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)
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.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (35)
Brigitta G. Baumert
Department of Radiotherapy, Haaglanden Medisch Centrum, The Hague, the Netherlands
Monika E. Hegi
Department of Radiation-Oncology (MAASTRO), Maastricht University Medical Center (MUMC) and GROW (School for Oncology), Maastricht, the Netherlands
Martin J. van den Bent
Erasmus MC University MC Cancer Center, Rotterdam, the Netherlands
Andreas von Deimling
Thierry Gorlia
European Organisation for Research and Treatment of Cancer, Brussels, Belgium
Khe Hoang-Xuan
1Hôpital Pitié-Salpêtrière, Paris, France
Alba A. Brandes
Department of Medical Oncology, AUSL-IRCCS Scienze Neurologiche, Bologna, Italy
Paul Sargos
Department of Radiotherapy, Institut Bergonié, Bordeaux, France
Martin J.B. Taphoorn
Department of Neurology, Medical Center Haaglanden, The Hague, the Netherlands
Elodie Vauleon
Department of Medical Oncology and Radiotherapy, Centre Eugène Marquis, Rennes, France
Claire Philips
Department of Radiation Oncology and Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia
Johan M. Kros
Department of Pathology, Erasmus Medical Center, Rotterdam, the Netherlands
Pierre Bady
Neuroscience Research Center and Service of Neurosurgery, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
Wolfgang Wick
Roelien Enting
24Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Michele Reni
Brian Thiessen
BC Cancer Agency, Vancouver, BC, Canada
Frédéric Dhermain
Jacoline E. Bromberg
Erasmus MC University MC Cancer Center, Rotterdam, the Netherlands
Julian Jacob
Department of Radiation-Oncology, Pitié-Salpêtrière Hospital, AP-HP, Sorbonne University, Paris, France
Jaap C. Reijneveld
Department of Neurology & Brain Tumor Center Amsterdam, Amsterdam University Medical Center, Amsterdam, the Netherlands
Olivier Chinot
Hôpital La Timone, Marseille, France
Johanna M.M. Gijtenbeek
Department of Neurology, Radboud University Medical Centre, Nijmegen, the Netherlands
John P. Rossiter
Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada
Carmen Balana
Ana Luisa Silva Azevedo
Instituto Portugues de Oncologia de Lisboa (IPO), Lissabon, Portugal
Paul M. Clement
Department of Oncology, KU Leuven, Leuven, Belgium
Anna Berghoff
3Division of Oncology Medical University of Vienna, Department of Medicine I, Vienna, Austria
Tzahala Tzuk-Shina
Rambam, Haifa, Israel
Michael Weller
Robert A. Nordal
Department of Oncology, Arthur Child Comprehensive Cancer Centre, University of Calgary, Calgary, Canada
Jeremy Rees
National Hospital for Neurology and Neurosurgery, London, United Kingdom
Denis A. Lacombe
European Organisation for Research and Treatment of Cancer, Brussels, Belgium
Warren P. Mason
Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
Roger Stupp