Kunwar Sandeep, Prados Michael D, Chang Susan M, Berger Mitchel S, Lang Frederick F, Piepmeier Joseph M, Sampson John H, Ram Zvi, Gutin Philip H, Gibbons Robert D, Aldape Kenneth D, Croteau David J, Sherman Jeffrey W, Puri Raj K
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143-0350, USA.
J Clin Oncol. 2007 Mar 1;25(7):837-44. doi: 10.1200/JCO.2006.08.1117.
Glioblastoma multiforme (GBM) is a devastating brain tumor with a median survival of 6 months after recurrence. Cintredekin besudotox (CB) is a recombinant protein consisting of interleukin-13 (IL-13) and a truncated form of Pseudomonas exotoxin (PE38QQR). Convection-enhanced delivery (CED) is a locoregional-administration method leading to high-tissue concentrations with large volume of distributions. We assessed the use of intracerebral CED to deliver CB in patients with recurrent malignant glioma (MG).
Three phase I clinical studies evaluated intracerebral CED of CB along with tumor resection. The main objectives were to assess the tolerability of various concentrations and infusion durations; tissue distribution; and methods for optimizing delivery. All patients underwent tumor resection followed by a single intraparenchymal infusion (in addition to the intraparenchymal one following resection), with a portion of patients who had a preresection intratumoral infusion.
A total of 51 patients with MG were treated including 46 patients with GBM. The maximum tolerated intraparenchymal concentration was 0.5 microg/mL and tumor necrosis was observed at this concentration. Infusion durations of up to 6 days were well tolerated. Postoperative catheter placement appears to be important for optimal drug distribution. CB- and procedure-related adverse events were primarily limited to the CNS. Overall median survival for GBM patients is 42.7 weeks and 55.6 weeks for patients with optimally positioned catheters with patient follow-up extending beyond 5 years.
CB appears to have a favorable risk-benefit profile. CED is a complex delivery method requiring catheter placement via a second procedure to achieve accurate catheter positioning, better drug distribution, and better outcome.
多形性胶质母细胞瘤（GBM）是一种极具破坏性的脑肿瘤，复发后的中位生存期为6个月。辛特瑞得金贝苏托克斯（CB）是一种重组蛋白，由白细胞介素-13（IL-13）和截短形式的铜绿假单胞菌外毒素（PE38QQR）组成。对流增强递送（CED）是一种局部给药方法，可导致高组织浓度和大分布容积。我们评估了在复发性恶性胶质瘤（MG）患者中使用脑内CED递送CB的情况。
三项I期临床研究评估了CB的脑内CED联合肿瘤切除术。主要目的是评估不同浓度和输注持续时间的耐受性、组织分布以及优化递送的方法。所有患者均接受肿瘤切除，随后进行单次脑实质内输注（除切除后进行的脑实质内输注外），部分患者在切除前进行瘤内输注。
共治疗了51例MG患者，其中46例为GBM患者。最大耐受脑实质内浓度为0.5μg/mL，在此浓度下观察到肿瘤坏死。长达6天的输注持续时间耐受性良好。术后导管放置对于最佳药物分布似乎很重要。与CB和手术相关的不良事件主要局限于中枢神经系统。GBM患者的总体中位生存期为42.7周，导管位置最佳的患者为55.6周，患者随访时间超过5年。
CB似乎具有良好的风险效益比。CED是一种复杂的递送方法，需要通过第二次手术放置导管以实现准确的导管定位、更好的药物分布和更好的结果。
