Levin V A, Uhm J H, Jaeckle K A, Choucair A, Flynn P J, Prados M D, Bruner J M, Chang S M, Kyritsis A P, Gleason M J, Hess K R
Department of Neuro-Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Clin Cancer Res. 2000 Oct;6(10):3878-84.
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.
尽管基于亚硝基脲的联合化疗方案（丙卡巴肼、N-(2-氯乙基)-N'-环己基-N-亚硝基脲和长春新碱，即PCV）在间变性/中级胶质瘤的治疗中已显示出疗效，但对胶质母细胞瘤患者的益处仍未得到证实。在本研究中，我们试图确定在基于亚硝基脲的治疗方案（PCV）中加入α-二氟甲基鸟氨酸（依氟鸟氨酸）是否会构成一种更有效的辅助治疗方法，依氟鸟氨酸是鸟氨酸脱羧酶的抑制剂，在复发性胶质瘤患者中已显示出令人鼓舞的结果，本研究针对多形性胶质母细胞瘤患者在放疗后的治疗情况。在常规放疗后，272例胶质母细胞瘤（GBM）患者被随机分为接受α-二氟甲基鸟氨酸-PCV（DFMO-PCV；134例患者）或单独接受PCV（138例患者），生存和肿瘤进展时间为主要终点。DFMO的起始剂量为3.0 g/m²，口服，每8小时一次，在接受N-(2-氯乙基)-N-环己基-N-亚硝基脲治疗前后各14天；PCV按先前描述的方法给药。临床和影像学（钆增强MRI）随访名义上在每6或8周周期结束时进行（PCV在6周时；DFMO-PCV在8周时）。血液学和其他不良反应的实验室评估每2周进行一次。从放疗后化疗开始之日起测量，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[中位生存期（月）：DFMO-PCV为10.5；PCV为10.4]。从首次手术时肿瘤诊断时间开始测量的总生存期，DFMO-PCV组和PCV组的中位生存期分别为13.3个月和14.2个月，5年时分别为6.2%和8.7%。使用多变量Cox比例风险模型对年龄、性能状态（KPS）、手术范围和其他因素进行调整后治疗效果不变。与DFMO相关的不良反应包括胃肠道反应（腹泻、恶心/呕吐）、血细胞减少，以及在测试剂量范围内的轻微耳毒性（仅限于耳鸣）。在这项III期研究中，在基于亚硝基脲的PCV方案中加入DFMO对胶质母细胞瘤患者没有显示出额外的益处，这突出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）胶质瘤患者，先前已证明放疗后化疗的益处更大，DFMO-PCV与PCV的评估仍在进行中，有望产生更令人鼓舞的结果。
