Ulrich Herrlinger1, Theophilos Tzaridis2, Frederic Mack2, Joachim Peter Steinbach3, Uwe Schlegel4, Michael Sabel5, Peter Hau6, Rolf-Dieter Kortmann7, Dietmar Krex8, Oliver Grauer9, Roland Goldbrunner10, Oliver Schnell11, Oliver Bähr3, Martin Uhl6, Clemens Seidel7, Ghazaleh Tabatabai12, Thomas Kowalski4, Florian Ringel13, Friederike Schmidt-Graf14, Bogdana Suchorska15, Stefanie Brehmer16, Astrid Weyerbrock17, Miriam Renovanz18, Lars Bullinger19, Norbert Galldiks20, Peter Vajkoczy21, Martin Misch21, Hartmut Vatter22, Moritz Stuplich2, Niklas Schäfer2, Sied Kebir2, Johannes Weller2, Christina Schaub2, Walter Stummer23, Jörg-Christian Tonn15, Matthias Simon22, Vera C Keil24, Michael Nelles24, Horst Urbach25, Martin Coenen26, Wolfgang Wick27, Michael Weller28, Rolf Fimmers29, Matthias Schmid29, Elke Hattingen24, Torsten Pietsch30, Christoph Coch26, Martin Glas31. 1. Division of Clinical Neurooncology, Department of Neurology and Centre of Integrated Oncology, University Hospital Bonn, Bonn, Germany. Electronic address: ulrich.herrlinger@ukbonn.de. 2. Division of Clinical Neurooncology, Department of Neurology and Centre of Integrated Oncology, University Hospital Bonn, Bonn, Germany. 3. Dr Senckenberg Institute of Neurooncology, University of Frankfurt, Frankfurt, Germany. 4. Department of Neurology, University Hospital Knappschaftskrankenhaus, Ruhr-Universität Bochum, Bochum, Germany. 5. Department of Neurosurgery, University of Düsseldorf, Düsseldorf, Germany. 6. Department of Neurology and Wilhelm Sander Neurooncology Unit, University Hospital Regensburg, Regensburg, Germany. 7. Department of Radiation Oncology, University of Leipzig, Leipzig, Germany. 8. Department of Neurosurgery, University of Dresden, Dresden, Germany. 9. Department of Neurology, University of Münster, Münster, Germany. 10. Department of Neurosurgery, University of Cologne, Cologne, Germany. 11. Department of Neurosurgery, Ludwig Maximillian University of Munich and German Cancer Consortium, Partner Site Munich, Munich, Germany; Department of Neurosurgery, University of Freiburg, Freiburg, Germany. 12. Interdisciplinary Division of Neurooncology, University of Tübingen, Tübingen, Germany. 13. Department of Neurosurgery, Technical University of Munich, Munich, Germany; Department of Neurosurgery, University of Mainz, Mainz, Germany. 14. Department of Neurology, Technical University of Munich, Munich, Germany. 15. Department of Neurosurgery, Ludwig Maximillian University of Munich and German Cancer Consortium, Partner Site Munich, Munich, Germany. 16. Department of Neurosurgery, University of Mannheim, Mannheim, Germany. 17. Department of Neurosurgery, University of Freiburg, Freiburg, Germany. 18. Department of Neurosurgery, University of Mainz, Mainz, Germany. 19. Department of Internal Medicine, University of Ulm, Ulm, Germany. 20. Department of Neurology, University of Cologne, Cologne, Germany; Institute of Neuroscience and Medicine (INM-3), Juelich, Germany. 21. Department of Neurosurgery, Charité University of Berlin, Berlin, Germany. 22. Department of Neurosurgery, University Hospital Bonn, Bonn, Germany. 23. Department of Neurosurgery, University of Münster, Münster, Germany. 24. Department of Neuroradiology, University Hospital Bonn, Bonn, Germany. 25. Department of Neuroradiology, University Hospital Bonn, Bonn, Germany; Department of Neuroradiology, University of Freiburg, Freiburg, Germany. 26. Study Centre Bonn, University Hospital Bonn, Bonn, Germany. 27. Department of Neurology, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany. 28. Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland. 29. Institute for Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, Bonn, Germany. 30. Institute of Neuropathology and DGNN Brain Tumor Reference Centre, University Hospital Bonn, Bonn, Germany. 31. Division of Clinical Neurooncology, Department of Neurology and Centre of Integrated Oncology, University Hospital Bonn, Bonn, Germany; Division of Clinical Neurooncology, Department of Neurology and West German Cancer Center, German Cancer Consortium, Partner Site Essen, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Abstract
BACKGROUND: There is an urgent need for more effective therapies for glioblastoma. Data from a previous unrandomised phase 2 trial suggested that lomustine-temozolomide plus radiotherapy might be superior to temozolomide chemoradiotherapy in newly diagnosed glioblastoma with methylation of the MGMT promoter. In the CeTeG/NOA-09 trial, we aimed to further investigate the effect of lomustine-temozolomide therapy in the setting of a randomised phase 3 trial. METHODS: In this open-label, randomised, phase 3 trial, we enrolled patients from 17 German university hospitals who were aged 18-70 years, with newly diagnosed glioblastoma with methylated MGMT promoter, and a Karnofsky Performance Score of 70% and higher. Patients were randomly assigned (1:1) with a predefined SAS-generated randomisation list to standard temozolomide chemoradiotherapy (75 mg/m2 per day concomitant to radiotherapy [59-60 Gy] followed by six courses of temozolomide 150-200 mg/m2 per day on the first 5 days of the 4-week course) or to up to six courses of lomustine (100 mg/m2 on day 1) plus temozolomide (100-200 mg/m2 per day on days 2-6 of the 6-week course) in addition to radiotherapy (59-60 Gy). Because of the different schedules, patients and physicians were not masked to treatment groups. The primary endpoint was overall survival in the modified intention-to-treat population, comprising all randomly assigned patients who started their allocated chemotherapy. The prespecified test for overall survival differences was a log-rank test stratified for centre and recursive partitioning analysis class. The trial is registered with ClinicalTrials.gov, number NCT01149109. FINDINGS: Between June 17, 2011, and April 8, 2014, 141 patients were randomly assigned to the treatment groups; 129 patients (63 in the temozolomide and 66 in the lomustine-temozolomide group) constituted the modified intention-to-treat population. Median overall survival was improved from 31·4 months (95% CI 27·7-47·1) with temozolomide to 48·1 months (32·6 months-not assessable) with lomustine-temozolomide (hazard ratio [HR] 0·60, 95% CI 0·35-1·03; p=0·0492 for log-rank analysis). A significant overall survival difference between groups was also found in a secondary analysis of the intention-to-treat population (n=141, HR 0·60, 95% CI 0·35-1·03; p=0·0432 for log-rank analysis). Adverse events of grade 3 or higher were observed in 32 (51%) of 63 patients in the temozolomide group and 39 (59%) of 66 patients in the lomustine-temozolomide group. There were no treatment-related deaths. INTERPRETATION: Our results suggest that lomustine-temozolomide chemotherapy might improve survival compared with temozolomide standard therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. The findings should be interpreted with caution, owing to the small size of the trial. FUNDING: German Federal Ministry of Education and Research.
