Dose-Dense Temozolomide for Newly Diagnosed Glioblastoma: A Randomized Phase III Clinical Trial
Dose-Dense Temozolomide for Newly Diagnosed Glioblastoma: A Randomized Phase III Clinical Trial
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DOI：
10.1200/jco.2013.49.6968
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发表时间：
2013-11-10
影响因子：
45.3
通讯作者：
Mehta, Minesh P.
中科院分区：
文献类型：
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作者：
Gilbert, Mark R.;Wang, Meihua;Mehta, Minesh P.
目的配合替莫唑胺辅助放射治疗是新诊断的胶质母细胞瘤的标准治疗方案。O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)甲基化状态可能是治疗反应的重要决定因素。剂量密度(DD)替莫唑胺导致血液中单个核细胞和可能的肿瘤中MGMT的长期耗竭。这项试验测试了DD替莫唑胺是否改善了新诊断的银屑病患者的总存活率(OS)或无进展存活率(PFS)。患者和方法这项III期试验纳入了卡诺夫斯基评分为>；=60且组织充足的18岁以上患者。分层包括临床因素和肿瘤MGMT甲基化状态。患者随机分为标准替莫唑胺(第1组)和DD替莫唑胺(第2组)，疗程6~12个周期。主要的终点是操作系统。二次分析评估MGMT状态的影响。结果总共833名患者被随机分配到1组或2组(登记1173人)。在中位OS(16.6个月比14.9个月；风险比1.03；P=.63)或中位PFS(5.5个月比6.7个月；HR，0.87；P=.06)方面，ARMS之间的差异无统计学意义。甲基化状态不同，疗效也不同。MGMT甲基化与OS(21.2比14个月；HR，1.74；P=.001)、PFS(8.7比5.7个月；HR，1.63；P=.001)和应答(P=.012)相关。ARM 2的毒性增加了3级(34%比53%；P=.001)，主要是淋巴细胞减少和疲劳。结论本研究没有显示出DD替莫唑胺对新诊断的GBM的改善效果，无论甲基化状态如何。然而，它确实证实了MGMT甲基化的预后意义。论证了大规模累加、前瞻性肿瘤采集和分子分层的可行性。(C)美国临床肿瘤学会2013年
PurposeRadiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O6-methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM.Patients and MethodsThis phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of >= 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status.ResultsA total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio [HR], 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P = .001), PFS (8.7 v 5.7 months; HR, 1.63; P = .001), and response (P = .012). There was increased grade >= 3 toxicity in arm 2 (34% v 53%; P = .001), mostly lymphopenia and fatigue.ConclusionThis study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated. (C) 2013 by American Society of Clinical Oncology