Herrlinger, Ulrich, Tzaridis, Theophilos ORCID: 0000-0001-9651-1144, Mack, Frederic, Steinbach, Joachim Peter, Schlegel, Uwe, Sabel, Michael, Hau, Peter ORCID: 0000-0003-3894-5053, Kortmann, Rolf-Dieter, Krex, Dietmar, Grauer, Oliver, Goldbrunner, Roland, Schnell, Oliver, Baehr, Oliver, Uhl, Martin, Seidel, Clemens, Tabatabai, Ghazaleh ORCID: 0000-0002-3542-8782, Kowalski, Thomas, Ringel, Florian, Schmidt-Graf, Friederike, Suchorska, Bogdana, Brehmer, Stefanie, Weyerbrock, Astrid ORCID: 0000-0001-9060-4462, Renovanz, Miriam, Bullinger, Lars, Galldiks, Norbert ORCID: 0000-0002-2485-1796, Vajkoczy, Peter, Misch, Martin, Vatter, Hartmut, Stuplich, Moritz, Schaefer, Niklas, Kebir, Sied, Weller, Johannes ORCID: 0000-0001-5818-5392, Schaub, Christina, Stummer, Walter, Tonn, Joerg-Christian, Simon, Matthias, Keil, Vera C., Nelles, Michael, Urbach, Horst, Coenen, Martin, Wick, Wolfgang ORCID: 0000-0002-6171-634X, Weller, Michael, Fimmers, Rolf, Schmid, Matthias ORCID: 0000-0002-0788-0317, Hattingen, Elke ORCID: 0000-0002-8392-9004, Pietsch, Torsten, Coch, Christoph and Glas, Martin (2019). Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial. Lancet, 393 (10172). S. 678 - 689. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1474-547X

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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/m(2) per day concomitant to radiotherapy [59-60 Gy] followed by six courses of temozolomide 150-200 mg/m(2) per day on the first 5 days of the 4-week course) or to up to six courses of lomustine (100 mg/m(2) on day 1) plus temozolomide (100-200 mg/m(2) 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. Copyright (c) 2019 Elsevier Ltd. All rights reserved.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Herrlinger, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tzaridis, TheophilosUNSPECIFIEDorcid.org/0000-0001-9651-1144UNSPECIFIED
Mack, FredericUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinbach, Joachim PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlegel, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sabel, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hau, PeterUNSPECIFIEDorcid.org/0000-0003-3894-5053UNSPECIFIED
Kortmann, Rolf-DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krex, DietmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grauer, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldbrunner, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schnell, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baehr, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uhl, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seidel, ClemensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tabatabai, GhazalehUNSPECIFIEDorcid.org/0000-0002-3542-8782UNSPECIFIED
Kowalski, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ringel, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt-Graf, FriederikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suchorska, BogdanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brehmer, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weyerbrock, AstridUNSPECIFIEDorcid.org/0000-0001-9060-4462UNSPECIFIED
Renovanz, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bullinger, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Galldiks, NorbertUNSPECIFIEDorcid.org/0000-0002-2485-1796UNSPECIFIED
Vajkoczy, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Misch, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vatter, HartmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stuplich, MoritzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaefer, NiklasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kebir, SiedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weller, JohannesUNSPECIFIEDorcid.org/0000-0001-5818-5392UNSPECIFIED
Schaub, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stummer, WalterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tonn, Joerg-ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simon, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keil, Vera C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nelles, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Urbach, HorstUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coenen, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wick, WolfgangUNSPECIFIEDorcid.org/0000-0002-6171-634XUNSPECIFIED
Weller, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fimmers, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmid, MatthiasUNSPECIFIEDorcid.org/0000-0002-0788-0317UNSPECIFIED
Hattingen, ElkeUNSPECIFIEDorcid.org/0000-0002-8392-9004UNSPECIFIED
Pietsch, TorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coch, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Glas, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-156534
DOI: 10.1016/S0140-6736(18)31791-4
Journal or Publication Title: Lancet
Volume: 393
Number: 10172
Page Range: S. 678 - 689
Date: 2019
Publisher: ELSEVIER SCIENCE INC
Place of Publication: NEW YORK
ISSN: 1474-547X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RADIOTHERAPY; CHEMOTHERAPY; BEVACIZUMAB; CLASSIFICATION; SURVIVAL; GLIOMA; TUMORSMultiple languages
Medicine, General & InternalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15653

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