BACKGROUND: There is an urgent need for more effective therapies for glioblastoma. Data from a previous unrandomised phase 2 trial suggested that lomustine-temozolomide plus radiotherapy might be superior to temozolomide chemoradiotherapy in newly diagnosed glioblastoma with methylation of the MGMT promoter. In the CeTeG/NOA-09 trial, we aimed to further investigate the effect of lomustine-temozolomide therapy in the setting of a randomised phase 3 trial. METHODS: In this open-label, randomised, phase 3 trial, we enrolled patients from 17 German university hospitals who were aged 18-70 years, with newly diagnosed glioblastoma with methylated MGMT promoter, and a Karnofsky Performance Score of 70% and higher. Patients were randomly assigned (1:1) with a predefined SAS-generated randomisation list to standard temozolomide chemoradiotherapy (75 mg/m2 per day concomitant to radiotherapy [59-60 Gy] followed by six courses of temozolomide 150-200 mg/m2 per day on the first 5 days of the 4-week course) or to up to six courses of lomustine (100 mg/m2 on day 1) plus temozolomide (100-200 mg/m2 per day on days 2-6 of the 6-week course) in addition to radiotherapy (59-60 Gy). Because of the different schedules, patients and physicians were not masked to treatment groups. The primary endpoint was overall survival in the modified intention-to-treat population, comprising all randomly assigned patients who started their allocated chemotherapy. The prespecified test for overall survival differences was a log-rank test stratified for centre and recursive partitioning analysis class. The trial is registered with ClinicalTrials.gov, number NCT01149109. FINDINGS: Between June 17, 2011, and April 8, 2014, 141 patients were randomly assigned to the treatment groups; 129 patients (63 in the temozolomide and 66 in the lomustine-temozolomide group) constituted the modified intention-to-treat population. Median overall survival was improved from 31·4 months (95% CI 27·7-47·1) with temozolomide to 48·1 months (32·6 months-not assessable) with lomustine-temozolomide (hazard ratio [HR] 0·60, 95% CI 0·35-1·03; p=0·0492 for log-rank analysis). A significant overall survival difference between groups was also found in a secondary analysis of the intention-to-treat population (n=141, HR 0·60, 95% CI 0·35-1·03; p=0·0432 for log-rank analysis). Adverse events of grade 3 or higher were observed in 32 (51%) of 63 patients in the temozolomide group and 39 (59%) of 66 patients in the lomustine-temozolomide group. There were no treatment-related deaths. INTERPRETATION: Our results suggest that lomustine-temozolomide chemotherapy might improve survival compared with temozolomide standard therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. The findings should be interpreted with caution, owing to the small size of the trial. FUNDING: German Federal Ministry of Education and Research.
Authors: Patrick Y Wen; Michael Weller; Eudocia Quant Lee; Brian M Alexander; Jill S Barnholtz-Sloan; Floris P Barthel; Tracy T Batchelor; Ranjit S Bindra; Susan M Chang; E Antonio Chiocca; Timothy F Cloughesy; John F DeGroot; Evanthia Galanis; Mark R Gilbert; Monika E Hegi; Craig Horbinski; Raymond Y Huang; Andrew B Lassman; Emilie Le Rhun; Michael Lim; Minesh P Mehta; Ingo K Mellinghoff; Giuseppe Minniti; David Nathanson; Michael Platten; Matthias Preusser; Patrick Roth; Marc Sanson; David Schiff; Susan C Short; Martin J B Taphoorn; Joerg-Christian Tonn; Jonathan Tsang; Roel G W Verhaak; Andreas von Deimling; Wolfgang Wick; Gelareh Zadeh; David A Reardon; Kenneth D Aldape; Martin J van den Bent Journal: Neuro Oncol Date: 2020-08-17 Impact factor: 12.300
Authors: David M Peereboom; Tyler J Alban; Matthew M Grabowski; Alvaro G Alvarado; Balint Otvos; Defne Bayik; Gustavo Roversi; Mary McGraw; Pengjing Huang; Alireza M Mohammadi; Harley I Kornblum; Tomas Radivoyevitch; Manmeet S Ahluwalia; Michael A Vogelbaum; Justin D Lathia Journal: JCI Insight Date: 2019-11-14
Authors: Antje Wick; Tobias Kessler; Michael Platten; Christoph Meisner; Michael Bamberg; Ulrich Herrlinger; Jörg Felsberg; Astrid Weyerbrock; Kirsten Papsdorf; Joachim P Steinbach; Michael Sabel; Jan Vesper; Jürgen Debus; Jürgen Meixensberger; Ralf Ketter; Caroline Hertler; Regine Mayer-Steinacker; Sarah Weisang; Hanna Bölting; David Reuss; Guido Reifenberger; Felix Sahm; Andreas von Deimling; Michael Weller; Wolfgang Wick Journal: Neuro Oncol Date: 2020-08-17 Impact factor: 12.300