NOA - 04关于间变性胶质瘤序贯放化疗采用PCV或替莫唑胺的随机III期试验的长期分析。
Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide.
作者信息
Wick Wolfgang, Roth Patrick, Hartmann Christian, Hau Peter, Nakamura Makoto, Stockhammer Florian, Sabel Michael C, Wick Antje, Koeppen Susanne, Ketter Ralf, Vajkoczy Peter, Eyupoglu Ilker, Kalff Rolf, Pietsch Torsten, Happold Caroline, Galldiks Norbert, Schmidt-Graf Friederike, Bamberg Michael, Reifenberger Guido, Platten Michael, von Deimling Andreas, Meisner Christoph, Wiestler Benedikt, Weller Michael
机构信息
Department of Neurology Clinic, University of Heidelberg, Heidelberg, Germany (W.W., A.W., M.P., B.W.); Clinical Cooperation Unit (CCU Neurooncology), German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany (W.W., B.W.); Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland (P.R., C.H., M.W.); Department of Neuropathology, Hannover Medical School, Hannover, Germany (C.H.); Department of Neurology, Regensburg University, Regensburg, Germany (P.H.); Department of Neurosurgery Clinic, Hannover Medical School, Hannover, Germany (M.N.); Department of Neurosurgery Clinic, Charité, Berlin, Germany (F.S., P.V.); Department of Neurosurgery, Heinrich Heine University, Düsseldorf, Germany (M.C.S.); Department of Neurology Clinic, Essen Medical Center, Essen, Germany (S.K.); Department of Neurosurgery Clinic, Saarland University, Homburg, Germany (R.K.); Department of Neurosurgery Clinic, University of Göttingen, Göttingen, Germany (F.S.); Department of Neurosurgery Clinic, University of Erlangen, Erlangen, Germany (I.E.); Department of Neurosurgery Clinic, University of Jena, Jena, Germany (R.K.); Department of Neurology Clinic, Cologne University, Cologne, Germany (N.G.); Department of Neurology Clinic, TU Munich, Munich, Germany (F.S.-G.); Department of Neuropathology, University of Heidelberg, Heidelberg, Germany (A.v.D.); CCU Neuropathology, (C.H., A.v.D.); CCU Brain Tumor Immunology, DKFZ, all Heidelberg, Germany (M.P.); Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany (G.R.); DKTK partner site Essen/Düsseldorf, Düsseldorf, Germany (G.R.), Department of General Neurology, Tübingen, Germany (W.W., A.W., F.S.-G., M.P., M.W.), Department of Radiation Oncology, Tübingen, Germany (M.B.), Department of Medical Biometry, University Hospital Tübingen, Tübingen, Germany (C.M.).
出版信息
Neuro Oncol. 2016 Nov;18(11):1529-1537. doi: 10.1093/neuonc/now133. Epub 2016 Jul 1.
BACKGROUND
Optimal treatment and precise classification for anaplastic glioma are needed.
METHODS
The objective for long-term follow-up of NOA-04 is to optimize the treatment sequence for patients with anaplastic gliomas. Patients were randomized 2:1:1 to receive the standard radiotherapy (RT) (arm A), procarbazine, lomustine and vincristine (PCV) (arm B1), or temozolomide (TMZ) (arm B2).
RESULTS
Primary endpoint was time-to-treatment-failure (TTF), defined as progression after 2 lines of therapy or any time before if no further therapy was administered. Exploratory analyses examined associations of molecular marker status with TTF, progression-free survival (PFS), and overall survival (OS). At 9.5 (95% CI: 8.6-10.2) years, no difference between arms (A vs B1/B2) was observed: median TTF (4.6 [3.4-5.1] y vs 4.4 [3.3-5.3) y), PFS (2.5 [1.3-3.5] y vs 2.7 [1.9-3.2] y), and OS (8 [5.5-10.3] y vs 6.5 [5.4-8.3] y). Oligodendroglial versus astrocytic histology-but more so the subgroups according to CpG island methylator phenotype (CIMP) and 1p/19q co-deletion status-revealed a strong prognostic value of CIMP with (CIMP) versus without 1p/19 co-deletion (CIMP) versus CIMP. but no differential efficacy of RT versus chemotherapy for any of the endpoints. PFS was better for PCV- than for TMZ-treated patients with CIMP tumors (HR B1 vs B2 0.39 [0.17-0.92], P = .031). In CIMP. tumors, hypermethylation of the O6-methyl-guanyl-DNA methyltransferase promoter (MGMT) provided a risk reduction for PFS with chemotherapy.
CONCLUSIONS
There is no differential activity of primary chemotherapy versus RT in any subgroup of anaplastic glioma. Molecular diagnosis is superior to histology.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT00717210.
背景
间变性胶质瘤需要优化治疗方案并进行精确分类。
方法
NOA - 04长期随访的目的是优化间变性胶质瘤患者的治疗顺序。患者按2:1:1随机分组，分别接受标准放疗（RT）（A组）、丙卡巴肼、洛莫司汀和长春新碱（PCV）（B1组）或替莫唑胺（TMZ）（B2组）治疗。
结果
主要终点是治疗失败时间（TTF），定义为接受两线治疗后进展，或若未进行进一步治疗则为之前的任何时间。探索性分析研究了分子标志物状态与TTF、无进展生存期（PFS）和总生存期（OS）之间的关联。在9.5（95%CI：8.6 - 10.2）年时，各治疗组（A组与B1/B2组）之间未观察到差异：中位TTF（4.6 [3.4 - 5.1]年 vs 4.4 [3.3 - 5.3]年）、PFS（2.5 [1.3 - 3.5]年 vs 2.7 [1.9 - 3.2]年）和OS（8 [5.5 - 10.3]年 vs 6.5 [5.4 - 8.3]年）。少突胶质细胞与星形细胞组织学类型——尤其是根据CpG岛甲基化表型（CIMP）和1p/19q共缺失状态划分的亚组——显示CIMP具有很强的预后价值，有1p/19共缺失（CIMP+）与无1p/19共缺失（CIMP-）相比，以及CIMP+与CIMP-相比。但对于任何终点，放疗与化疗均无差异疗效。对于CIMP肿瘤患者，PCV治疗组的PFS优于TMZ治疗组（B1组与B2组的HR为0.39 [0.17 - 0.92]，P = 0.031）。在CIMP肿瘤中，O6-甲基鸟嘌呤-DNA甲基转移酶启动子（MGMT）的高甲基化使化疗的PFS风险降低。
结论
在间变性胶质瘤的任何亚组中，一线化疗与放疗的活性无差异。分子诊断优于组织学诊断。
试验注册
clinicaltrials.gov标识符：NCT00717210。
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