. 2023 Aug:189:112913.

doi: 10.1016/j.ejca.2023.05.002. Epub 2023 May 8.

Long-term survival with IDH wildtype glioblastoma: first results from the ETERNITY Brain Tumor Funders' Collaborative Consortium (EORTC 1419)

Caroline Hertler¹, Jörg Felsberg², Dorothee Gramatzki¹, Emilie Le Rhun³, Jennifer Clarke⁴, Riccardo Soffietti⁵, Wolfgang Wick⁶, Olivier Chinot⁷, François Ducray⁸, Patrick Roth¹, Kerrie McDonald⁹, Peter Hau¹⁰, Andreas F Hottinger¹¹, Jaap Reijneveld¹², Oliver Schnell¹³, Christine Marosi¹⁴, Michael Glantz¹⁵, Amélie Darlix¹⁶, Giuseppe Lombardi¹⁷, Dietmar Krex¹⁸, Martin Glas¹⁹, David A Reardon²⁰, Martin van den Bent²¹, Florence Lefranc²², Ulrich Herrlinger²³, Evangelia Razis²⁴, Antoine F Carpentier²⁵, Samuel Phillips⁴, Roberta Rudà⁵, Antje Wick²⁶, Emeline Tabouret⁷, David Meyronet²⁷, Claude-Alain Maurage²⁸, Elisabeth Rushing²⁹, Robert Rapkins⁹, Elisabeth Bumes¹⁰, Monika Hegi³⁰, Astrid Weyerbrock³¹, Dawit Aregawi¹⁵, Christian Gonzalez-Gomez⁴, Alessia Pellerino⁵, Martin Klein³², Matthias Preusser¹⁴, Martin Bendszus³³, Vassilis Golfinopoulos³⁴, Andreas von Deimling³⁵, Thierry Gorlia³⁴, Patrick Y Wen²⁰, Guido Reifenberger³⁶, Michael Weller³⁷

