Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study.
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/m2once 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 (<40 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.


RESULTS
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 (IDHmt, with or without 1p/19q co-deletion [IDHmt/codel], or IDH wild type [IDHwt]; p=0·013). Patients with IDHmt/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 IDHmt/codel and IDHwt tumours. Grade 3-4 haematological adverse events occurred in 32 (14%) of 236 patients treated with temozolomide and in one (<1%) of 228 patients treated with radiotherapy, and grade 3-4 infections occurred in eight (3%) of 236 patients treated with temozolomide and in two (1%) of 228 patients treated with radiotherapy. Moderate to severe fatigue was recorded in eight (3%) patients in the radiotherapy group (grade 2) and 16 (7%) in the temozolomide group. 119 (25%) of all 477 patients had died at database lock. Four patients died due to treatment-related causes: two in the temozolomide group and two in the radiotherapy group.


CONCLUSIONS
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.


BACKGROUND
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.
Maastricht University Medical Centre and GROW (School for Oncology), Maastricht, Netherlands; MediClin Robert-Janker-Clinic/Clinical Cooperation Unit of Neurooncology, University Bonn Medical Centre, Bonn, Germany. Electronic address: brigitta.baumert@gmail.com.
Brigitta G
BG
Baumert
Lausanne University Hospital, Lausanne, Switzerland.
Monika E
ME
Hegi
Erasmus MC Cancer Institute University Medical Centre, Rotterdam, Netherlands.
Martin J
MJ
van den Bent
University of Heidelberg and CCU Neuropathology German Cancer Research Centre, Heidelberg, Germany.
Andreas
A
von Deimling
European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium.
Thierry
T
Gorlia
APHP, Pitié-Salpêtrière, Hospital and UPMC, Sorbonne Universités, Paris, France.
Khê
K
Hoang-Xuan
AUSL-IRCCS Scienze Neurologiche, Bologna, Italy.
Alba A
AA
Brandes
Institut Bergonié, Comprehensive Cancer Center and University Bordeaux Segalen, Bordeaux, France.
Guy
G
Kantor
Medical Center Haaglanden, The Hague, Netherlands; Leiden University Center, Leiden, Netherlands.
Martin J B
MJB
Taphoorn
Centre Eugène Marquis, Rennes, France.
Mohamed Ben
MB
Hassel
University of Heidelberg and CCU Neuropathology German Cancer Research Centre, Heidelberg, Germany; Institute of Pathology, Medizinische Hochschule Hannover, Hannover, Germany.
Christian
C
Hartmann
Peter MacCallum Cancer Center, Melbourne, VIC, Australia.
Gail
G
Ryan
University of Heidelberg and CCU Neuropathology German Cancer Research Centre, Heidelberg, Germany.
David
D
Capper
Erasmus MC Cancer Institute University Medical Centre, Rotterdam, Netherlands.
Johan M
JM
Kros
Lausanne University Hospital, Lausanne, Switzerland; The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
Sebastian
S
Kurscheid
University of Heidelberg and CCU Neuropathology German Cancer Research Centre, Heidelberg, Germany.
Wolfgang
W
Wick
University of Groningen, Groningen, Netherlands.
Roelien
R
Enting
IRCCS San Raffaele Scientific Institute, Milan, Italy.
Michele
M
Reni
BC Cancer Agency, Vancouver, BC, Canada.
Brian
B
Thiessen
Institut Gustave Roussy, Villejuif, France.
Frederic
F
Dhermain
Erasmus MC Cancer Institute University Medical Centre, Rotterdam, Netherlands.
Jacoline E
JE
Bromberg
APHP, Pitié-Salpêtrière, Hospital and UPMC, Sorbonne Universités, Paris, France.
Loic
L
Feuvret
VU University Medical Center and Academic Medical Center, Amsterdam, Netherlands.
Jaap C
JC
Reijneveld
Aix Marseille, Université, APHM, Hôpital de la Timone, Marseille, France.
Olivier
O
Chinot
Radboud University Medical Center, Nijmegen, Netherlands.
Johanna M M
JMM
Gijtenbeek
Queen's University, Kingston, ON, Canada.
John P
JP
Rossiter
European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium.
Nicolas
N
Dif
ICO Badalona Hospital Germans Trias I Pujol, Barcelona, Spain.
Carmen
C
Balana
Instituto Portugues de Oncologia de Lisboa, Lisbon, Portugal.
Jose
J
Bravo-Marques
KU Leuven, Department of Oncology, Leuven, Belgium.
Paul M
PM
Clement
Medical University of Vienna, Vienna, Austria.
Christine
C
Marosi
Rambam Health Care Campus, Oncology Institute, Haifa, Israel.
Tzahala
T
Tzuk-Shina
Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada.
Robert A
RA
Nordal
National Hospital for Neurology and Neurosurgery, London, UK.
Jeremy
J
Rees
European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium.
Denis
D
Lacombe
Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada.
Warren P
WP
Mason
Lausanne University Hospital, Lausanne, Switzerland; University Hospital Zurich, Zurich, Switzerland.
Roger
R
Stupp
D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000401:mortality / Q000628:therapy*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005910:Glioma / Q000401:mortality / Q000628:therapy*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020266:Radiotherapy, Conformal; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D000077204:Temozolomide
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