




版权说明:本文档由用户提供并上传,收益归属内容提供方,若内容存在侵权,请进行举报或认领
文档简介
1、.,1,恶性脑肿瘤的化学治疗,四川省肿瘤医院内科 张智慧,.,2,Cerebrum and Cerebellum,.,3,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 39 years (US in 2002) Jemal et al CA: a cancer journal
2、for clinicians 55:10-30, 2005.,new cases deaths (estimated),.,4,流行病学趋势,每年以1.2%的速度在增加,.,5,.,6,CNS原发肿瘤发病率,Brain Tumor Facts 359(9311):1011-8.,.,20,胶质瘤的化疗原则,对高级别胶质瘤(WHO - 级) 应该常规给予化疗 低级别胶质瘤(WHO- 级) 可以根据手术切除程度、病理类型和基因缺失情况考虑是否化疗 选择能通过血脑屏障的脂溶性、小分子药物(安全-高效),.,21,Ino et al CCR 2001,.,22,存在于血一脑,血一脑脊液及脑一脑脊液之间
3、 选择性控制进入脑脊液和脑的物质,作为血与CNS之间的调节界面, 对维持CNS内环境恒定有至关重要的作用 主要形式: 脑毛细血管内皮细胞紧密连接 细胞之间无孔隙, “条焊状”连接,甚至某种程度重叠 基底部尚有一层连续的基底膜 内皮细胞内: 细胞器, 与物质转运有关的酶类 结构为脂性基架, 对大于3968(40KD)物质限制通过 药物要求 分子量小脂溶性 正常PH时不电离不与蛋白结合,血脑屏障(BBB),.,23,血脑屏障(BBB),.,24,脑胶质瘤理想化疗药物的特点,有效穿透血脑屏障 脑胶质瘤细胞敏感 脑肿瘤内维持长时间有效浓度 骨髓抑制尽量低,毒副作用小 可长期使用,CNS肿瘤的化学治疗,
4、亚硝脲类药物较容易通过血脑屏障,故被视为治疗脑肿瘤的首选药物。,.,25,Temozolomide (TMZ) development for glioma,Novel oral cytotoxic agent (imidazotetrazine-related to dacarbazine). Rapid absorption with 100% bioavailability. Good CSF penetration (20-40%) Well tolerated with good safety profile 1999 FDA approval for anaplastic astr
5、ocytoma (second line) refractory to nitrosourea and procarbazine. Ref: J Clin Onc 17:2762, 1999 2005 FDA approval for GBM (first line) Stupp et al. Phase III trial NEJM 352:987, 2005 Athanassiou et al Phase III trial ASCO 2005 Stupp et al. Phase II trial J Clin Onc 20:1375, 2002 Lanzetta et al. Phas
6、e II trial Anticancer Res 23:5159, 2003,Clin Cancer Res 11:6767, 2005,.,26,能通过BBB的药物,亚硝脲类:BCNU,Me-CCNU,ACNU 甲基苄肼(Procarbazine) VM-26,Teniposide MTX/CF Ara-C,Liposomal Ara-c Doxil,Idarubicin Docetaxel Temozolomide,Tamodal,.,27,CNS肿瘤的化学治疗,化疗方式: 1,全身化疗:IV;IA 2,椎管内化疗:穿刺化疗;置泵 3,间质化疗:Ommaya, Wafer,.,28,CN
7、S肿瘤的常用化学治疗方案,.,29,间质内化疗: 可避开BBB 机理: 提高肿瘤局部药物浓度 减少全身用药毒副作用 方法: 术中 术后,避开BBB的方式,.,30,BBBD治疗,Osmotic opening of the blood-brain barrier. When endothelial cells that line capillary walls are exposed to a concentrated sugar solution, the cells shrink, thus opening the tight junctions between them. (Adapte
8、d from: SI Rapoport, Blood-Brain Barrier in Physiology and Medicine. Raven Press, 1976.),Blood-Brain Barrier Disruption (BBBD)治疗,.,31,A/E: 颈动脉灌注高渗溶液, 迅速改变BBB 通透性 20%甘露醇150-250ml, 5-10ml/sec BBB血管内皮细胞收缩 胞间紧密联接增宽 脑组织含水量增加1.0%-1.5% 4hr恢复正常 20世纪80年代用于临床 尚未期研究证实 近年研究: BBB开放无选择性, 内皮细胞破坏: 正常脑组织肿瘤,正常脑组织暴露化疗
9、药物,高渗性BBB开放,.,32,.,33,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 pro
10、cedures,Pts CR PR ORR M OS(y) MPFS(y) PFS-5(y),177 101 41 80.2% 3.1 1.6 40%,.,34,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 Etop
11、oside 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 Carbopla
12、tin-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