Affiliations

¹ Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland; Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
² Institute of Neuropathology, Medical Faculty, Heinrich Heine University and University Hospital Düsseldorf, Düsseldorf, Germany.
³ Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland; Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland; Service de neurochirurgie, CHU Lille, F-59000 Lille, France; Univ. Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), Lille, France.
⁴ UCSF Department of Neurological Surgery, Division of Neuro-Oncology, 400 Parnassus Avenue, A-808 San Francisco, CA, USA.
⁵ Division of Neuro-Oncology, Department of Neuroscience, University and City of Health and Science Hospital, Turin, Italy.
⁶ Neurology Clinic, University of Heidelberg, Heidelberg, Germany; CCU Neurooncology, DKFZ, Heidelberg, Germany.
⁷ Aix-Marseille Univ, APHM, CNRS, INP, Inst Neurophysiopathol, CHU Timone, Service de Neuro-Oncologie, Marseille, France.
⁸ Departments of Neuro-Oncology, Hospices Civils de Lyon, Centre de recherche en Cancérologie de Lyon, Lyon, France; INSERM U1052, CNRS UMR 5286, Université Lyon 1, Lyon, France.
⁹ Cure Brain Cancer Neuro-Oncology group, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
¹⁰ Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University Hospital Regensburg, Regensburg, Germany.
¹¹ Lundin Family Brain Tumor Center, Departments of Oncology & Clinical Neurosciences, CHUV Lausanne University Hospital, Lausanne, Switzerland.
¹² Amsterdam UMC location Vrije Universiteit Amsterdam, Neurology, Brain Tumor Center Amsterdam, Amsterdam, the Netherlands; Department of Neurology, Stichting Epilepsie Instellingen Nederland, Heemstede, the Netherlands.
¹³ Department of Neurosurgery, Medical Center- University of Freiburg, Freiburg, Germany.
¹⁴ Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
¹⁵ Departments of Neurosurgery and Oncology, Penn State College of Medicine - Hershey Medical Center, Hershey, PA, USA.
¹⁶ Department of Medical Oncology, Institut régional du Cancer de Montpellier, University of Montpellier, Montpellier, France; Institut de Génomique Fonctionnelle, INSERM, CNRS, University of Montpellier, Montpellier, France.
¹⁷ Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Via Gattamelata 64, 35128 Padua, Italy.
¹⁸ Department of Neurosurgery, University Hospital Carl Gustav Carus, TU, Dresden, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, Germany.
¹⁹ Division of Clinical Neurooncology, Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, University Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Medicine Essen, Essen, Germany.
²⁰ Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, USA; Harvard Medical School, Boston, USA.
²¹ Brain Tumor Center at ErasmusMC Cancer Institute, Erasmus University Hospital Rotterdam, Rotterdam, the Netherlands.
²² Department of Neurosurgery, Hôpital Universitaire de Bruxelles HUB, Brussels, Belgium.
²³ Division of Clinical Neurooncology, Department of Neurology and Center of Integrated Oncology, University of Bonn, Bonn, Germany.
²⁴ Hygeia Hospital, Athens, Greece.
²⁵ Department of Neurology, Hôpital Saint-Louis, Université Paris Cité, APHP, Paris, France.
²⁶ Neurology Clinic, University of Heidelberg, Heidelberg, Germany.
²⁷ INSERM U1052, CNRS UMR 5286, Université Lyon 1, Lyon, France; Neuropathology, Hospices Civils de Lyon, Centre de recherche en Cancérologie de Lyon, Lyon, France.
²⁸ Service de biochimie et biologie moléculaire, CHU Lille, F-59000 Lille France.
²⁹ Department of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
³⁰ Neuroscience Research Center and Service of Neurosurgery & Lundin Family Brain Tumor Center, Lausanne University Hospital and University of Lausanne, 1066 Epalinges, Switzerland.
³¹ Department of Neurology, Stichting Epilepsie Instellingen Nederland, Heemstede, the Netherlands.
³² Amsterdam UMC location Vrije Universiteit Amsterdam, Medical Psychology, Amsterdam, the Netherlands.
³³ Department of Neuroradiology, University Hospital of Heidelberg, Heidelberg, Germany.
³⁴ EORTC Headquarters, Brussels, Belgium.
³⁵ Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany; CCU Neuropathology, German Cancer Center (DKFZ), Heidelberg, Germany.
³⁶ Institute of Neuropathology, Medical Faculty, Heinrich Heine University and University Hospital Düsseldorf, Düsseldorf, Germany; German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.
³⁷ Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland; Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland. Electronic address: michael.weller@usz.ch.

PMID: 37277265
DOI: 10.1016/j.ejca.2023.05.002

Free article

Long-term survival with IDH wildtype glioblastoma: first results from the ETERNITY Brain Tumor Funders' Collaborative Consortium (EORTC 1419)

Caroline Hertler et al. Eur J Cancer. 2023 Aug.

Free article

. 2023 Aug:189:112913.

doi: 10.1016/j.ejca.2023.05.002. Epub 2023 May 8.

