同步放化疗联合辅助替莫唑胺与单纯放疗对胶质母细胞瘤生存影响的随机III期研究：EORTC-NCIC试验的5年分析
Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial.
作者信息
Stupp Roger, Hegi Monika E, Mason Warren P, van den Bent Martin J, Taphoorn Martin J B, Janzer Robert C, Ludwin Samuel K, Allgeier Anouk, Fisher Barbara, Belanger Karl, Hau Peter, Brandes Alba A, Gijtenbeek Johanna, Marosi Christine, Vecht Charles J, Mokhtari Karima, Wesseling Pieter, Villa Salvador, Eisenhauer Elizabeth, Gorlia Thierry, Weller Michael, Lacombe Denis, Cairncross J Gregory, Mirimanoff René-Olivier
机构信息
Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
出版信息
Lancet Oncol. 2009 May;10(5):459-66. doi: 10.1016/S1470-2045(09)70025-7. Epub 2009 Mar 9.
BACKGROUND
In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years.
METHODS
Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353.
FINDINGS
Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy.
INTERPRETATION
Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide.
FUNDING
EORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough.
背景
2004年，欧洲癌症研究与治疗组织（EORTC）和加拿大国立癌症研究所临床试验组（NCIC）开展的一项随机III期试验报告称，同步放化疗联合辅助替莫唑胺治疗的胶质母细胞瘤患者，其生存期的中位数和2年生存率均有所提高。我们报告了中位随访时间超过5年的最终结果。
方法
新诊断的成年胶质母细胞瘤患者被随机分配接受标准放疗或同步替莫唑胺放疗，随后进行多达6个周期的辅助替莫唑胺治疗。从206例患者的肿瘤组织中回顾性测定甲基鸟嘌呤甲基转移酶基因（MGMT）的甲基化状态。主要终点为总生存期。分析采用意向性分析。本试验已在Clinicaltrials.gov注册，编号为NCT00006353。
结果
2000年8月17日至2002年3月22日期间，573例患者被分配接受治疗。单纯放疗组286例患者中有278例（97%）、联合治疗组287例患者中有254例（89%）在5年随访期内死亡。替莫唑胺治疗组2年总生存率为27.2%（95%CI 22.2-32.5），3年为16.0%（12.0-20.6），4年为12.1%（8.5-16.4），5年为9.8%（6.4-14.0）；单纯放疗组2年总生存率为10.9%（7.6-14.8），3年为4.4%（2.4-7.2），4年为3.0%（1.4-5.7），5年为1.9%（0.6-4.4）（风险比0.6，95%CI 0.5-0.7；p<0.0001）。在所有临床预后亚组中，包括60-70岁的患者，联合治疗均显示出获益。MGMT启动子甲基化是替莫唑胺化疗疗效和获益的最强预测指标。
解读
辅助替莫唑胺联合放疗的获益在长达5年的随访期内持续存在。少数预后良好的患者生存期超过5年。MGMT甲基化状态可识别最有可能从添加替莫唑胺治疗中获益的患者。
资助
EORTC、NCIC、内莉亚和阿马德奥·巴莱塔基金会、先灵葆雅公司。
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