Phase III randomized study of postradiotherapy chemotherapy with alpha-difluoromethylornithine-procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, vincristine (DFMO-PCV) versus PCV for glioblastoma multiforme.
Phase III randomized study of postradiotherapy chemotherapy with alpha-difluoromethylornithine-procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, vincristine (DFMO-PCV) versus PCV for glioblastoma multiforme.
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使用 α-二氟甲基鸟氨酸-丙卡巴肼、N-(2-氯乙基)-N-环己基-N-亚硝基脲、长春新碱 (DFMO-PCV) 与 PCV 治疗多形性胶质母细胞瘤的放疗后化疗的 III 期随机研究。
DOI：
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发表时间：
2000
影响因子：
11.5
通讯作者：
Kenneth R. Hess
中科院分区：
文献类型：
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作者：
Victor A. Levin;Joon H. Uhm;K. Jaeckle;Ali Choucair;Patrick J. Flynn;W. A. Yung;Michael D. Prados;Janet M. Bruner;Susan M. Chang;A. Kyritsis;M. J. Gleason;Kenneth R. Hess
尽管之前已经证明了以亚硝基脲为基础的联合化疗丙卡巴肼、N-（2-氯乙基）-N '-环己基-N-亚硝基脲和长春新碱（PCV）在间变性/中等级别胶质瘤中的疗效，但胶质母细胞瘤患者的获益仍未得到证实。在目前的研究中，我们试图确定是否添加α-二氟甲基鸟氨酸（依氟鸟氨酸），一种鸟氨酸脱羧酶的抑制剂，它已显示出令人鼓舞的结果，在复发性胶质瘤患者的设置，以亚硝基脲为基础的治疗（PCV）将构成一个更有效的辅助治疗多形性胶质母细胞瘤患者在放射治疗后的设置。在常规放射治疗后，272例胶质母细胞瘤（GBM）患者随机接受α-二氟甲基鸟氨酸-PCV（DFMO-PCV; 134例患者）或单独PCV（138例患者），生存期和肿瘤进展时间为主要终点。DFMO的起始剂量为3.0 g/m2 p.o.在用N-（2-氯乙基）-N-环己基-N-亚硝基脲处理之前和之后q8 h持续14天;如先前所述施用PCV 1。临床和放射学（钆增强MRI）随访通常在每个6周或8周周期结束时进行（PCV在6周; DFMO-PCV在8周）。血液学和其他不良反应的实验室评价间隔2周。两个治疗组之间的中位生存期或中位肿瘤进展时间没有差异，从放疗后化疗开始的那天开始测量[MS（月）：DFMO-PCV，10.5;从首次手术时肿瘤诊断开始测量的总生存期，中位数分别为13.3和14.2个月，5年分别为6.2%和8.7%，用于DFMO-PCV和PCV组。使用多变量考克斯比例风险模型校正年龄、体能状态（KPS）、手术范围和其他因素后，治疗效果不变。在试验剂量范围内，与DFMO相关的不良反应包括胃肠道（腹泻、恶心/呕吐）、血细胞减少和极轻微耳毒性（仅限于耳鸣）。在这项III期研究中，将DFMO添加到基于亚硝基脲的PCV方案中，证明在胶质母细胞瘤患者中没有额外的益处，强调了多形性胶质母细胞瘤肿瘤对烷化剂的耐药性。对于间变性（中级）神经胶质瘤患者，先前证明的放疗后化疗的获益更为显著，DFMO-PCV与PCV的评价仍在进行中，有望产生更令人鼓舞的结果。
Although the efficacy of the nitrosourea-based combination chemotherapy procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, and vincristine (PCV) has been previously demonstrated in the setting of anaplastic/intermediate-grade gliomas, the benefit for glioblastoma patients remains unproven. In the current study, we sought to determine whether the addition of alpha-difluoromethylornithine (eflornithine), an inhibitor of ornithine decarboxylase, which has shown encouraging results in the setting of recurrent glioma patients, to a nitrosourea-based therapy (PCV) would constitute a more effective adjuvant therapy in the treatment of glioblastoma multiforme patients in the postradiation therapy setting. Following conventional radiation therapy, 272 glioblastoma (GBM) patients were randomized to receive