Authors

Affiliations

¹ Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland; Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
² Institute of Neuropathology, Medical Faculty, Heinrich Heine University and University Hospital Düsseldorf, Düsseldorf, Germany.
³ Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland; Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland; Service de neurochirurgie, CHU Lille, F-59000 Lille, France; Univ. Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), Lille, France.
⁴ UCSF Department of Neurological Surgery, Division of Neuro-Oncology, 400 Parnassus Avenue, A-808 San Francisco, CA, USA.
⁵ Division of Neuro-Oncology, Department of Neuroscience, University and City of Health and Science Hospital, Turin, Italy.
⁶ Neurology Clinic, University of Heidelberg, Heidelberg, Germany; CCU Neurooncology, DKFZ, Heidelberg, Germany.
⁷ Aix-Marseille Univ, APHM, CNRS, INP, Inst Neurophysiopathol, CHU Timone, Service de Neuro-Oncologie, Marseille, France.
⁸ Departments of Neuro-Oncology, Hospices Civils de Lyon, Centre de recherche en Cancérologie de Lyon, Lyon, France; INSERM U1052, CNRS UMR 5286, Université Lyon 1, Lyon, France.
⁹ Cure Brain Cancer Neuro-Oncology group, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
¹⁰ Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University Hospital Regensburg, Regensburg, Germany.
¹¹ Lundin Family Brain Tumor Center, Departments of Oncology & Clinical Neurosciences, CHUV Lausanne University Hospital, Lausanne, Switzerland.
¹² Amsterdam UMC location Vrije Universiteit Amsterdam, Neurology, Brain Tumor Center Amsterdam, Amsterdam, the Netherlands; Department of Neurology, Stichting Epilepsie Instellingen Nederland, Heemstede, the Netherlands.
¹³ Department of Neurosurgery, Medical Center- University of Freiburg, Freiburg, Germany.
¹⁴ Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
¹⁵ Departments of Neurosurgery and Oncology, Penn State College of Medicine - Hershey Medical Center, Hershey, PA, USA.
¹⁶ Department of Medical Oncology, Institut régional du Cancer de Montpellier, University of Montpellier, Montpellier, France; Institut de Génomique Fonctionnelle, INSERM, CNRS, University of Montpellier, Montpellier, France.
¹⁷ Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Via Gattamelata 64, 35128 Padua, Italy.
¹⁸ Department of Neurosurgery, University Hospital Carl Gustav Carus, TU, Dresden, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, Germany.
¹⁹ Division of Clinical Neurooncology, Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, University Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Medicine Essen, Essen, Germany.
²⁰ Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, USA; Harvard Medical School, Boston, USA.
²¹ Brain Tumor Center at ErasmusMC Cancer Institute, Erasmus University Hospital Rotterdam, Rotterdam, the Netherlands.
²² Department of Neurosurgery, Hôpital Universitaire de Bruxelles HUB, Brussels, Belgium.
²³ Division of Clinical Neurooncology, Department of Neurology and Center of Integrated Oncology, University of Bonn, Bonn, Germany.
²⁴ Hygeia Hospital, Athens, Greece.
²⁵ Department of Neurology, Hôpital Saint-Louis, Université Paris Cité, APHP, Paris, France.
²⁶ Neurology Clinic, University of Heidelberg, Heidelberg, Germany.
²⁷ INSERM U1052, CNRS UMR 5286, Université Lyon 1, Lyon, France; Neuropathology, Hospices Civils de Lyon, Centre de recherche en Cancérologie de Lyon, Lyon, France.
²⁸ Service de biochimie et biologie moléculaire, CHU Lille, F-59000 Lille France.
²⁹ Department of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
³⁰ Neuroscience Research Center and Service of Neurosurgery & Lundin Family Brain Tumor Center, Lausanne University Hospital and University of Lausanne, 1066 Epalinges, Switzerland.
³¹ Department of Neurology, Stichting Epilepsie Instellingen Nederland, Heemstede, the Netherlands.
³² Amsterdam UMC location Vrije Universiteit Amsterdam, Medical Psychology, Amsterdam, the Netherlands.
³³ Department of Neuroradiology, University Hospital of Heidelberg, Heidelberg, Germany.
³⁴ EORTC Headquarters, Brussels, Belgium.
³⁵ Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany; CCU Neuropathology, German Cancer Center (DKFZ), Heidelberg, Germany.
³⁶ Institute of Neuropathology, Medical Faculty, Heinrich Heine University and University Hospital Düsseldorf, Düsseldorf, Germany; German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.
³⁷ Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland; Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland. Electronic address: michael.weller@usz.ch.

PMID: 37277265
DOI: 10.1016/j.ejca.2023.05.002

Abstract

Background: Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined.

Methods: European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumours, prognostic factors were analysed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich.

Results: At the database lock of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 incompletely characterised) had been registered. In the IDH wildtype population, median age was 56 years (range 24-78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumours with O⁶-methylguanine DNA methyltransferase (MGMT) promoter methylation. Median overall survival was 9.9 years (95% confidence interval [95% CI] 7.9-11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p < 0.001) and had a high rate (48.8%) of MGMT promoter-unmethylated tumours.

Conclusions: Freedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Patients without relapse often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma.

