1Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida.
2Department of Radiology, NewYork-Presbyterian Hospital-Weill Cornell Medicine, New York, New York.
J Neurosurg Pediatr. 2021 Aug 6;28(4):371-379. doi: 10.3171/2021.3.PEDS20738. Print 2021 Oct 1.
Delivery of drugs intraarterially to brain tumors has been demonstrated in adults. In this study, the authors initiated a phase I trial of superselective intraarterial cerebral infusion (SIACI) of bevacizumab and cetuximab in pediatric patients with refractory high-grade glioma (diffuse intrinsic pontine glioma [DIPG] and glioblastoma) to determine the safety and efficacy in this population.
SIACI was used to deliver mannitol (12.5 ml of 20% mannitol) to disrupt the blood-brain barrier (BBB), followed by bevacizumab (15 mg/kg) and cetuximab (200 mg/m2) to target VEGF and EGFR, respectively. Patients with brainstem tumors had a balloon inflated in the distal basilar artery during mannitol infusion.
Thirteen patients were treated (10 with DIPG and 3 with high-grade glioma). Toxicities included grade I epistaxis (2 patients) and grade I rash (2 patients). There were no dose-limiting toxicities. Of the 10 symptomatic patients, 6 exhibited subjective improvement; 92% showed decreased enhancement on day 1 posttreatment MRI. Of 10 patients who underwent MRI at 1 month, 5 had progressive disease and 5 had stable disease on FLAIR, whereas contrast-enhanced scans demonstrated progressive disease in 4 patients, stable disease in 2, partial response in 2, and complete response in 1. The mean overall survival for the 10 DIPG patients was 519 days (17.3 months), with a mean posttreatment survival of 214.8 days (7.2 months).
SIACI of bevacizumab and cetuximab was well tolerated in all 13 children. The authors' results demonstrate safety of this method and warrant further study to determine efficacy. As molecular targets are clarified, novel means of bypassing the BBB, such as intraarterial therapy and convection-enhanced delivery, become more critical. Clinical trial registration no.: NCT01884740 (clinicaltrials.gov).
向脑肿瘤动脉内给药已在成人中得到证实。在这项研究中，作者在患有难治性高级别胶质瘤（弥漫性内在脑桥胶质瘤[DIPG]和胶质母细胞瘤）的儿科患者中开始进行贝伐单抗和西妥昔单抗超选择性动脉内脑输注（SIACI）的 I 期试验，以确定该人群中的安全性和有效性。
SIACI 用于递送甘露醇（20%甘露醇 12.5 毫升）以破坏血脑屏障（BBB），随后分别给予贝伐单抗（15mg/kg）和西妥昔单抗（200mg/m2）以靶向 VEGF 和 EGFR。脑干肿瘤患者在甘露醇输注期间在基底动脉远端充气气球。
共治疗了 13 名患者（10 名 DIPG 和 3 名高级别胶质瘤）。毒性包括 I 级鼻出血（2 例）和 I 级皮疹（2 例）。无剂量限制毒性。在 10 名有症状的患者中，6 名患者出现主观改善；92%的患者在治疗后第 1 天 MRI 显示增强减少。10 名接受 1 个月 MRI 的患者中，5 例疾病进展，5 例 FLAIR 稳定，而增强扫描显示 4 例疾病进展，2 例稳定，2 例部分缓解，1 例完全缓解。10 例 DIPG 患者的总生存中位数为 519 天（17.3 个月），治疗后生存中位数为 214.8 天（7.2 个月）。
13 名儿童均耐受良好地接受了贝伐单抗和西妥昔单抗的 SIACI。作者的结果表明该方法的安全性，值得进一步研究以确定疗效。随着分子靶标的明确，如动脉内治疗和对流增强递送等绕过 BBB 的新方法变得更加关键。临床试验注册号：NCT01884740（clinicaltrials.gov）。
