Developing an advanced risk stratification model for pediatric intracranial ependymoma based on the prospective trial E-HIT2000 and subsequent registries

Katja von Hoff^{1

2

3}, Denise Obrecht-Sturm¹, David R Ghasemi^{1

4

5

6

7

8

9}, Janna Wenning¹, Martin Mynarek^{1

9}, Nicolas U Gerber¹⁰, Martin Benesch¹¹, Björn O Juhnke¹, Brigitte Bison¹², Monika Warmuth-Metz¹³, Beate Timmermann^{14

15}, Andreas Faldum¹⁶, Stephan Tippelt¹⁷, Gudrun Fleischhack¹⁷, Michael Grotzer¹⁰, Pablo Hernáiz Driever³, Andreas Beilken¹⁸, Martin Ebinger¹⁹, Norbert Graf²⁰, Michael C Frühwald²¹, Irene Schmid²², Irene Slavc²³, Arend Koch²⁴, Markus Bergmann²⁵, Christian Hagel²⁶, Roland Coras²⁷, Ingmar Blümcke²⁷, Guido Reifenberger^{28

29}, Jörg Felsberg²⁸, Kathy Keyvani³⁰, Patrick N Harter^{31

32

33}, Marco Prinz³⁴, Ori Staszewski³⁴, Till Acker³⁵, Christine Stadelmann-Nessler³⁶, Christian Hartmann³⁷, Andreas von Deimling^{38

39}, Clemens Sommer⁴⁰, Martin Hasselblatt⁴¹, Markus J Riemenschneider⁴², Camelia-Maria Monoranu⁴³, Elisabeth Rushing⁴⁴, Christine Haberler⁴⁵, Marcel Kool^{4

5

7

46}, Martin Sill^{4

5

7}, Stefan M Pfister^{4

5

6

7}, Ulrich Schüller^{1

26

8}, Torsten Pietsch⁴⁷, Rolf D Kortmann⁴⁸, Robert Kwiecien¹⁶, Hendrik Witt^{4

5

6

7}, Kristian W Pajtler^{4

5

6

7}, Stefan Rutkowski¹; German, Austrian and Swiss HIT-Network

Affiliations

¹ Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.
² Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, and Department of Clinical Medicine, University of Aarhus, Aarhus, Denmark.
³ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology and Hematology, Germany.
⁴ Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
⁵ Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
⁶ Heidelberg University, Heidelberg Faculty of Medicine, Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Germany.
⁷ National Center for Tumor Diseases (NCT) Heidelberg.
⁸ Research Institute Children's Cancer Center, Hamburg, Germany.
⁹ Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁰ Department of Pediatric Oncology, University Children's Hospital Zürich, Zürich, Switzerland.
¹¹ Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Austria.
¹² Diagnostic and interventional Neuroradiology, Faculty of Medicine, University of Augsburg, Augsburg, Germany.
¹³ Institute of Diagnostic and Interventional Neuroradiology, University Hospital Wuerzburg, Würzburg, Germany.
¹⁴ West German Proton Therapy Center Essen (WPE), University Hospital Essen, Essen, Germany.
¹⁵ Clinic for Particle Therapy, University Hospital Essen, Essen, Germany.
¹⁶ Institute of Biostatistics and Clinical Research, Westfälische Wilhelms-Universität Münster, Münster, Germany.
¹⁷ Pediatric Hematology and Oncology, Pediatrics III, Center for Translational Neuro- and Behavioral Sciences (CTNBS), University Hospital of Essen, Essen, Germany.
¹⁸ Department of Pediatrics, Klinikum Braunschweig gGmbH, Braunschweig, Germany.
¹⁹ Department of Hematology and Oncology, University Children's Hospital Tübingen, Tuebingen, Germany.
²⁰ Department of Pediatric Haematology and Oncology, Saarland University Hospital, Homburg, Germany.
²¹ Pediatrics and Adolescent Medicine, Swabian Childrens' Cancer Center, University Medical Center Augsburg, Augsburg, Germany.
²² Division of Pediatric Hematology and Oncology, Dr. von Hauner Children's Hospital, University Hospital Munich, LMU, Munich, Germany.
²³ Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
²⁴ Department of Neuropathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany.
²⁵ Institute of Neuropathology, Center for Pathology, Klinikum Bremen Mitte, Bremen, Germany.
²⁶ Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁷ Department of Neuropathology, University Hospital Erlangen, Member of EpiCARE ERN, Erlangen, Germany.
²⁸ Institute of Neuropathology, Heinrich Heine University, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.
²⁹ German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁰ Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany.
³¹ Institute of Neurology (Edinger Institute), Goethe-University Frankfurt am Main, Frankfurt am Main, Germany.
³² Center for Neuropathology and Prion Research, Faculty of Medicine, LMU Munich, Germany.
³³ German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and University / University Hospital, LMU Munich, Germany.
³⁴ Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany.
³⁵ Institute of Neuropathology, University of Giessen, Giessen, Germany.
³⁶ Institute of Neuropathology, University Medical Center, Göttingen, Germany.
³⁷ Department for Neuropathology, Institute for Pathology, Hannover Medical School, Hannover, Germany.
³⁸ Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.
³⁹ Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴⁰ Department of Neuropathology, University Medical Centre, Johannes Gutenberg-University of Mainz, 55131 Mainz, Germany.
⁴¹ Institute of Neuropathology, University Hospital Münster, Münster, Germany.
⁴² Department of Neuropathology, Regensburg University Hospital, Regensburg, Germany.
⁴³ Department of Neuropathology, Institute for Pathology, University of Würzburg, 97080, Würzburg, Germany.
⁴⁴ Division of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
⁴⁵ Department of Neurology, Division of Neuropathology and Neurochemistry, Medical University of Vienna, Vienna, Austria.
⁴⁶ Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
⁴⁷ Department of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany.
⁴⁸ Department of Radiation Oncology, University of Leipzig, Leipzig, Germany.

