Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study
Brigitta G. Baumert,Brigitta G. Baumert,Monika E. Hegi,Martin J. van den Bent,Andreas von Deimling,Thierry Gorlia,Khê Hoang-Xuan,Alba A. Brandes,Guy Kantor,Martin J.B. Taphoorn,Mohamed Ben Hassel,Christian Hartmann,Christian Hartmann,Gail Ryan,David Capper,Johan M. Kros,Sebastian Kurscheid,Sebastian Kurscheid,Wolfgang Wick,Roelien H. Enting,Michele Reni,Brian Thiessen,Frédéric Dhermain,Jacoline E C Bromberg,Loïc Feuvret,Jaap C. Reijneveld,Olivier Chinot,J.M.M. Gijtenbeek,John P. Rossiter,Nicolas Dif,Carmen Balana,Jose Bravo-Marques,Paul Clement,Christine Marosi,Tzahala Tzuk-Shina,Robert A Nordal,Jeremy Rees,Denis Lacombe,Warren P. Mason,Roger Stupp,Roger Stupp +40 more
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There was no significant difference in outcome of the overall patient population treated with either radiotherapy alone or TMZ chemotherapy alone, and further data maturation is needed for overall survival analyses and evaluation of the full predictive impact of the molecular subtypes for individualized treatment choices.Abstract:
Summary Background Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors. Methods For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration. Eligible patients were randomly assigned (1:1) to receive either conformal radiotherapy (up to 50·4 Gy; 28 doses of 1·8 Gy once daily, 5 days per week for up to 6·5 weeks) or dose-dense oral temozolomide (75 mg/m 2 once daily for 21 days, repeated every 28 days [one cycle], for a maximum of 12 cycles). Random treatment allocation was done online by a minimisation technique with prospective stratification by institution, 1p deletion (absent vs present vs undetermined), contrast enhancement (yes vs no), age ( vs ≥40 years), and WHO performance status (0 vs ≥1). Patients, treating physicians, and researchers were aware of the assigned intervention. A planned analysis was done after 216 progression events occurred. Our primary clinical endpoint was progression-free survival, analysed by intention-to-treat; secondary outcomes were overall survival, adverse events, neurocognitive function (will be reported separately), health-related quality of life and neurological function (reported separately), and correlative analyses of progression-free survival by molecular markers (1p/19q co-deletion, MGMT promoter methylation status, and IDH1/IDH2 mutations). This trial is closed to accrual but continuing for follow-up, and is registered at the European Trials Registry, EudraCT 2004-002714-11, and at ClinicalTrials.gov, NCT00182819. Findings Between Sept 23, 2005, and March 26, 2010, 707 patients were registered for the study. Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 patients to receive either radiotherapy (n=240) or temozolomide chemotherapy (n=237). At a median follow-up of 48 months (IQR 31–56), median progression-free survival was 39 months (95% CI 35–44) in the temozolomide group and 46 months (40–56) in the radiotherapy group (unadjusted hazard ratio [HR] 1·16, 95% CI 0·9–1·5, p=0·22). Median overall survival has not been reached. Exploratory analyses in 318 molecularly-defined patients confirmed the significantly different prognosis for progression-free survival in the three recently defined molecular low-grade glioma subgroups ( IDH mt, with or without 1p/19q co-deletion [ IDH mt/codel], or IDH wild type [ IDH wt]; p=0·013). Patients with IDH mt/non-codel tumours treated with radiotherapy had a longer progression-free survival than those treated with temozolomide (HR 1·86 [95% CI 1·21–2·87], log-rank p=0·0043), whereas there were no significant treatment-dependent differences in progression-free survival for patients with IDH mt/codel and IDH wt tumours. Grade 3–4 haematological adverse events occurred in 32 (14%) of 236 patients treated with temozolomide and in one ( Interpretation Overall, there was no significant difference in progression-free survival in patients with low-grade glioma when treated with either radiotherapy alone or temozolomide chemotherapy alone. Further data maturation is needed for overall survival analyses and evaluation of the full predictive effects of different molecular subtypes for future individualised treatment choices. Funding Merck Sharpe & Dohme-Merck & Co, Canadian Cancer Society, Swiss Cancer League, UK National Institutes of Health, Australian National Health and Medical Research Council, US National Cancer Institute, European Organisation for Research and Treatment of Cancer Cancer Research Fund.read more
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European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas
Michael Weller,Martin J. van den Bent,Jörg C. Tonn,Roger Stupp,Matthias Preusser,Elizabeth Cohen-Jonathan-Moyal,Roger Henriksson,Emilie Le Rhun,Carmen Balana,Olivier Chinot,Martin Bendszus,Jaap C. Reijneveld,F. Dhermain,Pim J. French,Christine Marosi,Colin Watts,Ingela Oberg,Geoffrey J. Pilkington,Brigitta G. Baumert,Martin J.B. Taphoorn,Monika E. Hegi,Manfred Westphal,Guido Reifenberger,Riccardo Soffietti,Wolfgang Wick,Wolfgang Wick +25 more
TL;DR: The European Association for Neuro-Oncology guideline provides recommendations for the clinical care of adult patients with astrocytic and oligodendroglial gliomas, including glioblastomas, based on the 2016 WHO classification of tumours of the central nervous system and on scientific developments since the 2014 guideline.
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Primary brain tumours in adults.
TL;DR: Progress in genomics has defined a new era in neuro-oncology and holds promise for diagntic and therapeutic improvement, and combination therapies seem to be required to achieve a broad and durable antitumour response.
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EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood.
Michael Weller,Martin J. van den Bent,Matthias Preusser,Emilie Le Rhun,Jörg C. Tonn,Giuseppe Minniti,Martin Bendszus,Carmen Balana,Olivier Chinot,Linda Dirven,Pim J. French,Monika E. Hegi,Asgeir Store Jakola,Michael Platten,Michael Platten,Patrick Roth,Roberta Rudà,Susan C Short,Marion Smits,Martin J B Taphoorn,Andreas von Deimling,Manfred Westphal,Riccardo Soffietti,Guido Reifenberger,Wolfgang Wick +24 more
TL;DR: These evidence-based guidelines incorporate major changes in diagnostic algorithms based on the 2016 update of the WHO Classification of Tumors of the Central Nervous System as well as on evidence from recent large clinical trials.
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Advances in the molecular genetics of gliomas - implications for classification and therapy.
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Genetic and molecular epidemiology of adult diffuse glioma
TL;DR: This Review focuses on the two dominant trends in glioma science: the characterization of diagnostic and prognostic tumour markers and the identification of genetic and other risk factors included in the 2016 WHO integrated classification system.
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Sevin Turcan,Daniel Rohle,Daniel Rohle,Anuj Goenka,Logan A. Walsh,Fang Fang,Emrullah Yilmaz,Carl Campos,Armida W. M. Fabius,Chao Lu,Chao Lu,Patrick S. Ward,Patrick S. Ward,Craig B. Thompson,Andrew Kaufman,Olga A. Guryanova,Ross L. Levine,Adriana Heguy,Agnes Viale,Luc G. T. Morris,Jason T. Huse,Ingo K. Mellinghoff,Ingo K. Mellinghoff,Timothy A. Chan,Timothy A. Chan +24 more
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