Keywords: IDH; MGMT; Outcome; Prognosis; Registry; Wildtype.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.H. has received a research grant for protected time by the Filling the Gap foundation and honoraria for lecture from Vifor; E.L.R. has received honoraria for lectures or advisory board from Bayer, Janssen, Leo Pharma, Pierre Fabre, Seattle Genetics; J.C. has received research funding from Servier and Merck and consultant for Servier; R.S. reports consultation for Bayer, Astra Zeneca; W.W. reports consultation for Apogenix, Astra Zeneca, Bayer, Enterome, Medac, MSD and Roche/Genentech with honoraria paid to the Medical Faculty at the University of Heidelberg; F.D. has received honoraria for lectures or advisory board participation from Novocure; P.R. has received honoraria for lectures or advisory board participation from Bristol-Myers Squibb, Boehringer Ingelheim, Debiopharm, Merck Sharp and Dohme, Midatech, Novocure, QED, and Roche and research support from Merck Sharp and Dohme and Novocure; P.H. has received honoraria for lectures or advisory board participation or consulting from Bayer, Lilly, medac, Novartis, Novocure and Seagen; A.H. has received honoraria for lectures, consultation or advisory board participation from Novocure and Novartis; G.L. has received funding for a consulting or advisory role from Bayer, AbbVie, Orbus Therapeutics, BrainFarm, Health4U, Novartis, Braun and Janssen, and funding for travel from Roche, Bayer, and Ipsen; D.K. has received honoraria for lectures, consultation or advisory board participation from Novocure and BrainLab; M.G. reports honoraria from Roche, Novartis, UCB, AbbVie, Daiichi Sankyo, Novocure, Seagen, Bayer, Janssen-Cilag, Medac, Merck, Kyowa Kirin, travel support from Novocure and Medac, research grant from Novocure; D.R. reports support from Agenus, Agios; AnHeart Therapeutics, Avita Biomedical, Inc., Blue Rock Therapeutics, Bristol Myers Squibb, Boston Biomedica, CureVac AG, Del Mar Pharma, DNAtrix, Enterome, Hoffman-LaRoche, Ltd, Imvax, Janssen, Kiyatec, Medicenna Therapeutics, Neuvogen, Novartis, Novocure, Pyramid Bio, Sumitomo Dainippon Pharma. Vivacitas Oncology, Inc, Y-mabs Therapeutics; M.v.d.B has received honoraria for consultancy from Genenta, Servier, Astra Zeneca, Boehringer-Ingelheim, Carthera, Nerviano, Chimerix, Roche, Fore Biotherapeutics, Menarini-Stemline, Incyte and Sumitomo Pharma Oncology; F.L. received research funding from the Fonds Erasme; U.H. reports honoraria for lectures and and/or advisory board participation from Medac, Janssen, Bayer; E.R. reports travels grants BMS, Pfizer, MSD, Sanofi, Roche, Karyo labs Honorarium MSD, Servier; AF.C. received honoraria for lectures and/or advisory board participation from Gilead, Novartis; R.Ru. has received honoraria for lectures or consultation or advisory board from UCB, Novocure, Bayer, Genenta; M.P. has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals; P.W. has received research support from Astra Zeneca/Medimmune, Beigene, Celgene, Chimerix, Eli Lily, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Puma, Servier, Vascular Biogenics, VBI Vaccines and honoraria for advisory board participation or serving on data safety monitoring board from Astra Zeneca, Bayer, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, Novartis, Prelude Therapeutics, Sapience, Servier, Sagimet, Vascular Biogenics, VBI Vaccines; MW has received research grants from Quercis and Versameb, and honoraria for lectures or advisory board participation or consulting from Bayer, Medac, Merck (EMD), Novartis, Orbus, and Philogen. All remaining authors declare that they have no conflict of interest.

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Long-term survival with IDH wildtype glioblastoma: first results from the ETERNITY Brain Tumor Funders' Collaborative Consortium (EORTC 1419)

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Long-term survival with IDH wildtype glioblastoma: first results from the ETERNITY Brain Tumor Funders' Collaborative Consortium (EORTC 1419)

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