恶性脑肿瘤的化学治疗ppt课件

恶恶性脑肿脑肿 瘤的化学治疗疗 1 Cerebrum and Cerebellum 2 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 肿肿瘤,正常脑组织脑组织 暴露化疗药疗药 物 高渗性BBB开放 31 32 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% 33 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% 41 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 42 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 43 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 44 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% 45 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 46 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% 47 48 49 50 51 52 53 ASCO 2009,Abstract 2037 2009年ASCO有关神经系统肿瘤的文献80余篇 54 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) 55 脑脑胶质质瘤和转转移性瘤耐药药的研究 1) 6-甲基鸟嘌呤DNA甲基转移酶 (MGMT) (6-methylguanine-DNA hyltransferase ) 2) P-glycoprotein 56 Fruehauf, J. P. et al. Clin Cancer Res 2006;12:4523-4532 脑脑胶质质瘤和转转移性瘤耐药药的研究 57 Fruehauf, J. P. et al. Clin Cancer Res 2006;12:4523-4532 58 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 59 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. 60 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 61 BBBD(blood-brain barrier disruption)化疗疗 高渗性、缓缓激肽肽衍生物：BBB开放 选择选择 性开放血瘤屏障(blood-tumor barrier, BTB) 克服化疗疗耐药药性 多药药耐药药及逆转转 MGMT表达预测预测 化疗疗疗疗 效，避免无效化疗疗。 脑脑胶质质瘤和转转移性瘤耐药药的研究 62 联联合化疗疗提高化疗疗敏感性 VM-26和BCNU联联合显显著提高胶质质瘤对对化疗疗的敏感性 机理：抑制MDR-I或P-gp过过表达 PCV方案显显著增强多形胶质质母细细胞瘤对对BCNU类药类药 制 的敏感性 机理：肿肿瘤细细胞先暴露于烷烷化剂类药剂类药 物使瘤 细细胞中AGT（O6-烷烷基鸟鸟嘌呤-DNA烷烷基化转转酶 ） 活性受抑 AGT是增强肿肿瘤细细胞对对BCNU类类 药药物敏感性的主要靶点 63 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 64 2008年NCCN指南 成人侵润润性低度恶恶性幕上星形细细胞瘤/少突胶质细质细 胞瘤 辅辅助化疗疗：高剂剂量替莫唑唑胺 5/28方案 复发发或进进展： 一线线方案：替莫唑唑胺 5/28方案（初治） 二线线方案：BCUN210mg/m2 iv 6w重复;,80mg/m2x3 6w重复； CCNU 110mg/m2 口服 6w重复；PCV联联合化疗疗 成人室管膜瘤：复发发用vp-16,替莫唑唑胺 ，亚亚硝脲类脲类 ，铂铂及联联合方案 原发发性CNS肿肿瘤化疗疗指南 65 多形性胶母细细胞瘤 辅辅助化疗疗： 同步替莫唑唑胺 75mg/m2 daily 替莫唑唑胺150-200mg/ m2 5/28方案 复发发/挽救治疗疗： 替莫唑唑胺 5/28方案（初治） Bevacizumab+Irinotecan BCUN; CCNU ;PCV联联合化疗疗 间变间变 形星形细细胞瘤/少突胶质细质细 胞瘤 辅辅助化疗疗： 替莫唑唑胺或亚亚硝脲脲 复发发/挽救治疗疗： 替莫唑唑胺 5/28方案（初治） Bevacizumab+Irinotecan BCUN; CCNU ;PCV