Blaney S M, Phillips P C, Packer R J, Heideman R L, Berg S L, Adamson P C, Allen J C, Sallan S E, Jakacki R I, Lange B J, Reaman G H, Horowitz M E, Poplack D G, Balis F M
The Pediatric Branch, National Cancer Institute, Bethesda, Maryland, USA.
Cancer. 1996 Aug 1;78(3):527-31. doi: 10.1002/(SICI)1097-0142(19960801)78:3<527::AID-CNCR21>3.0.CO;2-#.
Topotecan is a topoisomerase I inhibitor that has good penetration across the blood-brain barrier and significant antitumor activity against human brain tumor xenografts. In a Phase I trial in children with refractory cancer, topotecan was well tolerated when administered as a 24-hour infusion. The maximum tolerated dose was 5.5 mg/m2 and the dose-limiting toxicity was myelosuppression. This Phase II study of topotecan was performed to assess the activity of topotecan against childhood brain tumors.
Forty-five children with either a previously treated primary brain tumor that was refractory to standard therapy, or an untreated brain stem glioma or glioblastoma multiforme, received topotecan administered as a 24-hour intravenous infusion every 21 days. The initial dose was 5.5 mg/m2 with escalation to 7.5 mg/m2 on the second and subsequent doses in patients who did not experience dose-limiting toxicity.
There were no complete or partial responses in the patients with high grade glioma (n=9), medulloblastoma (n=9), or brain stem glioma (n=14). One of 2 patients with a low grade glioma had a partial response lasting more than 17 months; 3 patients with a brain stem glioma had stable disease for 12 to 28 weeks; and 1 patient with a malignant neuroepithelial tumor and 1 patient with an optic glioma had stable disease for 41 weeks and 22 weeks, respectively. Dose escalation from 5.5 mg/m2 to 7.5 mg/m2 was well tolerated in the first 11 patients enrolled on this study who had not received prior craniospinal radiation therapy. The starting dose was subsequently increased to 7.5 mg/m2 for patients without prior craniospinal radiation.
Topotecan administered as a 24-hour infusion every 21 days is inactive in high grade gliomas, medulloblastomas, and brain stem tumors.
拓扑替康是一种拓扑异构酶I抑制剂，具有良好的血脑屏障穿透能力，对人脑肿瘤异种移植瘤具有显著的抗肿瘤活性。在一项针对难治性癌症儿童的I期试验中，拓扑替康以24小时持续静脉输注给药时耐受性良好。最大耐受剂量为5.5mg/m²，剂量限制性毒性为骨髓抑制。进行这项拓扑替康的II期研究以评估其对儿童脑肿瘤的活性。
45名儿童，他们要么患有先前接受过治疗但对标准治疗无效的原发性脑肿瘤，要么患有未经治疗的脑干胶质瘤或多形性胶质母细胞瘤，每21天接受一次拓扑替康24小时静脉输注。初始剂量为5.5mg/m²，对于未出现剂量限制性毒性的患者，第二次及后续剂量递增至7.5mg/m²。
高级别胶质瘤（n = 9）、髓母细胞瘤（n = 9）或脑干胶质瘤（n = 14）患者中无完全或部分缓解。2例低级别胶质瘤患者中有1例出现持续超过17个月的部分缓解；3例脑干胶质瘤患者病情稳定12至28周；1例恶性神经上皮肿瘤患者和1例视神经胶质瘤患者病情分别稳定41周和22周。在本研究中最初入组的11名未接受过先前颅脊髓放疗的患者中，从5.5mg/m²剂量递增至7.5mg/m²耐受性良好。随后，对于未接受过先前颅脊髓放疗的患者，起始剂量增加至7.5mg/m²。
每21天进行一次24小时输注的拓扑替康对高级别胶质瘤、髓母细胞瘤和脑干肿瘤无活性。