PMID: 41026848
DOI: 10.1093/neuonc/noaf218

Developing an advanced risk stratification model for pediatric intracranial ependymoma based on the prospective trial E-HIT2000 and subsequent registries

Katja von Hoff et al. Neuro Oncol. 2025.

. 2025 Sep 30:noaf218.

doi: 10.1093/neuonc/noaf218. Online ahead of print.

Authors

Affiliations

¹ Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.
² Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, and Department of Clinical Medicine, University of Aarhus, Aarhus, Denmark.
³ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology and Hematology, Germany.
⁴ Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
⁵ Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
⁶ Heidelberg University, Heidelberg Faculty of Medicine, Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Germany.
⁷ National Center for Tumor Diseases (NCT) Heidelberg.
⁸ Research Institute Children's Cancer Center, Hamburg, Germany.
⁹ Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁰ Department of Pediatric Oncology, University Children's Hospital Zürich, Zürich, Switzerland.
¹¹ Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Austria.
¹² Diagnostic and interventional Neuroradiology, Faculty of Medicine, University of Augsburg, Augsburg, Germany.
¹³ Institute of Diagnostic and Interventional Neuroradiology, University Hospital Wuerzburg, Würzburg, Germany.
¹⁴ West German Proton Therapy Center Essen (WPE), University Hospital Essen, Essen, Germany.
¹⁵ Clinic for Particle Therapy, University Hospital Essen, Essen, Germany.
¹⁶ Institute of Biostatistics and Clinical Research, Westfälische Wilhelms-Universität Münster, Münster, Germany.
¹⁷ Pediatric Hematology and Oncology, Pediatrics III, Center for Translational Neuro- and Behavioral Sciences (CTNBS), University Hospital of Essen, Essen, Germany.
¹⁸ Department of Pediatrics, Klinikum Braunschweig gGmbH, Braunschweig, Germany.
¹⁹ Department of Hematology and Oncology, University Children's Hospital Tübingen, Tuebingen, Germany.
²⁰ Department of Pediatric Haematology and Oncology, Saarland University Hospital, Homburg, Germany.
²¹ Pediatrics and Adolescent Medicine, Swabian Childrens' Cancer Center, University Medical Center Augsburg, Augsburg, Germany.
²² Division of Pediatric Hematology and Oncology, Dr. von Hauner Children's Hospital, University Hospital Munich, LMU, Munich, Germany.
²³ Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
²⁴ Department of Neuropathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany.
²⁵ Institute of Neuropathology, Center for Pathology, Klinikum Bremen Mitte, Bremen, Germany.
²⁶ Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁷ Department of Neuropathology, University Hospital Erlangen, Member of EpiCARE ERN, Erlangen, Germany.
²⁸ Institute of Neuropathology, Heinrich Heine University, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.
²⁹ German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁰ Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany.
³¹ Institute of Neurology (Edinger Institute), Goethe-University Frankfurt am Main, Frankfurt am Main, Germany.
³² Center for Neuropathology and Prion Research, Faculty of Medicine, LMU Munich, Germany.
³³ German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and University / University Hospital, LMU Munich, Germany.
³⁴ Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany.
³⁵ Institute of Neuropathology, University of Giessen, Giessen, Germany.
³⁶ Institute of Neuropathology, University Medical Center, Göttingen, Germany.
³⁷ Department for Neuropathology, Institute for Pathology, Hannover Medical School, Hannover, Germany.
³⁸ Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.
³⁹ Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴⁰ Department of Neuropathology, University Medical Centre, Johannes Gutenberg-University of Mainz, 55131 Mainz, Germany.
⁴¹ Institute of Neuropathology, University Hospital Münster, Münster, Germany.
⁴² Department of Neuropathology, Regensburg University Hospital, Regensburg, Germany.
⁴³ Department of Neuropathology, Institute for Pathology, University of Würzburg, 97080, Würzburg, Germany.
⁴⁴ Division of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
⁴⁵ Department of Neurology, Division of Neuropathology and Neurochemistry, Medical University of Vienna, Vienna, Austria.
⁴⁶ Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
⁴⁷ Department of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany.
⁴⁸ Department of Radiation Oncology, University of Leipzig, Leipzig, Germany.

