EJC Paediatric Oncology (Dec 2025)
Temozolomide-based radio-chemotherapy for newly diagnosed pediatric high-grade gliomas (HIT-HGG-2007): A prospective, multicenter, single-arm, phase II trial
- Michael Karremann,
- Thomas Perwein,
- André O. von Bueren,
- Gerrit H. Gielen,
- Martin Benesch,
- Gunther Nussbaumer,
- Lea L. Friker,
- Andreas Waha,
- Dominik Sturm,
- David T.W. Jones,
- Olaf Witt,
- Stefan M. Pfister,
- Matthias Eyrich,
- Ulrich W. Thomale,
- Chiara Valentini,
- Mechthild Krause,
- Stefaan W. Van Gool,
- Michael C. Frühwald,
- Pablo Hernaiz-Driever,
- Martin Ebinger,
- Georg Ebetsberger-Dachs,
- Roman Crazzolara,
- Christine Haberler,
- Felix Sahm,
- Nicolas U. Gerber,
- Carl Friedrich Classen,
- Ronald Sträter,
- Kornelius Kerl,
- Stefan Rutkowski,
- Gudrun Fleischhack,
- Miriam van Buiren,
- Rolf-Dieter Kortmann,
- Christian Hagel,
- Gabriele Calaminus,
- Andreas Faldum,
- Monika Warmuth-Metz,
- Brigitte Bison,
- Torsten Pietsch,
- Marion Hoffmann,
- Robert Kwiecien,
- Christof M. Kramm
Affiliations
- Michael Karremann
- Department of Pediatric and Adolescent Medicine and Mannheim Cancer Center, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Corresponding author.
- Thomas Perwein
- Division of Pediatric Hemato-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz and Styrian Children’s Cancer Research – Research Unit for Cancer and Inborn Errors of the Blood and Immunity in Children, Graz, Austria
- André O. von Bueren
- Division of Pediatric Oncology and Hematology, Department of Pediatrics, Gynecology and Obstetrics, University Hospital of Geneva, Geneva, Switzerland; Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany
- Gerrit H. Gielen
- Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany
- Martin Benesch
- Division of Pediatric Hemato-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz and Styrian Children’s Cancer Research – Research Unit for Cancer and Inborn Errors of the Blood and Immunity in Children, Graz, Austria
- Gunther Nussbaumer
- Division of Pediatric Hemato-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz and Styrian Children’s Cancer Research – Research Unit for Cancer and Inborn Errors of the Blood and Immunity in Children, Graz, Austria
- Lea L. Friker
- Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany
- Andreas Waha
- Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany
- Dominik Sturm
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Division Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- David T.W. Jones
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Division Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Olaf Witt
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
- Stefan M. Pfister
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
- Matthias Eyrich
- Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University Children's Hospital, University Medical Center, University of Würzburg, Würzburg, Germany
- Ulrich W. Thomale
- Pediatric Neurosurgery, Charité Universitätsmedizin Berlin, Berlin, Germany
- Chiara Valentini
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
- Mechthild Krause
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT) Partner Site Dresden, Germany; German Cancer Consortium (DKTK) Dresden, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Stefaan W. Van Gool
- Immune-Oncological Center Cologne (IOZK), Cologne, Germany
- Michael C. Frühwald
- Pediatrics and Adolescent Medicine, Swabian Children's Cancer Center, University Medical Center Augsburg, Augsburg, Germany
- Pablo Hernaiz-Driever
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology/Hematology, Berlin, Germany
- Martin Ebinger
- Department of General Pediatrics, Hematology and Oncology, University Children's Hospital, Tübingen, Germany
- Georg Ebetsberger-Dachs
- Department of Pediatrics and Adolescent Medicine, Johannes Kepler University Linz, Kepler University Hospital, Linz, Austria
- Roman Crazzolara
- Department of Child and Adolescent Health, Medical University of Innsbruck, Innsbruck, Austria
- Christine Haberler
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria
- Felix Sahm
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany; CCU Neuropathology, German Consortium for Translational Cancer research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany
- Nicolas U. Gerber
