Johannes Weller1, Theophilos Tzaridis1, Frederic Mack1, Joachim Peter Steinbach2, Uwe Schlegel3, Peter Hau4, Dietmar Krex5, Oliver Grauer6, Roland Goldbrunner7, Oliver Bähr2, Martin Uhl4, Clemens Seidel8, Ghazaleh Tabatabai9, Stefanie Brehmer10, Lars Bullinger11, Norbert Galldiks12, Christina Schaub1, Sied Kebir1, Walter Stummer13, Matthias Simon14, Rolf Fimmers15, Christoph Coch16, Martin Glas17, Ulrich Herrlinger18, Niklas Schäfer1. 1. Division of Clinical Neurooncology, Department of Neurology and Center of Integrated Oncology, University Hospital Bonn, Bonn, Germany. 2. Dr Senckenberg Institute of Neurooncology, University of Frankfurt, Frankfurt am Main, Germany. 3. Department of Neurology, University Hospital Knappschaftskrankenhaus, Ruhr-Universität Bochum, Bochum, Germany. 4. Department of Neurology and Wilhelm Sander Neurooncology Unit, University Hospital Regensburg, Regensburg, Germany. 5. Department of Neurosurgery, University of Dresden, Dresden, Germany. 6. Department of Neurology, University of Münster, Münster, Germany. 7. Department of Neurosurgery, University of Cologne, Cologne, Germany. 8. Department of Radiation Oncology, University of Leipzig, Leipzig, Germany. 9. Interdisciplinary Division of Neurooncology, University of Tübingen, Tübingen, Germany. 10. Department of Neurosurgery, University of Mannheim, Mannheim, Germany. 11. Department of Internal Medicine, University of Ulm, Ulm, Germany. 12. Department of Neurology, University of Cologne, Cologne, Germany; Institute of Neuroscience and Medicine, Forschungszentrum Juelich, Juelich, Germany. 13. Department of Neurosurgery, University of Münster, Münster, Germany. 14. Department of Neurosurgery, University Hospital Bonn, Bonn, Germany. 15. Institute for Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, Bonn, Germany. 16. Study Center Bonn, University Hospital Bonn, Bonn, Germany. 17. 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. 18. Division of Clinical Neurooncology, Department of Neurology and Center of Integrated Oncology, University Hospital Bonn, Bonn, Germany. Electronic address: ulrich.herrlinger@ukbonn.de.
Abstract
BACKGROUND: The CeTeG/NOA-09 trial showed significantly longer overall survival with combined lomustine-temozolomide therapy compared with standard temozolomide for patients with glioblastoma with methylated MGMT promoter. The trial also aimed to investigate the effect of lomustine-temozolomide therapy on health-related quality of life (HRQOL) and neurocognitive function, which we report here. METHODS: In this randomised, multicentre, open-label, phase 3 trial, newly diagnosed, chemoradiotherapy-naive patients with MGMT-methylated glioblastoma, aged 18-70 years, with a Karnofsky performance score of 70% or higher, were recruited and enrolled at 17 university hospitals in Germany. Patients received standard radiotherapy (60 Gy) and were randomly assigned (1:1, stratified by centre by allocating complete blocks of six to a centre, without masking) to either six 6-week courses of oral combined lomustine (100 mg/m2 on day 1) plus temozolomide (100-200 mg/m2 on days 2-6) or standard oral temozolomide (75 mg/m2 daily during radiotherapy plus six 4-week courses of temozolomide [150-200 mg/m2] on days 1-5, every 4 weeks). The primary endpoint was overall survival. HRQOL, assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 and the EORTC brain cancer module (BN20); and neurocognitive function, assessed using the Mini Mental State Examination (MMSE), plus a neurocognitive test battery (NOA-07), including Trail Making Test A and B (TMT-A and B), working memory tests, and tests for lexical (Controlled Oral Word Association [COWA]) and semantic verbal fluency, were secondary endpoints analysed in the modified intention-to-treat population (mITT; all randomly assigned patients who received at least one dose of study chemotherapy). We used linear mixed-model analyses to investigate differences between treatment groups regarding HRQOL (clinically relevant ≥10 points) and MMSE scores (clinically relevant ≥3 points). The trial is registered with ClinicalTrials.gov, NCT01149109. FINDINGS:Between June 17, 2011 and April 8, 2014, 141 patients were randomly assigned and 129 patients began treatment and were included in the mITT population (63 in thetemozolomide and 66 in the lomustine-temozolomide group). Median follow-up for HRQOL (the item global health) was 19·4 months (IQR 7·8-38·6), for MMSE was 15·3 months (4·1-29·6), and for COWA was 11·0 months (0-27·5). We found no significant impairment regarding any item of HRQOL in the lomustine-temozolomide group (difference between the groups for global health 0·30 [95% CI -0·23 to 0·83]; p=0·26). Differences in MMSE were in favour of the temozolomide group (difference -0·11 [95% CI -0·19 to -0·03]; p=0·0058) but were not clinically relevant (1·76/30 points over 4 years). We found no significant difference between the groups in any subtest of the neurocognitive test battery (difference for COWA 0·04 [95% CI -0·01 to 0·09]; p=0·14). INTERPRETATION: The absence of systematic and clinically relevant changes in HRQOL and neurocognitive function combined with the survival benefit of lomustine-temozolomide versus temozolomide alone suggests that a long-term net clinical benefit exists for patients with newly diagnosed glioblastoma with methylation of the MGMT promoter and supports the use of lomustine-temozolomide as a treatment option for these patients. FUNDING: German Federal Ministry of Education and Research.