PMID: 41026848
DOI: 10.1093/neuonc/noaf218

Abstract

Background: Current treatment strategies for pediatric intracranial ependymoma do not consider molecular heterogeneity. Here, we evaluated molecular group-specific determinants of outcome and developed an improved risk stratification model.

Methods: Patients aged 0-21 years with localized intracranial ependymoma were enrolled into the prospective clinical trial E-HIT2000. Treatment included maximum safe surgery, local radiotherapy, and chemotherapy, stratified according to age, histology and, following a major amendment, residual tumor. Clinical data were analyzed in a pooled molecularly annotated cohort with data from patients treated analogously within subsequent registries.

Results: For 291 trial patients, the 5-year PFS and OS were 62±3% and 81±2%, respectively. For the molecularly annotated pooled cohort (n = 228), 5-year PFS/OS were: EPN-PFA (n = 146): 45±4%/77±4%; EPN-PFB (n = 19): 90±7%/100%; EPN-ZFTA (n = 59): 64±7%/86±5%; EPN-YAP1 (n = 4): 50±25%/100%. Patients with EPN-PFA without molecular risk factors (1q gain, and/or subtype EPN-PFA1c/d/e,2a), with complete resection, and postoperative radiotherapy showed favorable outcomes (5-year PFS/OS 75±10%/92±7%). For patients with EPN-PFA with molecular risk factors, prognosis was poor irrespective of residual tumor status (5-year PFS/OS: 33±6%/64±6%). Among EPN-ZFTA, 11/59 tumors were classified as EPN-ZFTA with alternative fusions, associated with inferior PFS (5-year PFS/OS: 36±15%/91±9%). For EPN-ZFTA-RELA, homozygous deletions of CDKN2A were associated with unfavorable outcomes (4-year PFS/OS: 19±16%/57±18% vs. 79±7%/97±3%, p = 0.0001). Finally, we developed a novel stratification model that discriminates standard and intermediate risk patients from those at high risk (p < 0.0001 for PFS and OS).

Conclusions: These results strongly suggest the inclusion of molecular parameters into stratification, and the use of distinct treatment strategies within future ependymoma trials.

Keywords: Clinical trial; DNA methylation profiling; Ependymoma; Molecular stratification; Risk stratification.

© The Author(s) 2025. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

PubMed Disclaimer

LinkOut - more resources

Full Text Sources
- Ovid Technologies, Inc.
- Silverchair Information Systems
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Developing an advanced risk stratification model for pediatric intracranial ependymoma based on the prospective trial E-HIT2000 and subsequent registries

Affiliations

Developing an advanced risk stratification model for pediatric intracranial ependymoma based on the prospective trial E-HIT2000 and subsequent registries

Authors

Affiliations

Abstract

LinkOut - more resources

Full Text Sources

Miscellaneous