Martin J van den Bent1, C Mircea S Tesileanu2, Wolfgang Wick3, Marc Sanson4, Alba Ariela Brandes5, Paul M Clement6, Sarah Erridge7, Michael A Vogelbaum8, Anna K Nowak9, Jean Français Baurain10, Warren P Mason11, Helen Wheeler12, Olivier L Chinot13, Sanjeev Gill14, Matthew Griffin15, Leland Rogers16, Walter Taal2, Roberta Rudà17, Michael Weller18, Catherine McBain19, Jaap Reijneveld20, Roelien H Enting21, Francesca Caparrotti22, Thierry Lesimple23, Susan Clenton24, Anja Gijtenbeek25, Elizabeth Lim26, Ulrich Herrlinger27, Peter Hau28, Frederic Dhermain29, Iris de Heer2, Kenneth Aldape30, Robert B Jenkins31, Hendrikus Jan Dubbink32, Johan M Kros32, Pieter Wesseling33, Sarah Nuyens34, Vassilis Golfinopoulos34, Thierry Gorlia34, Pim French2, Brigitta G Baumert35. 1. Brain Tumor Center, Erasmus MC Cancer Institute, Rotterdam, Netherlands. Electronic address: m.vandenbent@erasmusmc.nl. 2. Brain Tumor Center, Erasmus MC Cancer Institute, Rotterdam, Netherlands. 3. Neurologische Klinik und Nationales Zentrum für Tumorerkrankungen Universitätsklinik Heidelberg, Heidelberg, Germany. 4. Sorbonne Universités, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM AP-HP, Paris, France; Hôpital Univeristaires Pitié-salpêtrière -Chales Foix, service de Neurologie 2-Mazarin, Paris, France. 5. Medical Oncology Department, AUSL-IRCCS Scienze Neurologiche, Bologna, Italy. 6. Department of Oncology, KU Leuven and Department of General Medical Oncology, UZ Leuven, Leuven Cancer Institute, Leuven, Belgium. 7. Edinburgh Centre for Neuro-Oncology, Western General Hospital, University of Edinburgh, Edinburgh, UK. 8. Department of NeuroOncology, Moffitt Cancer Center, Tampa, FL, USA. 9. Medical School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, Australia; CoOperative Group for NeuroOncology, University of Sydney, Camperdown, NSW, Australia; Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia. 10. Medical Oncology Department, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium. 11. Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. 12. Northern Sydney Cancer Centre, St Leonards, Sydney, NSW, Australia. 13. Aix-Marseille University, AP-HM, Neuro-Oncology division, Marseille, France. 14. Department of Medical Oncology, Alfred Hospital, Melbourne, QLD, Australia. 15. Department of Clinical Oncology, Nottingham University Hospitals NHS Trust, Nottingham, UK. 16. Department of Radiation Oncology, Barrow Neurological Institute, Phoenix, AZ, USA. 17. Department of Neuro-Oncology, City of Health and Science Hospital and University of Turin, Turin, Italy. 18. Department of Neurology and Brain Tumor Center, University Hospital and University of Zurich, Zurich, Switzerland. 19. Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK. 20. Brain Tumor Center Amsterdam and Department of Neurology, VU University Medical Center, Amsterdam, Netherlands; Department of Neurology, Academic Medical Center, 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 Neurooncology, Department of Neurology, University of Bonn Medical Center, Bonn, Germany. 28. Wilhelm Sander-NeuroOncology Unit and Department of Neurology, University Hospital, Regensburg, Regensburg, Germany. 29. Radiotherapy Department, Gustave Roussy University Hospital, Villejuif, Cedex, France. 30. Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA. 31. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester MN, USA. 32. Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, Netherlands. 33. Department of Pathology, Amsterdam University Medical Centers, Amsterdam, Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands; Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands. 34. EORTC, Brussels, Belgium. 35. Department of Radiation-Oncology (MAASTRO), Maastricht University Medical Center (MUMC) GROW (School for Oncology), Maastricht, Netherlands; Institute of Radiation-Oncology, Cantonal Hospital Graubünden, Chur, Switzerland.
Abstract
BACKGROUND: The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear. METHODS: This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m2 per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990. FINDINGS: Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7-82·3] with concurrent temozolomide vs 60·4 months [45·7-71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73-1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2-116·6] vs 46·9 months [37·9-56·9]; HR 0·64 [95% CI 0·52-0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported. INTERPRETATION: Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status. FUNDING: Merck Sharpe & Dohme.
BACKGROUND: The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear. METHODS: This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m2 per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990. FINDINGS: Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7-82·3] with concurrent temozolomide vs 60·4 months [45·7-71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73-1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2-116·6] vs 46·9 months [37·9-56·9]; HR 0·64 [95% CI 0·52-0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported. INTERPRETATION: Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status. FUNDING: Merck Sharpe & Dohme.