13、 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%,.,42,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 i
14、n 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,.,43,2007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 I
15、II 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 m
16、alignant gliomas,.,44,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 2
17、010b,.,45,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%,.,46,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
18、 36 34%,Neuro Oncol. 2008 Feb 26,.,47,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%,
19、.,48,.,49,.,50,.,51,.,52,.,53,.,54,ASCO 2009,Abstract 2037,2009年ASCO有关神经系统肿瘤的文献80余篇,.,55,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
20、 progressive or recurrent GBM.,ASCO 2009, Abstract 2047,26Pts. PR SD PD 6-PFS(ms),38% 35% 27%,(9pts received bevacizumab),.,56,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,.,57,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
21、,.,58,Fruehauf, J. P. et al. Clin Cancer Res 2006;12:4523-4532,.,59,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(
22、ms),48.6 38,p=0.09,ASCO 2009 Abstract 2052,.,60,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.,.,61,K1735 cells,K1735 cells,MDR,The biology and mechanism of chemoresistance of brain m
23、etastases,THE UNIVERSITY OF TEXAS GRAD. SCH. OF BIOMED. SCI. AT HOUSTON 1995,.,62,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,.,63,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
24、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,.,64,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
25、 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 82,IA 59 24 -,IV 56 45 -,Journal of neuro-oncology2000,vol.49,no1,pp.63-70,.,65,2008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
温馨提示
- 1. 本站所有资源如无特殊说明,都需要本地电脑安装OFFICE2007和PDF阅读器。图纸软件为CAD,CAXA,PROE,UG,SolidWorks等.压缩文件请下载最新的WinRAR软件解压。
- 2. 本站的文档不包含任何第三方提供的附件图纸等,如果需要附件,请联系上传者。文件的所有权益归上传用户所有。
- 3. 本站RAR压缩包中若带图纸,网页内容里面会有图纸预览,若没有图纸预览就没有图纸。
- 4. 未经权益所有人同意不得将文件中的内容挪作商业或盈利用途。
- 5. 人人文库网仅提供信息存储空间,仅对用户上传内容的表现方式做保护处理,对用户上传分享的文档内容本身不做任何修改或编辑,并不能对任何下载内容负责。
- 6. 下载文件中如有侵权或不适当内容,请与我们联系,我们立即纠正。
- 7. 本站不保证下载资源的准确性、安全性和完整性, 同时也不承担用户因使用这些下载资源对自己和他人造成任何形式的伤害或损失。
最新文档
- 景区监控布点方案
- 大书店开业活动方案
- 财务总监负责下的财务报表编制与分析聘用合同
- 农场水灾处理措施方案
- 企业商标保护课件的意义
- 工厂饭堂承包方案
- 票据扫描面试题及答案
- 校医防疫面试题及答案
- 2026版《全品高考》选考复习方案生物0502 第14讲 第2课时 基因分离定律的拓展应用含答案
- 移动升降车安全操作规程培训
- 呼吸科慢阻肺教学查房(模板)
- 住院医师规范化培训临床小讲课的设计与实施培训课件
- 中考重庆作文满分范文英语
- 伤口造口进修汇报护理
- 2024年萃智创新方法理论考试题库(含答案)
- 2023-2023学年贵州省黔西南州八年级(下)期末数学试卷(附答案详解)
- 《初中语文名著演绎舞台剧》-通过戏剧欣赏名著
- 2024年中智集团招聘笔试参考题库附带答案详解
- 林下种植中药材的可行性方案
- 东北大学分析化学期末试卷
- 老年健康照护课件
评论
0/150
提交评论