Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study
Martin van den Bent
(1)
,
Brigitta Baumert
(2, 3)
,
Sara Erridge
(4)
,
Michael Vogelbaum
(5)
,
Anna Nowak
(6)
,
Marc Sanson
(7)
,
Alba Ariela Brandes
(8)
,
Paul Clement
(9)
,
Jean Francais Baurain
(10, 11)
,
Warren Mason
(12)
,
Helen Wheeler
(13)
,
Olivier Chinot
(14)
,
Sanjeev Gill
(15)
,
Matthew Griffin
(16)
,
David Brachman
(17)
,
Walter Taal
(1)
,
Roberta Rudà
(18)
,
Michael Weller
(19)
,
Catherine Mcbain
(20)
,
Jaap Reijneveld
(21)
,
Roelien Enting
(22)
,
Damien Weber
(23)
,
Thierry Lesimple
(24)
,
Susan Clenton
,
Anja Gijtenbeek
(25)
,
Sarah Pascoe
,
Ulrich Herrlinger
(26)
,
Peter Hau
(27)
,
Frederic Dhermain
(28)
,
Irene van Heuvel
(1)
,
Roger Stupp
(19)
,
Ken Aldape
(12)
,
Robert Jenkins
(29)
,
Hendrikus Jan Dubbink
(1)
,
Winand Dinjens
(1)
,
Pieter Wesseling
(30)
,
Sarah Nuyens
(31)
,
Vassilis Golfinopoulos
(31)
,
Thierry Gorlia
(31)
,
Wolfgang Wick
,
Johan Kros
(1)
1
Erasmus MC -
Erasmus University Medical Center [Rotterdam]
2 MUMC - Maastricht University Medical Centre
3 WWU - Westfälische Wilhelms-Universität Münster = University of Münster
4 Edin. - University of Edinburgh
5 Cleveland Clinic
6 UWA - The University of Western Australia
7 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
8 AOUB - IRCCS Azienda Ospedaliero-Universitaria di Bologna
9 VIB-KU-CCB - Leuven Center for Cancer Biology
10 Cliniques Universitaires Saint-Luc [Bruxelles]
11 UCL - Université Catholique de Louvain = Catholic University of Louvain
12 University of Toronto
13 Cancer Institute NSW
14 AMU - Aix Marseille Université
15 Melbourne Medical School [Melbourne]
16 Cardiff University
17 Barrow Neurological Institute
18 UNITO - Università degli studi di Torino = University of Turin
19 University hospital of Zurich [Zurich]
20 The Christie NHS Foundation Trust [Manchester, Royaume-Uni]
21 VUMC - Vrije Universiteit Medical Centre
22 UMCG - University Medical Center Groningen [Groningen]
23 HUG - Hôpitaux universitaires de Genève = University Hospitals of Geneva
24 CRLCC - CRLCC Eugène Marquis
25 Radboud University Medical Center [Nijmegen]
26 Universität Bonn = University of Bonn
27 University Hospital Regensburg
28 Département de radiothérapie [Gustave Roussy]
29 Mayo Clinic [Rochester]
30 VU University Medical Center [Amsterdam]
31 EORTC - European Organisation for Research and Treatment of Cancer [Bruxelles]
2 MUMC - Maastricht University Medical Centre
3 WWU - Westfälische Wilhelms-Universität Münster = University of Münster
4 Edin. - University of Edinburgh
5 Cleveland Clinic
6 UWA - The University of Western Australia
7 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
8 AOUB - IRCCS Azienda Ospedaliero-Universitaria di Bologna
9 VIB-KU-CCB - Leuven Center for Cancer Biology
10 Cliniques Universitaires Saint-Luc [Bruxelles]
11 UCL - Université Catholique de Louvain = Catholic University of Louvain
12 University of Toronto
13 Cancer Institute NSW
14 AMU - Aix Marseille Université
15 Melbourne Medical School [Melbourne]
16 Cardiff University
17 Barrow Neurological Institute
18 UNITO - Università degli studi di Torino = University of Turin
19 University hospital of Zurich [Zurich]
20 The Christie NHS Foundation Trust [Manchester, Royaume-Uni]
21 VUMC - Vrije Universiteit Medical Centre
22 UMCG - University Medical Center Groningen [Groningen]
23 HUG - Hôpitaux universitaires de Genève = University Hospitals of Geneva
24 CRLCC - CRLCC Eugène Marquis
25 Radboud University Medical Center [Nijmegen]
26 Universität Bonn = University of Bonn
27 University Hospital Regensburg
28 Département de radiothérapie [Gustave Roussy]
29 Mayo Clinic [Rochester]
30 VU University Medical Center [Amsterdam]
31 EORTC - European Organisation for Research and Treatment of Cancer [Bruxelles]
Résumé
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.