DEGRO practical guideline for central nervous system radiation necrosis part 1: classification and a multistep approach for diagnosis

Denise Bernhardt^{1

2}, Laila König^{3

4

5

6

7}, Anca Grosu^{8

9}, Benedikt Wiestler¹⁰, Stefan Rieken¹¹, Wolfgang Wick^{12

13}, Jens Gempt¹⁴, Sandro M Krieg¹⁴, Friederike Schmidt-Graf¹⁵, Felix Sahm¹⁶, Bernhard Meyer¹⁴, Bernd J Krause¹⁷, Cordula Petersen¹⁸, Rainer Fietkau^{19

20}, Michael Thomas^{21

22}, Frank Giordano²³, Andrea Wittig-Sauerwein²⁴, Jürgen Debus^{8

3

4

5

6

7}, Ghazaleh Tabatabai^{25

26

27

28}, Peter Hau²⁹, Joachim Steinbach³⁰, Stephanie E Combs^{31

32

8}; Expert Panel of the German Society of Radiation Oncology (DEGRO)

Affiliations

¹ Klinik und Poliklinik für Radioonkologie und Strahlentherapie, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, München, Germany. denise.bernhardt@mri.tum.de.
² Partner Sites Munich, Freiburg and Heidelberg, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Heidelberg, Germany. denise.bernhardt@mri.tum.de.
³ Klinik für Radioonkologie und Strahlentherapie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
⁴ Heidelberger Ionenstrahltherapie-Zentrum (HIT), Im Neuenheimer Feld 450, 69120, Heidelberg, Germany.
⁵ Heidelberg Institute of Radiation Oncology (HIRO), Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
⁶ Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
⁷ National Center for Tumor diseases (NCT), Heidelberg, Germany.
⁸ Partner Sites Munich, Freiburg and Heidelberg, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Heidelberg, Germany.
⁹ Department of Radiation Oncology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Robert-Koch-Str. 3, 79106, Freiburg, Germany.
¹⁰ Department of Neuroradiology, School of Medicine, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
¹¹ Clinic of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
¹² Clinical Cooperation Unit Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹³ Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
¹⁴ Department of Neurosurgery, School of Medicine, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
¹⁵ Department of Neurology, School of Medicine, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
¹⁶ Department of Neuropathology, University Hospital Heidelberg and CCU Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁷ Department of Nuclear Medicine, Rostock University Medical Centre, Rostock, Germany.
¹⁸ Department of Radiotherapy and Radiation Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
¹⁹ Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
²⁰ Comprehensive Cancer Center Erlangen-European Metropolitan Region of Nuremberg (CCC ER-EMN), Erlangen, Germany.
²¹ Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.
²² Member of the German Center for Lung Research (DZL), Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany.
²³ Department of Radiation Oncology, University Hospital Bonn, Bonn, Germany.
²⁴ Department of Radiotherapy and Radiation Oncology, University Hospital Jena, Bachstr. 18, 07743, Jena, Germany.
²⁵ Department of Neurosurgery, University Hospital Tuebingen, Eberhard Karls University Tuebingen, Tuebingen, Germany.
²⁶ Center for Neuro-Oncology, Comprehensive Cancer Center Tuebingen Stuttgart, University Hospital Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
²⁷ Department of Neurology, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
²⁸ Department Interdisciplinary Neuro-Oncology, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
²⁹ Wilhelm Sander-NeuroOncology Unit and Department of Neurology, University Hospital Regensburg, 93053, Regensburg, Germany.
³⁰ Dr Senckenberg Institute of Neurooncology, University Hospital, Frankfurt am Main, Germany.
³¹ Klinik und Poliklinik für Radioonkologie und Strahlentherapie, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, München, Germany.
³² Institute of Radiation Medicine (IRM), Department of Radiation Sciences (DRS), Helmholtz Zentrum München (HMGU), Ingolstädter Landstr. 1, 85764, Oberschleißheim, Germany.

PMID: 36038669
PMCID: PMC9515024
DOI: 10.1007/s00066-022-01994-3

Review

DEGRO practical guideline for central nervous system radiation necrosis part 1: classification and a multistep approach for diagnosis

Denise Bernhardt et al. Strahlenther Onkol. 2022 Oct.

. 2022 Oct;198(10):873-883.

doi: 10.1007/s00066-022-01994-3. Epub 2022 Aug 29.

