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Abstract

BACKGROUND:

The role of temozolomide chemotherapy in newly diagnosed 1p/19q non-co-deleted anaplastic gliomas, which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours, is unclear. We assessed the use of radiotherapy with concurrent and adjuvant temozolomide in adults with non-co-deleted anaplastic gliomas.

METHODS:

This was a phase 3, randomised, open-label study with a 2 × 2 factorial design. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with WHO performance status scores of 0-2. The randomisation schedule was generated with the electronic EORTC web-based ORTA system. Patients were assigned in equal numbers (1:1:1:1), using the minimisation technique, to receive radiotherapy (59·4 Gy in 33 fractions of 1·8 Gy) alone or with adjuvant temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5); or to receive radiotherapy with concurrent temozolomide 75 mg/m2 per day, with or without adjuvant temozolomide. The primary endpoint was overall survival adjusted for performance status score, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and MGMT promoter methylation status, analysed by intention to treat. We did a planned interim analysis after 219 (41%) deaths had occurred to test the null hypothesis of no efficacy (threshold for rejection p<0·0084). This trial is registered with ClinicalTrials.gov, number NCT00626990.

FINDINGS:

At the time of the interim analysis, 745 (99%) of the planned 748 patients had been enrolled. The hazard ratio for overall survival with use of adjuvant temozolomide was 0·65 (99·145% CI 0·45-0·93). Overall survival at 5 years was 55·9% (95% CI 47·2-63·8) with and 44·1% (36·3-51·6) without adjuvant temozolomide. Grade 3-4 adverse events were seen in 8-12% of 549 patients assigned temozolomide, and were mainly haematological and reversible.

INTERPRETATION:

Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. Further analysis of the role of concurrent temozolomide treatment and molecular factors is needed.

FUNDING:

Schering Plough and MSD.​

Author information​

van den Bent MJ1, Baumert B2, Erridge SC3, Vogelbaum MA4, Nowak AK5, Sanson M6, Brandes AA7, Clement PM8, Baurain JF9, Mason WP10, Wheeler H11, Chinot OL12, Gill S13, Griffin M14, Brachman DG15, Taal W16, Rudà R17, Weller M18, McBain C19, Reijneveld J20, Enting RH21, Weber DC22, Lesimple T23, Clenton S24, Gijtenbeek A25, Pascoe S26, Herrlinger U27, Hau P28, Dhermain F29, van Heuvel I16, Stupp R30, Aldape K10, Jenkins RB31, Dubbink HJ32, Dinjens WNM32, Wesseling P33, Nuyens S34, Golfinopoulos V34, Gorlia T34, Wick W35, Kros JM32.

1 Neuro-Oncology Unit, Brain Tumour Centre at Erasmus MC Cancer Institute, Rotterdam, Netherlands. Electronic address: m.vandenbent@erasmusmc.nl.

2 Department of Radiation-Oncology (MAASTRO), Maastricht University Medical Centre (MUMC), Maastricht, Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre (MUMC), Maastricht, Netherlands; Department of Radiation-Oncology, University of Münster, Münster, Germany; Paracelsus Clinic, Osnabrück, Germany.

3 Edinburgh Centre for Neuro-Oncology, Western General Hospital, University of Edinburgh, Edinburgh, UK.

4 Department of Neurosurgery, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA.

5 School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, Australia; Co-Operative Group for Neuro-Oncology, University of Sydney, Camperdown, NSW, Australia; Department of Medical Oncology, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, WA, Australia.

6 Sorbonne Universités UPMC, University Paris VI, INSERM, CNRS, APHP, Institut du Cerveau et de la Moelle (ICM), Hôpital Pitié-Salpêtrière, F-75013, Paris, France.

7 Medical Oncology Department, AUSL-IRCCS Scienze Neurologiche, Bologna, Italy.

8 Department of Oncology, KU Leuven, Leuven, Belgium; Department of General Medical Oncology, UZ Leuven, Leuven Cancer Institute, Leuven, Belgium.

9 Medical Oncology Department, King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.

10 Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.

11 Northern Sydney Cancer Centre, North Shore Hospital, St Leonards, NSW, Australia; Department of Medicine, University of Sydney, Sydney, NSW, Australia.

12 Neuro-Oncology Division, Aix-Marseille University, AP-HM, Marseille, France.

13 Department of Medical Oncology, Alfred Hospital, Melbourne, VIC, Australia.

14 Department of Clinical Oncology, Nottingham University Hospitals NHS Trust, Nottingham, UK.

15 Department of Radiation Oncology, Barrow Neurological Institute, Phoenix, AZ, USA.

16 Neuro-Oncology Unit, Brain Tumour Centre at Erasmus MC Cancer Institute, Rotterdam, Netherlands.

17 Department of Neuro-Oncology, City of Health and Science Hospital and University of Turin, Turin, Italy.

18 Department of Neurology and Brain Tumour Centre, University Hospital and University of Zurich, Zurich, Switzerland.

19 Department of Clinical Oncology, Christie NHS Foundation Trust, Manchester, UK.

20 VUmc Cancer Centre Amsterdam, VU University Medical Centre, Amsterdam, Netherlands; Department of Neurology, VU University Medical Centre, Amsterdam, Netherlands; Department of Neurology, Academic Medical Centre, Amsterdam, Netherlands.

21 Department of Neurology, UMCG, University of Groningen, Groningen, Netherlands.

22 Department of Radiation Oncology, University Hospital of Geneva, Geneva, Switzerland.

23 Department of Clinical Oncology, Comprehensive Cancer Center Eugène Marquis, Rennes, France.

24 Weston Park Hospital, Sheffield, UK.

25 Department of Neurology, Radboud University Medical Centre, Nijmegen, Netherlands.

26 Department of Clinical Oncology, Plymouth Hospitals NHS Trust, Plymouth, UK.

27 Division of Clinical Neuro-Oncology, Department of Neurology, University of Bonn Medical Centre, Bonn, Germany.

28 Wilhelm Sander-Neuro-Oncology Unit and Department of Neurology, University Hospital Regensburg, Regensburg, Germany.

29 Radiotherapy Department, Gustave Roussy University Hospital, Villejuif, France.

30 Department of Medical Oncology, University Hospital and University of Zurich, Zurich, Switzerland.

31 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

32 Department of Pathology, Brain Tumour Centre at Erasmus MC Cancer Institute, Rotterdam, Netherlands.

33 Department of Pathology, VU University Medical Centre, Amsterdam, Netherlands; Department of Pathology, Radboud University Medical Centre, Nijmegen, Netherlands.

34 EORTC, Brussels, Belgium.

35 Neurologische Klinik und Nationales Zentrum für Tumorerkrankungen Universitätsklinik, Heidelberg, Germany.