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1、恶性脑肿瘤的化学治疗四川省肿瘤医院内科 张智慧Cerebrum and Cerebellum流行病学趋势2005 (US) 18,500* 12,760Incidence 11.47 per 100,000 (annual rate)Adjusted 5 yr survival rate (1995-2000) 33% adults73% children 2nd leading cause of cancer deaths in persons 肿瘤,正常脑组织暴露化疗药物高渗性BBB开放Blood brain barrier disruption (BBBD) and intra-arte
2、rial methotrexate based therapy for newly diagnosed primary CNS lymphoma: The BBBD Consortium Experience.2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S 4 institutions： 1982-2005， 177 PCNSLBBBD/IA MTX ；2,469 procedures Pts CR PR ORR M OS(y) MPFS(y) PFS-5(y)177 101 41 80.2% 3.1 1.6 40%A
3、Phase II Trial Involving Patients with Recurrent PCNSL Treated with Carboplatin/BBBD, by Adding Rituxan (Rituximab), an anti CD-20 Antibody, to the Treatment RegimenPhase I/II Study of Carboplatin, Melphalan and Etoposide Phosphate in Conjunction with Osmotic Opening of the Blood-Brain Barrier and D
4、elayed Intravenous Sodium Thiosulfate Chemoprotection, in Subjects with Anaplastic Oligodendroglioma or OligoastrocytomaPhase II Clinical Trial of Patients with High-Grade Glioma Treated with Intra -arterial Carboplatin-based Chemotherapy, Randomized to Treatment with or without Delayed Intravenous
5、Sodium Thiosulfate as a Potential Chemoprotectant against Severe ThrombocytopeniaIntra-arterial Melphalan (L-phenylalanine mustard) Administered in Conjunction with Osmotic Blood-Brain Barrier Disruption in Patients with Brain Malignancies: A Phase I StudyNeuro-Oncology Blood-Brain Barrier ProgramOr
6、egon Health 6(1): 3337 可评价病人数 PR SD MTTP(w) PFS-6 MS(w) MPFS(w) OS-6 1Year53 2 21 17 21% 34 11 68% 26%可评价病人数 CR PR MTTP(w) PFS-6(m)42 0 9 17 30.3%Second-line chemotherapy with irinotecan plus carmustine in glioblastoma recurrent or progressive after first-line temozolomide chemotherapy: a phase II s
7、tudy of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). J Clin Oncol. 2004 Dec 1;22(23):4779-86 2007年ASCO有关Gliomas的文献有36篇病人数 可评价病人数 PR MPFS(w) MOS(w) PFS-668 59 59% 23 40 43%In grade III patients the median PFS was 42 weeks, the 6 month PFS was 61% the medial overall survival was 60 week
8、s Conclusion: The combination of bevacizumab and irinotecan is safe and demonstrates superior activity against malignant gliomas.Phase II trial of bevacizumab and irinotecan in the treatment of malignant gliomasA phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV)
9、alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM). J Clin Oncol 26: 2008 (May 20 suppl; abstr 2010bBevacizumab plus irinotecan in recurrent glioblastoma multiforme J Clin Oncol. 2007 Oct 20;25(30):4722-9可评价
10、病人数 PR PFS-6 OS-635 57% 46% 77%Phase II trial of irinotecan and thalidomide in adults with recurrent glioblastoma multiforme可评价病人数 CR PR SD MPFS(w) MOS(w) 1Year32 1 11 19 13 36 34%Neuro Oncol. 2008 Feb 26 Bevacizumab and irinotecan for recurrentoligodendroglial tumors.Conclusions: This regimen is ef
11、fective in recurrent oligodendrogliomas, and the overall tolerance is acceptable.ASCO 2009,Abstract 205425Pts. CR PR M-PFS(d) MOS(d) 6-PFS(ms)20% 52% 174 328 42%ASCO 2009,Abstract 20372009年ASCO有关神经系统肿瘤的文献80余篇A phase II study of XL184 in patients (pts) with progressive glioblastomamultiforme (GBM) in
12、 first or second relapse.Conclusions: XL184at a dose of 175 mg PO qd, has demonstrated substantial activity in ptswith progressive or recurrent GBM.ASCO 2009, Abstract 204726Pts. PR SD PD 6-PFS(ms)38% 35% 27%(9pts received bevacizumab)脑胶质瘤和转移性瘤耐药的研究1) 6-甲基鸟嘌呤DNA甲基转移酶 (MGMT) (6-methylguanine-DNA hylt
13、ransferase )2) P-glycoproteinFruehauf, J. P. et al. Clin Cancer Res 2006;12:4523-4532脑胶质瘤和转移性瘤耐药的研究Fruehauf, J. P. et al. Clin Cancer Res 2006;12:4523-4532MGMT methylation status as a prognostic factorin anaplastic astrocytomas.Conclusions: MGMT methylation status is an independent prognostic factor
14、 together with age in AA.Pts.71/80(88.8%)30/71(M) 41/71(UM)MGMT methylationM-PFS(ms)48.6 38p=0.09ASCO 2009 Abstract 2052P-gp expression in brain capillary endothelial cells suggests that P-gp may restrict drug entry into brain tumors and thus be another mechanism of drug resistance. K1735 cellsK1735
15、 cellsMDRThe biology and mechanism of chemoresistance of brain metastases THE UNIVERSITY OF TEXAS GRAD. SCH. OF BIOMED. SCI. AT HOUSTON 1995BBBD(blood-brain barrier disruption)化疗 高渗性、缓激肽衍生物：BBB开放 选择性开放血瘤屏障(blood-tumor barrier, BTB) 克服化疗耐药性 多药耐药及逆转MGMT表达预测化疗疗效，避免无效化疗。脑胶质瘤和转移性瘤耐药的研究联合化疗提高化疗敏感性VM-26和BC
16、NU联合显著提高胶质瘤对化疗的敏感性 机理：抑制MDR-I或P-gp过表达 PCV方案显著增强多形胶质母细胞瘤对BCNU类药制的敏 感性 机理：肿瘤细胞先暴露于烷化剂类药物使瘤 细胞中AGT（O6-烷基鸟嘌呤-DNA烷基化转酶）活性受抑 AGT是增强肿瘤细胞对BCNU类药物敏感性的主要靶点Randomized Comparison of Intra-arterial Versus Intravenous Infusion of ACNU for Newly Diagnosed Patients with Glioblastoma To compare the effectiveness of intra-arterial ACNUwith intravenous ACNU in newly diagnosed patients with supratentorial glio
