation. He has received speakers honoraria from Roche, Medac and sigma tau, and a scientific grant from Medac. Niklas Schäfer received honoraria from Roche. All other authors declare that they have no conflict of interest.

Ethical approval

GLARIUS was a randomized, controlled, unblinded, phase II trial (EudraCT No. 2009010390-21; ClinicalTrials.gov NCT00967330) approved by ethic committees of all participating centers. All patients gave written informed consent. All trial procedures adhered to the Declaration of Helsinki and the Guidelines of Good Clinical Practice. An independent data monitoring and safety board constantly reviewed all safety-relevant information.The trial was funded by Roche Pharmaceuticals. Data collection was performed by an independent clinical research organization funded by Roche. The principal investigator (U.H.) had full access to the data, reviewed all data, and had the final responsibility for manuscript submission.

Statement of translational relevance

There is conflicting data as to whether angiogenesis inhibitors such as bevacizumab induce more distant and/or invasive recurrent tumors as compared to alkylating standard chemotherapy in malignant glioma. In recurrent glioblastoma, a radiographically determined increase in distant and infiltrative growth pattern has been linked to bevacizumab treatment. However, almost all these data stem from uncontrolled retrospective observations after failure of standard alkylating chemotherapy with temozolomide. Given bevacizumab treatment has become a standard in the recurrence scenario, it is important to shed light on this issue. To this end, we assessed the tumor growth patterns at first recurrence of patients in the GLARIUS trial, a randomized phase II trial comparing treatment with bevacizumab/irinotecan vs standard temozolomide in MGMT-non-methylated glioblastoma. We show that recurrence patterns (invasiveness and tumor growth) are similar in both groups, thus not supporting the hypothesis of a bevacizumab induced invasive or distant tumor recurrence phenotype.

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Schaub, C., Kebir, S., Junold, N. et al. Tumor growth patterns of MGMT-non-methylated glioblastoma in the randomized GLARIUS trial. J Cancer Res Clin Oncol 144, 1581–1589 (2018). https://doi.org/10.1007/s00432-018-2671-z

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  • DOI: https://doi.org/10.1007/s00432-018-2671-z

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