- Department of Oncology and Children's Research Centre, University Children's Hospital, Zurich, Switzerland
- Carl Friedrich Classen
- Pediatric Oncology and Palliative Care Section, University Medicine Rostock, Childrens' and Adolescents Hospital Rostock, Rostock, Germany
- Ronald Sträter
- Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany
- Kornelius Kerl
- Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany
- Stefan Rutkowski
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Gudrun Fleischhack
- Pediatric Hematology and Oncology, Pediatrics III, University Hospital of Essen, Essen, Germany
- Miriam van Buiren
- Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Children’s Hospital, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Rolf-Dieter Kortmann
- Department of Radiotherapy and Radiation Oncology, University Hospital Leipzig, Leipzig, Germany
- Christian Hagel
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Gabriele Calaminus
- Department of Pediatric Hematology and Oncology, University Hospital Bonn, Bonn, Germany
- Andreas Faldum
- Institute of Biostatistics and Clinical Research, Faculty of Medicine, University of Münster, Münster, Germany
- Monika Warmuth-Metz
- Institute of Diagnostic and Interventional Neuroradiology, University of Würzburg, Würzburg, Germany; Neuroradiological Reference Center for the pediatric brain tumor (HIT) studies of the German Society of Pediatric Oncology and Hematology, until 2020 University Hospital Würzburg, Würzburg, Germany, since 2021 Faculty of Medicine, University of Augsburg, Augsburg, Germany
- Brigitte Bison
- Neuroradiological Reference Center for the pediatric brain tumor (HIT) studies of the German Society of Pediatric Oncology and Hematology, until 2020 University Hospital Würzburg, Würzburg, Germany, since 2021 Faculty of Medicine, University of Augsburg, Augsburg, Germany; Diagnostic and Interventional Neuroradiology, Faculty of Medicine, University of Augsburg, Augsburg, Germany
- Torsten Pietsch
- Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany
- Marion Hoffmann
- Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany
- Robert Kwiecien
- Institute of Biostatistics and Clinical Research, Faculty of Medicine, University of Münster, Münster, Germany
- Christof M. Kramm
- Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany
- DOI
- https://doi.org/10.1016/j.ejcped.2025.100308
- Journal volume & issue
-
Vol. 6
p. 100308
Abstract
Background: The HIT-HGG-2007 trial investigated temozolomide (TMZ) radio-chemotherapy for pediatric patients with high-grade gliomas (pHGG) to demonstrate therapeutic non-inferiority compared to previous intensive radio-chemotherapy regimens (HIT-GBM-C/-D). Methods: Between June 2009 and December 2016, 456 patients were enrolled into this international, prospective, single-arm, multicenter phase II trial in Germany, Austria, and Switzerland of whom 438 patients were evaluable for confirmatory analysis. Patients from the HIT-GBM-C/-D trials served as historic control (n = 439). Tumors of both cohorts with available tissue were re-classified according to the 2021 WHO classification of CNS tumors (n = 140). Results: Regarding event-free-survival (EFS) rate at 6 months, non-inferiority of the HIT-HGG-2007 regimen was confirmed (p = 0.0125). In terms of exploratory analyses, median EFS and overall survival (OS) was 9.5 months (95 % confidence interval [CI95], 8.9–10.4) and 14.7 months (CI95, 13.5–16.3), superior to intensive chemotherapy regimens (p < 0.0001 and p = 0.0328). EFS and OS remained superior after re-classification of tumors according to WHO2021 criteria. TMZ radio-chemotherapy had lower rates of severe hematological, gastrointestinal, and hepatic toxicity compared to HIT-GBM-C/-D. Younger age, WHO grade IV histology, tumor location in the brainstem or basal ganglia, and lower extent of resection were independent adverse risk factors for OS and EFS. MGMT gene promoter methylation status had no impact on EFS and OS. Conclusions: The HIT-HGG-2007 trial demonstrated non-inferiority compared with intensive chemotherapy regimens. MGMT promotor methylation status had no impact on survival. Exploratory analysis supports treatment of newly diagnosed non-pontine pHGG according to the HIT-HGG-2007 regimen due to improved EFS and OS rates together with a favorable toxicity profile.
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