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
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
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DOI：
10.1016/s0140-6736(18)31791-4
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发表时间：
2019-02-16
期刊：
影响因子：
168.9
通讯作者：
Glas, Martin
中科院分区：
文献类型：
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作者：
Herrlinger, Ulrich;Tzaridis, Theophilos;Glas, Martin
研究背景迫切需要更有效的胶质母细胞瘤治疗方法。先前一项非随机2期试验的数据表明，对于MGMT启动子甲基化的新诊断胶质母细胞瘤，洛莫司汀-替莫唑胺加放疗可能优于替莫唑胺放化疗。在CeTeG/ noaa -09试验中，我们旨在进一步研究洛莫司汀-替莫唑胺治疗在随机3期试验中的效果。方法：在这项开放标签、随机、3期试验中，我们招募了来自17家德国大学医院的患者，年龄在18-70岁之间，新诊断为胶质母细胞瘤，MGMT启动子甲基化，Karnofsky Performance Score为70%及以上。根据sas生成的预定义随机化列表，患者被随机分配（1:1）至标准替莫唑胺放化疗组(75 mg/m（2) /天，伴随放疗[59-60 Gy]，随后在4周疗程的前5天使用替莫唑胺150-200 mg/m(2) /天6个疗程）或在放疗（59-60 Gy）之外使用洛莫司汀（100 mg/m(2) /天）+替莫唑胺（100-200 mg/m(2) /天，6周疗程的第2-6天）。由于时间表的不同，病人和医生并没有被掩盖到治疗组。主要终点是修改意向治疗人群的总生存率，包括所有随机分配的开始分配化疗的患者。预先指定的总生存差异检验是按中心和递归划分分析类分层的对数秩检验。该试验已在ClinicalTrials.gov注册，编号NCT01149109。在2011年6月17日至2014年4月8日期间，141例患者被随机分配到治疗组；129名患者（替莫唑胺组63名，洛莫唑胺-替莫唑胺组66名）构成了修改意向治疗人群。替莫唑胺组的中位总生存期从31.4个月（95% CI 27.7-47.1）改善至洛莫司汀-替莫唑胺组的48.1个月（32.6个月，无法评估）（风险比[HR] 0.60, 95% CI 0.35-1.03； log-rank分析p=0.0492）。在意向治疗人群的二次分析中也发现了组间显著的总生存差异（n=141, HR 0.60, 95% CI 0.35-1.03； log-rank分析p=0.0432）。替莫唑胺组63例患者中有32例（51%）出现3级或以上不良事件，洛莫唑胺-替莫唑胺组66例患者中有39例（59%）出现不良事件。没有与治疗相关的死亡。我们的研究结果表明，与替莫唑胺标准治疗相比，洛莫司汀-替莫唑胺化疗可能提高MGMT启动子甲基化的新诊断胶质母细胞瘤患者的生存率。由于试验规模较小，对研究结果的解释应谨慎。版权所有2019 Elsevier Ltd.版权所有。
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.