Fetell M R, Grossman S A, Fisher J D, Erlanger B, Rowinsky E, Stockel J, Piantadosi S
Department of Neurology, Columbia University, New York, NY, USA.
J Clin Oncol. 1997 Sep;15(9):3121-8. doi: 10.1200/JCO.1997.15.9.3121.
The purpose of this study was to determine the response rate of paclitaxel administered at maximal tolerated doses (MTD) in patients with newly diagnosed glioblastoma multiform.
All patients in this multicenter study were 45 years or older and had measurable residual tumor on postoperative MRI scans. Up to 3 cycles of paclitaxel were administered as a continuous 96-hour intravenous infusion prior to radiation, provided that the tumor did not enlarge on serial MRIs. The initial 10 patients were treated with the previously recommended phase II dose of 140 mg/m2. Less than anticipated toxicity led to the development of a phase I/II study in 24 patients in which paclitaxel doses were escalated separately in patients receiving (+EIAED) or not receiving (-EIAED), concomitant enzyme-inducing antiepileptic drugs. Paclitaxel plasma steady-state concentrations (Css) were measured during the first cycle of chemotherapy. Response was the primary efficacy endpoint for this study, although survival was also assessed.
The MTD was 140 mg/m2 in the -EIAED, and 200 mg/m2 in the +EIAED patient groups. The mean Css for the -EIAED patients treated at 140 mg/m2 was 38 nM, whereas the mean Css for +EIAED patients were 17 nm at 140 mg/m2, 27 nM at 175 mg/m2, 46 nM at 200 mg/m2, and 51 nM at 230 mg/m2. One patient, who had a verified partial response, had his diagnosis changed to an anaplastic oligodendroglioma on subsequent central neuropathologic review. None of the 15 assessable glioblastoma patients treated at or above the MTD doses showed a radiographic response to paclitaxel. The median survival of eligible patients on this protocol was 355 days (95% CI, 255 to 485 days), which is similar to the survival of comparable patients treated with conventional therapy.
These results suggest that (1) paclitaxel given as a 96-hour infusion at the MTD has minimal activity in patients with untreated glioblastoma, (2) the concomitant administration of EIAEDs alters the pharmacology of paclitaxel, resulting in a lower Css, reduced systemic toxicity, and higher dose requirements, (3) this study design, in which a new agent is given prior to radiation therapy (with serial monitoring of MRI), did not adversely affect survival in this patient population.
本研究旨在确定最大耐受剂量（MTD）的紫杉醇对新诊断的多形性胶质母细胞瘤患者的缓解率。
本多中心研究中的所有患者年龄均在45岁及以上，术后MRI扫描显示有可测量的残留肿瘤。在放疗前，以96小时持续静脉输注的方式给予最多3个周期的紫杉醇，前提是肿瘤在系列MRI检查中未增大。最初的10名患者接受了先前推荐的II期剂量140mg/m²的治疗。由于毒性低于预期，因此对24名患者开展了I/II期研究，在接受（+EIAED）或未接受（-EIAED）伴随酶诱导抗癫痫药物的患者中分别提高紫杉醇剂量。在化疗的第一个周期中测量紫杉醇血浆稳态浓度（Css）。缓解是本研究的主要疗效终点，同时也评估了生存率。
-EIAED患者组的MTD为140mg/m²，+EIAED患者组的MTD为200mg/m²。接受140mg/m²治疗的-EIAED患者的平均Css为38nM，而接受+EIAED治疗的患者在140mg/m²时的平均Css为17nM，在175mg/m²时为27nM，在200mg/m²时为46nM，在230mg/m²时为51nM。一名经证实有部分缓解的患者在随后的中枢神经病理学复查中诊断变为间变性少突胶质细胞瘤。在接受MTD剂量或以上治疗的15名可评估的胶质母细胞瘤患者中，没有一人对紫杉醇表现出影像学缓解。按照本方案治疗的符合条件患者的中位生存期为355天（95%CI，255至485天），这与接受传统治疗的类似患者的生存期相似。
这些结果表明，（1）以MTD进行96小时输注给予的紫杉醇对未经治疗的胶质母细胞瘤患者的活性极小；（2）伴随给予EIAED会改变紫杉醇的药理学特性，导致较低的Css、降低全身毒性并需要更高的剂量；（3）本研究设计（在放疗前给予新药物并对MRI进行系列监测）对该患者群体的生存率没有不利影响。