Authors

Affiliations

¹ Klinik und Poliklinik für Radioonkologie und Strahlentherapie, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, München, Germany. denise.bernhardt@mri.tum.de.
² Partner Sites Munich, Freiburg and Heidelberg, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Heidelberg, Germany. denise.bernhardt@mri.tum.de.
³ Klinik für Radioonkologie und Strahlentherapie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
⁴ Heidelberger Ionenstrahltherapie-Zentrum (HIT), Im Neuenheimer Feld 450, 69120, Heidelberg, Germany.
⁵ Heidelberg Institute of Radiation Oncology (HIRO), Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
⁶ Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
⁷ National Center for Tumor diseases (NCT), Heidelberg, Germany.
⁸ Partner Sites Munich, Freiburg and Heidelberg, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Heidelberg, Germany.
⁹ Department of Radiation Oncology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Robert-Koch-Str. 3, 79106, Freiburg, Germany.
¹⁰ Department of Neuroradiology, School of Medicine, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
¹¹ Clinic of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
¹² Clinical Cooperation Unit Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹³ Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
¹⁴ Department of Neurosurgery, School of Medicine, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
¹⁵ Department of Neurology, School of Medicine, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
¹⁶ Department of Neuropathology, University Hospital Heidelberg and CCU Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁷ Department of Nuclear Medicine, Rostock University Medical Centre, Rostock, Germany.
¹⁸ Department of Radiotherapy and Radiation Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
¹⁹ Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
²⁰ Comprehensive Cancer Center Erlangen-European Metropolitan Region of Nuremberg (CCC ER-EMN), Erlangen, Germany.
²¹ Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.
²² Member of the German Center for Lung Research (DZL), Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany.
²³ Department of Radiation Oncology, University Hospital Bonn, Bonn, Germany.
²⁴ Department of Radiotherapy and Radiation Oncology, University Hospital Jena, Bachstr. 18, 07743, Jena, Germany.
²⁵ Department of Neurosurgery, University Hospital Tuebingen, Eberhard Karls University Tuebingen, Tuebingen, Germany.
²⁶ Center for Neuro-Oncology, Comprehensive Cancer Center Tuebingen Stuttgart, University Hospital Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
²⁷ Department of Neurology, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
²⁸ Department Interdisciplinary Neuro-Oncology, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
²⁹ Wilhelm Sander-NeuroOncology Unit and Department of Neurology, University Hospital Regensburg, 93053, Regensburg, Germany.
³⁰ Dr Senckenberg Institute of Neurooncology, University Hospital, Frankfurt am Main, Germany.
³¹ Klinik und Poliklinik für Radioonkologie und Strahlentherapie, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, München, Germany.
³² Institute of Radiation Medicine (IRM), Department of Radiation Sciences (DRS), Helmholtz Zentrum München (HMGU), Ingolstädter Landstr. 1, 85764, Oberschleißheim, Germany.

PMID: 36038669
PMCID: PMC9515024
DOI: 10.1007/s00066-022-01994-3

Abstract

Purpose: The Working Group for Neuro-Oncology of the German Society for Radiation Oncology in cooperation with members of the Neuro-Oncology Working Group of the German Cancer Society aimed to define a practical guideline for the diagnosis and treatment of radiation-induced necrosis (RN) of the central nervous system (CNS).

Methods: Panel members of the DEGRO working group invited experts, participated in a series of conferences, supplemented their clinical experience, performed a literature review, and formulated recommendations for medical treatment of RN including bevacizumab in clinical routine.

Conclusion: Diagnosis and treatment of RN requires multidisciplinary structures of care and defined processes. Diagnosis has to be made on an interdisciplinary level with the joint knowledge of a neuroradiologist, radiation oncologist, neurosurgeon, neuropathologist, and neuro-oncologist. A multistep approach as an opportunity to review as many characteristics as possible to improve diagnostic confidence is recommended. Additional information about radiotherapy (RT) techniques is crucial for the diagnosis of RN. Misdiagnosis of untreated and progressive RN can lead to severe neurological deficits. In this practice guideline, we propose a detailed nomenclature of treatment-related changes and a multistep approach for their diagnosis.

Keywords: Bevacizumab; Brain metastases; Glioma; Radioation necrosis; Reirradiation.

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Conflict of interest statement

D. Bernhardt, L. König, A. Grosu, B. Wiestler, S. Rieken, W. Wick, J. Gempt, S.M. Krieg, F. Schmidt-Graf, F. Sahm, B. Meyer, B.J. Krause, C. Petersen, R. Fietkau, M. Thomas, F. Giordano, A. Wittig-Sauerwein, J. Debus, G. Tabatabai, P. Hau, J. Steinbach, and S.E. Combs declare that they have no competing interests. L. König reports grants from Ruprecht-Karls Universität Heidelberg, personal fees from Accuray Inc., and Novocure GmbH outside the submitted work. D. Bernhardt reports personal fees and honoraria from Accuray Inc., AstraZeneca, and Novocure GmbH outside the submitted work. D. Bernhardt’s spouse is employed at Gilead Science. M. Thomas reports personal fees, honoraria for advisory boards, and research funding from AstraZeneca, Beigene, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Daiichi Sankyo, GlaxoSmithKline, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. F. Giordano reports research grants, honoraria, and travel expenses from Carl Zeiss Meditec AG and NOXXON Pharma AG, personal fees from MVZ Venusberg GmbH, and consulting/speaker honoraria from Bristol Myers Squibb, Medac GmbH, Merck Sharp & Dohme, Elsevier, AstraZeneca, and Guerbet SA. S.M. Krieg is consultant for Brainlab AG (Munich, Germany) and Ulrich Medical (Ulm, Germany). S.M. Krieg received honoraria from Nexstim Plc (Helsinki, Finland), Spineart Deutschland GmbH (Frankfurt, Germany), Medtronic (Meerbusch, Germany), and Carl Zeiss Meditec (Oberkochen, Germany). J. Debus: institution received research grants from Merck Serono, institution received consultation honoraria from Merck serono, J. Debus received travel reimbursement from Merck Serono, institution received research grants from Siemens Healthineers and Accuray.

Figures

**Fig. 1**
Pathogenesis of blood–brain barrier disruptions and radionecrosis with the targeting point of bevacizumab as an inhibitor of vascular endothelial growth factor, therefore being a potent effector for disrupting the vicious cycle (adaption of Fig. 1 from Zhuang et al. [15])

See this image and copyright information in PMC

References

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DEGRO practical guideline for central nervous system radiation necrosis part 1: classification and a multistep approach for diagnosis

Affiliations

DEGRO practical guideline for central nervous system radiation necrosis part 1: classification and a multistep approach for diagnosis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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