either alpha-difluoromethylornithine-PCV (DFMO-PCV; 134 patients) or PCV alone (138 patients), with survival and time to tumor progression being the primary endpoints. The starting dosage of DFMO was 3.0 g/m2 p.o. q8h for 14 days before and after treatment with N-(2-chloroethyl)-N-cyclohexyl-N-nitrosurea; PCV was administered as previously described1. Clinical and radiological (Gadolinium-enhanced MRI) follow-ups were nominally at the end of each 6 or 8 week cycle (PCV at 6 weeks; DFMO-PCV at 8 weeks). Laboratory evaluations for hematologic and other adverse effects were at 2 week intervals. There was no difference in median survival or median time-to-tumor progression between the two treatment groups, as measured from day of commencement of postradiotherapy chemotherapy [MS (months): DFMO-PCV, 10.5; Overall survival, as measured from time of tumor diagnosis at first surgery, was 13.3 and 14.2 months at the median and 6.2 and 8.7% at 5 years, respectively, for the DFMO-PCV and PCV arms. The treatment effect was unchanged after adjustment for age, performance status (KPS), extent of surgery, and other factors using the multivariate Cox proportional hazard model. Adverse effects associated with DFMO consisted of gastrointestinal (diarrhea nausea/vomiting), cytopenias, and minimal ototoxicity (limited to tinnitus) at the dose range tested. The addition of DFMO to the nitrosourea-based PCV regimen in this phase III study demonstrated no additional benefit in glioblastoma patients, underscoring the resistance of glioblastoma multiforme tumors to alkylating agents. For patients with anaplastic (intermediate grade) gliomas, in which the previously demonstrated benefit of post-radiation chemotherapy is more substantial, the evaluation of DFMO-PCV vs. PCV is still ongoing and hopefully will yield more encouraging results.
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通过 D,L-α-二氟甲基鸟氨酸处理消除 9L 大鼠脑肿瘤细胞多胺含量，抑制增殖和 G1 到 S 的转变。
影响因子：
3.7
作者：
Seidenfeld,J;Gray,JW;Marton,LJ
通讯作者：
Marton,LJ
用 1,3-双(2-氯乙基)-1-亚硝基脲和 α-二氟甲基鸟氨酸治疗复发性神经胶质瘤。
影响因子：
4.8
作者：
Prados,M;Rodriguez,L;Chamberlain,M;Silver,P;Levin,V
通讯作者：
Levin,V
9L 大鼠脑肿瘤细胞中 α-二氟甲基鸟氨酸诱导的多胺消耗引起的 1,3-双（2-氯乙基）-1-亚硝基脲细胞毒性增强的时间依赖性。
影响因子：
11.2
作者：
Alhonen-Hongisto,L;Deen,DF;Marton,LJ
通讯作者：
Marton,LJ
α-二氟甲基鸟氨酸（一种鸟氨酸脱羧酶抑制剂）增强 1,3-双（2-氯乙基）-1-亚硝基脲的抗肿瘤治疗作用。
影响因子：
11.2
作者：
Marton,LJ;Levin,VA;Hervatin,SJ;Koch-Weser,J;McCann,PP;Sjoerdsma,A
通讯作者：
Sjoerdsma,A
体外对氯乙基亚硝基脲敏感和耐药的 9L 大鼠脑肿瘤细胞中 α-二氟甲基鸟氨酸对 1,3-双（2-氯乙基）-1-亚硝基脲的差异增强作用。
影响因子：
11.2
作者：
Oredsson,SM;Tofilon,PJ;Feuerstein,BG;Deen,DF;Rosenblum,ML;Marton,LJ
通讯作者：
Marton,LJ