Authors: Martin J van den Bent; Brigitta Baumert; Sara C Erridge; Michael A Vogelbaum; Anna K Nowak; Marc Sanson; Alba Ariela Brandes; Paul M Clement; Jean Francais Baurain; Warren P Mason; Helen Wheeler; Olivier L Chinot; Sanjeev Gill; Matthew Griffin; David G Brachman; Walter Taal; Roberta Rudà; Michael Weller; Catherine McBain; Jaap Reijneveld; Roelien H Enting; Damien C Weber; Thierry Lesimple; Susan Clenton; Anja Gijtenbeek; Sarah Pascoe; Ulrich Herrlinger; Peter Hau; Frederic Dhermain; Irene van Heuvel; Roger Stupp; Ken Aldape; Robert B Jenkins; Hendrikus Jan Dubbink; Winand N M Dinjens; Pieter Wesseling; Sarah Nuyens; Vassilis Golfinopoulos; Thierry Gorlia; Wolfgang Wick; Johan M Kros Journal: Lancet Date: 2017-08-08 Impact factor: 79.321
Authors: Gregory Cairncross; Brian Berkey; Edward Shaw; Robert Jenkins; Bernd Scheithauer; David Brachman; Jan Buckner; Karen Fink; Luis Souhami; Normand Laperierre; Minesh Mehta; Walter Curran Journal: J Clin Oncol Date: 2006-06-20 Impact factor: 44.544
Authors: Hendrikus J Dubbink; Peggy N Atmodimedjo; Johan M Kros; Pim J French; Marc Sanson; Ahmed Idbaih; Pieter Wesseling; Roelien Enting; Wim Spliet; Cees Tijssen; Winand N M Dinjens; Thierry Gorlia; Martin J van den Bent Journal: Neuro Oncol Date: 2015-09-09 Impact factor: 12.300
Authors: Walter Taal; Dieta Brandsma; Hein G de Bruin; Jacoline E Bromberg; Annemarie T Swaak-Kragten; Peter A E Sillevis Smitt; Corine A van Es; Martin J van den Bent Journal: Cancer Date: 2008-07-15 Impact factor: 6.860
Authors: J Gregory Cairncross; Meihua Wang; Robert B Jenkins; Edward G Shaw; Caterina Giannini; David G Brachman; Jan C Buckner; Karen L Fink; Luis Souhami; Normand J Laperriere; Jason T Huse; Minesh P Mehta; Walter J Curran Journal: J Clin Oncol Date: 2014-02-10 Impact factor: 44.544
Authors: Maarten M J Wijnenga; Pim J French; Hendrikus J Dubbink; Winand N M Dinjens; Peggy N Atmodimedjo; Johan M Kros; Marion Smits; Renske Gahrmann; Geert-Jan Rutten; Jeroen B Verheul; Ruth Fleischeuer; Clemens M F Dirven; Arnaud J P E Vincent; Martin J van den Bent Journal: Neuro Oncol Date: 2018-01-10 Impact factor: 12.300
Authors: Deborah Y Park; Martin C Tom; Yanwen Chen; Surabhi Tewari; Manmeet S Ahluwalia; Jennifer S Yu; Samuel T Chao; John H Suh; David M Peereboom; Glen H J Stevens; Gene H Barnett; Lilyana Angelov; Alireza Mohammadi; Thomas Hogan; Courtney Kissel; Brittany Lapin; Isabel Schuermeyer; Michael W Parsons; Richard Naugle; Erin S Murphy Journal: J Neurooncol Date: 2022-04-29 Impact factor: 4.130
Authors: C Mircea S Tesileanu; Thierry Gorlia; Vassilis Golfinopoulos; Pim J French; Martin J van den Bent Journal: Neuro Oncol Date: 2022-04-01 Impact factor: 12.300
Authors: Andrew B Lassman; Khê Hoang-Xuan; Mei-Yin C Polley; Alba A Brandes; J Gregory Cairncross; Johan M Kros; Lynn S Ashby; Martin J B Taphoorn; Luis Souhami; Winand N M Dinjens; Nadia N Laack; Mathilde C M Kouwenhoven; Karen L Fink; Pim J French; David R Macdonald; Denis Lacombe; Minhee Won; Thierry Gorlia; Minesh P Mehta; Martin J van den Bent Journal: J Clin Oncol Date: 2022-06-22 Impact factor: 50.717
Authors: Deborah Y Park; Martin C Tom; Wei Wei; Surabhi Tewari; Manmeet S Ahluwalia; Jennifer S Yu; Samuel T Chao; John H Suh; David Peereboom; Glen H J Stevens; Gene H Barnett; Lilyana Angelov; Alireza M Mohammadi; Thomas Hogan; Courtney Kissel; Brittany Lapin; Isabel Schuermeyer; Michael W Parsons; Richard Naugle; Erin S Murphy Journal: J Neurooncol Date: 2022-01-22 Impact factor: 4.130
Authors: Jessica L Fleming; Stephanie L Pugh; Barbara J Fisher; Glenn J Lesser; David R Macdonald; Erica H Bell; Joseph P McElroy; Aline P Becker; Cynthia D Timmers; Kenneth D Aldape; C Leland Rogers; Thomas J Doyle; Maria Werner-Wasik; Jean-Paul Bahary; Hsiang-Hsuan Michael Yu; David P D'Souza; Nadia N Laack; Penny K Sneed; Young Kwok; Minhee Won; Minesh P Mehta; Arnab Chakravarti Journal: JCO Precis Oncol Date: 2021-09-01
Authors: C Mircea S Tesileanu; Marc Sanson; Wolfgang Wick; Alba A Brandes; Paul M Clement; Sara C Erridge; Michael A Vogelbaum; Anna K Nowak; Jean-Francois Baurain; Warren P Mason; Helen Wheeler; Olivier L Chinot; Sanjeev Gill; Matthew Griffin; Leland Rogers; Walter Taal; Roberta Rudà; Michael Weller; Catherine McBain; Myra E van Linde; Kenneth Aldape; Robert B Jenkins; Johan M Kros; Pieter Wesseling; Andreas von Deimling; Youri Hoogstrate; Iris de Heer; Peggy N Atmodimedjo; Hendrikus J Dubbink; Rutger W W Brouwer; Wilfred F J van IJcken; Kin Jip Cheung; Vassilis Golfinopoulos; Brigitta G Baumert; Thierry Gorlia; Pim J French; Martin J van den Bent Journal: Clin Cancer Res Date: 2022-06-13 Impact factor: 13.801