恶性脑肿瘤的化学治疗 幻灯片课件

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* 12,760 Incidence 11.47 per 100,000 (annual rate) Adjusted 5 yr survival rate (1995-2000) 33% adults 73% 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-arterial 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 PCNSL BBBD/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 Phase II Trial Involving Patients with Recurrent PCNSL Treated with Carboplatin/BBBD, by Adding Rituxan (Rituximab), an anti CD-20 Antibody, to the Treatment Regimen Phase I/II Study of Carboplatin, Melphalan and Etoposide Phosphate in Conjunction with Osmotic Opening of the Blood-Brain Barrier and Delayed Intravenous Sodium Thiosulfate Chemoprotection, in Subjects with Anaplastic Oligodendroglioma or Oligoastrocytoma Phase II Clinical Trial of Patients with High-Grade Glioma Treated with Intra -arterial Carboplatin-based Chemotherapy, Randomized to Treatment with or without Delayed Intravenous Sodium Thiosulfate as a Potential Chemoprotectant against Severe Thrombocytopenia Intra-arterial Melphalan (L-phenylalanine mustard) Administered in Conjunction with Osmotic Blood-Brain Barrier Disruption in Patients with Brain Malignancies: A Phase I Study Neuro-Oncology Blood-Brain Barrier Program Oregon Health 6(1): 3337 可评价病人数 PR SD MTTP(w) PFS-6 MS(w) MPFS(w) OS-6 1Year 53 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 study 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-6 68 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 weeks 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 gliomas A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) 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 2010b Bevacizumab plus irinotecan in recurrent glioblastoma multiforme J Clin Oncol. 2007 Oct 20;25(30):4722-9 可评价病人数 PR PFS-6 OS-6 35 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) 1Year 32 1 11 19 13 36 34% Neuro Oncol. 2008 Feb 26 Bevacizumab and irinotecan for recurrent oligodendroglial tumors. Conclusions: This regimen is effective in recurrent oligodendrogliomas, and the overall tolerance is acceptable. ASCO 2009,Abstract 2054 25Pts. CR PR M-PFS(d) MOS(d) 6-PFS(ms) 20% 52% 174 328 42% ASCO 2009,Abstract 2037 2009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 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 2047 26Pts. 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 hyltransferase ) 2) P-glycoprotein Fruehauf, 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;12:4523-4532 MGMT methylation status as a prognostic factor in anaplastic astrocytomas. Conclusions: MGMT methylation status is an independent prognostic factor together with age in AA. Pts.71/80(88.8%) 30/71(M) 41/71(UM)MGMT methylation M-PFS(ms)48.6 38 p=0.09 ASCO 2009 Abstract 2052 P-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 cells K1735 cells MDR The biology and mechanism of chemoresistance of brain metastases THE UNIVERSITY OF TEXAS GRAD. SCH. OF BIOMED. SCI. AT HOUSTON 1995 BBBD(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BCNU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 glioblastoma. ACNU (80mg/m2) once every 6 weeks concomitant with radiotherapy. 病人数 可评价病人数 MS(w) PFS(w) Toxicity 84 82IA 59 24 - IV 56 45 - Journal of neuro-oncology 2000, vol. 49, no1, pp. 63-70 2008年NCCN指南 成人侵润性低度恶性幕上星形细胞瘤/少突胶质细胞瘤 辅助化疗：高剂量替莫唑胺 5/28方案 复发或进展： 一线方案：替莫唑胺 5/28方案（初治） 二线方案：BCUN210mg/m2 iv 6w重复;,80mg/m2x3 6w重复； CCNU 110mg/m2 口服 6w重复；PCV联合化疗 成人室管膜瘤：复发用vp-16,替莫唑胺 ，亚硝脲类，铂及联合方案 原发性CNS肿瘤化疗指南 多形性胶母细胞瘤 辅助化疗： 同步替莫唑胺 75mg/m2 daily 替莫唑胺150-200mg/ m2 5/28方案 复发/挽救治疗： 替莫唑胺 5/28方案（初治） Bevacizumab+Irinotecan BCUN; CCNU ;PCV联合化疗 间变形星