Temozolomide Versus Radiotherapy as First-Line Therapy for Low-Grade Glioma: Mature Results of a Randomized Phase III Trial (EORTC 22033-26033/NCIC-CTG/TROG/MRC-CTU)

PURPOSE Prognosis in low-grade gliomas (LGGs) remains highly variable, and treatment-related late toxicity is a concern. This trial was comparing single-modality therapies in patients who often survive for years or decades and investigating differential responses according to molecular markers. METHODS Four hundred seventy-eight patients with clinical high-risk LGG (WHO grade 2) were randomly assigned to standard radiotherapy (RT; 28 × 1.8 Gy) or dose-dense temozolomide (TMZ; 75 mg/m 2 once daily × 21/28 days, up to 12 cycles). RESULTS There was no significant difference in progression-free survival or overall survival (OS) between study arms. Analyzable tumor tissue in 73% (351/478) of patients allowed for post hoc reclassification according to the 2021 WHO pathologic criteria. In astrocytoma, IDHmt/1p/19q noncodeleted (n = 178), median OS was similar, 6.6-6.7 years irrespective of arm (0.67-1.44, P = .93). In oligodendroglioma, IDHmt/1p/19q codeleted (n = 109), median OS was 12.9 years (9.4-not reached) with RT and 14.9 years (10.1-number of events not reached) with TMZ (hazard ratio [HR], 0.88 [0.52-1.49], P = .63). In 64 tumors without isocitrate dehydrogenase (IDH) mutations, survival favored the TMZ arm: OS 2.5 (1.8-3.3) versus 4.7 (2.2-7.2) years (HR, 0.47 [0.27-0.82], P = .0068). Patients age 40 years and older fared better than patients younger than 40 years, challenging the current notion of age alone as a negative prognostic factor. CONCLUSION The assigned initial treatment modality did not affect progression-free survival or OS, regardless of the molecular subtype. Combined-modality therapy was not tested in this trial but has since become a standard of care for IDH-mutant astrocytoma. With emerging novel therapeutic options, rational treatment strategies tailored at the individual clinical and pathologic recurrence risk profiles will be needed. The validity of an age cutoff as prognostic factor is challenged when tumors are molecularly classified.

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Journal
Journal of Clinical Oncology
Published
2026-07-02
DOI
https://doi.org/10.1200/jco-25-02735
Citations
1
Primary Topic
Glioma Diagnosis and Treatment
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article
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9.86
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article

Temozolomide Versus Radiotherapy as First-Line Therapy for Low-Grade Glioma: Mature Results of a Randomized Phase III Trial (EORTC 22033-26033/NCIC-CTG/TROG/MRC-CTU)

Michele Reni, Warren Mason, Martin J. van den Bent, Khê Hoang‐Xuan et al.
1 citations
Journal of Clinical Oncology
Glioma Diagnosis and Treatment
9.86
article

Temozolomide Versus Radiotherapy as First-Line Therapy for Low-Grade Glioma: Mature Results of a Randomized Phase III Trial (EORTC 22033-26033/NCIC-CTG/TROG/MRC-CTU)

Michele Reni, Warren Mason, Martin J. van den Bent, Khê Hoang‐Xuan, Johanna M. M. Gijtenbeek, Jaap C. Reijneveld, Michael Weller, Jacoline E. C. Bromberg, Paul Sargos, Élodie Vauléon, A. A. Brandes, Claire Phillips, Ana Azevedo, Monika E. Hegi, Andreas von Deimling, Roger Stupp, Martin Taphoorn, Carmen Balañá, Robert Nordal, Pierre Bady, Johan M. Kros, Olivier Chinot, Brigitta G. Baumert, Wolfgang Wick, Tzahala Tzuk-Shina, Anna Berghoff, Dr Jeremy Rees, John P. Rossiter, Julian Jacob, F Dhermain, Paul M. Clement, Roelien Enting, Brian Thiessen, Thierry Gorlia, Denis A. Lacombe
article en
1 citations

Abstract

PURPOSE Prognosis in low-grade gliomas (LGGs) remains highly variable, and treatment-related late toxicity is a concern. This trial was comparing single-modality therapies in patients who often survive for years or decades and investigating differential responses according to molecular markers. METHODS Four hundred seventy-eight patients with clinical high-risk LGG (WHO grade 2) were randomly assigned to standard radiotherapy (RT; 28 × 1.8 Gy) or dose-dense temozolomide (TMZ; 75 mg/m 2 once daily × 21/28 days, up to 12 cycles). RESULTS There was no significant difference in progression-free survival or overall survival (OS) between study arms. Analyzable tumor tissue in 73% (351/478) of patients allowed for post hoc reclassification according to the 2021 WHO pathologic criteria. In astrocytoma, IDHmt/1p/19q noncodeleted (n = 178), median OS was similar, 6.6-6.7 years irrespective of arm (0.67-1.44, P = .93). In oligodendroglioma, IDHmt/1p/19q codeleted (n = 109), median OS was 12.9 years (9.4-not reached) with RT and 14.9 years (10.1-number of events not reached) with TMZ (hazard ratio [HR], 0.88 [0.52-1.49], P = .63). In 64 tumors without isocitrate dehydrogenase (IDH) mutations, survival favored the TMZ arm: OS 2.5 (1.8-3.3) versus 4.7 (2.2-7.2) years (HR, 0.47 [0.27-0.82], P = .0068). Patients age 40 years and older fared better than patients younger than 40 years, challenging the current notion of age alone as a negative prognostic factor. CONCLUSION The assigned initial treatment modality did not affect progression-free survival or OS, regardless of the molecular subtype. Combined-modality therapy was not tested in this trial but has since become a standard of care for IDH-mutant astrocytoma. With emerging novel therapeutic options, rational treatment strategies tailored at the individual clinical and pathologic recurrence risk profiles will be needed. The validity of an age cutoff as prognostic factor is challenged when tumors are molecularly classified.

Journal of Clinical Oncology
Northwestern University (US), SIB Swiss Institute of Bioinformatics (CH), BC Cancer Agency (CA), University Medical Center Groningen (NL), Radboud University Nijmegen (NL), Vita-Salute San Raffaele University (IT), University of Calgary (CA), University of Groningen (NL), German Cancer Research Center (DE), University of Toronto (CA), Queen's University (CA), Heidelberg University (DE), Peter MacCallum Cancer Centre (AU), Rambam Health Care Campus (IL), Institut Gustave Roussy (FR), Erasmus MC (NL), Centre Hospitalier Universitaire Vaudois (CH), Princess Margaret Cancer Centre (CA), Radboud University Medical Center (NL), Sorbonne Université (FR), Assistance Publique – Hôpitaux de Paris (FR), Medisch Centrum Haaglanden (NL), University Hospital of Zurich (CH), Amsterdam Neuroscience (NL), Centre Eugène Marquis (FR), IPO Porto (PT), Pitié-Salpêtrière Hospital (FR), Istituto delle Scienze Neurologiche di Bologna (IT), European Organisation for Research and Treatment of Cancer (BE), Institut Bergonié (FR), Badalona Serveis Assistencials (ES), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES), Erasmus MC Cancer Institute (NL), National Hospital for Neurology and Neurosurgery (GB), Hospital Municipal de Badalona (ES), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Maastro Clinic (NL), Hôpital de la Timone (FR), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT), Robert H. Lurie Comprehensive Cancer Center of Northwestern University, University College London (GB), Medical University of Vienna (AT), University of Amsterdam (NL), University of Lausanne (CH), KU Leuven (BE)
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Openalex Percentile: Top 2%
Glioma Diagnosis and Treatment
9.86
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