RCT Entities:
BACKGROUND: The CeTeG/NOA-09 trial showed significantly longer overall survival with combined lomustine-temozolomide therapy compared with standard temozolomide for patients with glioblastoma with methylated MGMT promoter. The trial also aimed to investigate the effect of lomustine-temozolomide therapy on health-related quality of life (HRQOL) and neurocognitive function, which we report here. METHODS: In this randomised, multicentre, open-label, phase 3 trial, newly diagnosed, chemoradiotherapy-naive patients with MGMT-methylated glioblastoma, aged 18-70 years, with a Karnofsky performance score of 70% or higher, were recruited and enrolled at 17 university hospitals in Germany. Patients received standard radiotherapy (60 Gy) and were randomly assigned (1:1, stratified by centre by allocating complete blocks of six to a centre, without masking) to either six 6-week courses of oral combined lomustine (100 mg/m2 on day 1) plus temozolomide (100-200 mg/m2 on days 2-6) or standard oral temozolomide (75 mg/m2 daily during radiotherapy plus six 4-week courses of temozolomide [150-200 mg/m2] on days 1-5, every 4 weeks). The primary endpoint was overall survival. HRQOL, assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 and the EORTC brain cancer module (BN20); and neurocognitive function, assessed using the Mini Mental State Examination (MMSE), plus a neurocognitive test battery (NOA-07), including Trail Making Test A and B (TMT-A and B), working memory tests, and tests for lexical (Controlled Oral Word Association [COWA]) and semantic verbal fluency, were secondary endpoints analysed in the modified intention-to-treat population (mITT; all randomly assigned patients who received at least one dose of study chemotherapy). We used linear mixed-model analyses to investigate differences between treatment groups regarding HRQOL (clinically relevant ≥10 points) and MMSE scores (clinically relevant ≥3 points). The trial is registered with ClinicalTrials.gov, NCT01149109. FINDINGS: Between June 17, 2011 and April 8, 2014, 141 patients were randomly assigned and 129 patients began treatment and were included in the mITT population (63 in the temozolomide and 66 in the lomustine-temozolomide group). Median follow-up for HRQOL (the item global health) was 19·4 months (IQR 7·8-38·6), for MMSE was 15·3 months (4·1-29·6), and for COWA was 11·0 months (0-27·5). We found no significant impairment regarding any item of HRQOL in the lomustine-temozolomide group (difference between the groups for global health 0·30 [95% CI -0·23 to 0·83]; p=0·26). Differences in MMSE were in favour of the temozolomide group (difference -0·11 [95% CI -0·19 to -0·03]; p=0·0058) but were not clinically relevant (1·76/30 points over 4 years). We found no significant difference between the groups in any subtest of the neurocognitive test battery (difference for COWA 0·04 [95% CI -0·01 to 0·09]; p=0·14). INTERPRETATION: The absence of systematic and clinically relevant changes in HRQOL and neurocognitive function combined with the survival benefit of lomustine-temozolomide versus temozolomide alone suggests that a long-term net clinical benefit exists for patients with newly diagnosed glioblastoma with methylation of the MGMT promoter and supports the use of lomustine-temozolomide as a treatment option for these patients. FUNDING: German Federal Ministry of Education and Research.
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