Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study.
BACKGROUND
Temozolomide chemotherapy versus radiotherapy in patients with a high-risk low-grade glioma has been shown to have no significant effect on progression-free survival. If these treatments have a different effect on health-related quality of life (HRQOL), it might affect the choice of therapy. We postulated that temozolomide compromises HRQOL and global cognitive functioning to a lesser extent than does radiotherapy.


METHODS
We did a prospective, phase 3, randomised controlled trial at 78 medical centres and large hospitals in 19 countries. We enrolled adult patients (aged ≥18 years) with histologically confirmed diffuse (WHO grade II) astrocytoma, oligodendroglioma, or mixed oligoastrocytoma, with a WHO performance status of 2 or lower, without previous chemotherapy or radiotherapy, who needed active treatment other than surgery. We randomly assigned eligible patients (1:1) using a minimisation technique, stratified by WHO performance status (0-1 vs 2), age (<40 years vs ≥40 years), presence of contrast enhancement on MRI, chromosome 1p status (deleted vs non-deleted vs indeterminate), and the treating medical centre, to receive either radiotherapy (50·4 Gy in 28 fractions of 1·8 Gy for 5 days per week up to 6·5 weeks) or temozolomide chemotherapy (75 mg/m2daily, for 21 of 28 days [one cycle] for 12 cycles). The primary endpoint was progression-free survival (results published separately); here, we report the results for two key secondary endpoints: HRQOL (assessed using the European Organisation for Research and Treatment of Cancer's [EORTC] QLQ-C30 [version 3] and the EORTC Brain Cancer Module [QLQ-BN20]) and global cognitive functioning (assessed using the Mini-Mental State Examination [MMSE]). We did analyses on the intention-to-treat population. This study is closed and is registered at EudraCT, number 2004-002714-11, and at ClinicalTrials.gov, number NCT00182819.


RESULTS
Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 eligible patients to either radiotherapy (n=240) or temozolomide chemotherapy (n=237). The difference in HRQOL between the two treatment groups was not significant during the 36 months' follow-up (mean between group difference [averaged over all timepoints] 0·06, 95% CI -4·64 to 4·75, p=0·98). At baseline, 32 (13%) of 239 patients who received radiotherapy and 32 (14%) of 236 patients who received temozolomide chemotherapy had impaired cognitive function, according to the MMSE scores. After randomisation, five (8%) of 63 patients who received radiotherapy and three (6%) of 54 patients who received temozolomide chemotherapy and who could be followed up for 36 months had impaired cognitive function, according to the MMSE scores. No significant difference was recorded between the groups for the change in MMSE scores during the 36 months of follow-up.


CONCLUSIONS
The effect of temozolomide chemotherapy or radiotherapy on HRQOL or global cognitive functioning did not differ in patients with low-grade glioma. These results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma.


BACKGROUND
Merck Sharp & Dohme-Merck & Co, National Cancer Institute, Swiss Cancer League, National Institute for Health Research, Cancer Research UK, Canadian Cancer Society Research Institute, National Health and Medical Research Council, European Organisation for Research and Treatment of Cancer Cancer Research Fund.
Department of Neurology, Brain Tumor Centre Amsterdam, VU University Medical Centre and Academic Medical Centre, Amsterdam, Netherlands. Electronic address: jc.reijneveld@vumc.nl.
Jaap C
JC
Reijneveld
Department of Neurology, Medical Centre Haaglanden and Leiden University Medical Centre, The Hague, Netherlands.
Martin J B
MJB
Taphoorn
Department of Quality of Life, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium.
Corneel
C
Coens
Department of Neuro-oncology, Erasmus MC University MC Cancer Centre, Rotterdam, Netherlands.
Jacoline E C
JEC
Bromberg
Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada.
Warren P
WP
Mason
APHP, Department of Neurology, Pitié-Salpêtrière Hospital, UPMC, Sorbonne Universités, IHU, Paris, France.
Khê
K
Hoang-Xuan
Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
Gail
G
Ryan
Department of Medical Oncology and Department of Radiotherapy, Centre Eugène Marquis, Rennes, France.
Mohamed Ben
MB
Hassel
Department of Neurology, University of Groningen, University Medical Centre, Groningen, Netherlands.
Roelien H
RH
Enting
Department of Medical Oncology, AUSL-IRCCS Scienze Neurologiche, Bologna, Italy.
Alba A
AA
Brandes
Neurology Clinic, University of Heidelberg Medical Centre and NCT Neurooncology in DKTK of the German Cancer Research Center (DKFZ), Heidelberg, Germany.
Antje
A
Wick
Aix Marseille Universite, APHM, Hopital de La Timone, Department of Neuro-Oncology, Marseille, France.
Olivier
O
Chinot
IRCCS San Raffaele Scientific Institute, Milan, Italy.
Michele
M
Reni
Department of Radiotherapy, Institut Bergonié, Comprehensive Cancer Centre, Bordeaux, Bordeaux, France; Department of Radiotherapy, University Bordeaux Segalen, Bordeaux, France.
Guy
G
Kantor
BC Cancer Agency, Vancouver, BC, Canada.
Brian
B
Thiessen
Department of Medical Psychology, Brain Tumor Centre Amsterdam, VU University Medical Centre and Academic Medical Centre, Amsterdam, Netherlands.
Martin
M
Klein
Department of Radiation-Oncology, Hospital Clinic Universitari, Barcelona, Spain.
Eugenie
E
Verger
Department of Neurology, University Hospital Tübingen, Tübingen, Germany; Centre of Neuromedicine, North-West-Hospital Sanderbusch, Sande, Germany.
Christian
C
Borchers
Department of Neurology, University Hospital Regensburg, Regensburg, Germany.
Peter
P
Hau
Department of Radiation Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia.
Michael
M
Back
Department of Neuroscience, Neurology, Uppsala University and University Hospital, Uppsala, Sweden.
Anja
A
Smits
Medical Department, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium.
Vassilis
V
Golfinopoulos
Department of Statistics, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium.
Thierry
T
Gorlia
Department of Quality of Life, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium.
Andrew
A
Bottomley
Department of Clinical Neurosciences, Department of Neurosurgery, and Department of Oncology, University Hospital Lausanne, Lausanne, Switzerland.
Roger
R
Stupp
Department of Medical Oncology and Cancer Centre, University Hospital Zurich, Zurich, Switzerland; Department of Radiation-Oncology (MAASTRO), Maastricht University Medical Centre (MUMC) and GROW (School for Oncology), Maastricht, Netherlands; Department of Radiation-Oncology, MediClin Robert-Janker-Clinic, Clinical Cooperation Unit Neuro-oncology, University Bonn Medical Centre, Bonn, Germany.
Brigitta G
BG
Baumert
D001932:Brain Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000523:psychology* / Q000532:radiotherapy; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005910:Glioma / Q000188:drug therapy / Q000401:mortality / Q000523:psychology* / Q000532:radiotherapy; D006801:Humans; D060787:Neoplasm Grading; D011446:Prospective Studies; D011788:Quality of Life; D000077204:Temozolomide
D003606:Dacarbazine; D000077204:Temozolomide