课件：恶性脑肿瘤化疗的方案.ppt

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 39 years (US in 2002) Jemal et al CA: a cancer journal for clinicians 55:10-30, 2005.,new cases deaths (estimated),流行病学趋势,每年以1.2%的速度在增加,CNS原发肿瘤发病率,Brain Tumor Facts & Statistics 2007 Brain Tumor Society,CNS原发肿瘤五年生存率,/factsheet/factsheet.html.,转移性脑肿瘤 （Brain Metastases BM）,定义：源自CNS以外组织的肿瘤发生播散，累及脑组织 是成年人群最常见的颅内肿瘤，随全身肿瘤整体治疗水平提高和生存延长，脑转移瘤发生率不断上升，实体瘤患者15%-20%最终会发生脑转移。,Brain Tumor Facts & Statistics,不同肿瘤发生闹转移的比例,肺癌,乳腺癌,恶黑,大肠,肾,原发灶不明,小细胞 非小细胞,50% 33% 20% 50% 5% 5% 15% 多发性 多发性 多发性 单发 单发 混合,脑转移性肿瘤的发生率,Varies according to primary site Lung - 18-64% Breast - 2-21% Colo-rectal - 2-12% Melanoma - 4-16% Renal - 1-8% Thyroid - 1-10% Prostate, skin, oropharyngeal - rarely Overall incidence 6-24%,CNS转移性肿瘤发生率 (10倍于原发肿瘤),原发肿瘤 例数 % 肺 270 48 乳腺 82 15 黑色素瘤 50 9 结肠 26 5 其他已知原发瘤 72 13 未知原发瘤 61 10 合计 561 100,脑转移常见的部位,Brain mets may occur in several positions Meninges/leptomeninges Brain parenchyma (more common) 80% in cerebrum, mostly in grey-white matter interface 15% in cerebellum 5% in brainstem Result of haematogenous spread Median survival 1-2 months if untreated,ASCO 2009 Abstract文2068,全脑放疗转移性脑肿瘤的生存率,不同治疗模式转移性脑肿瘤的生存时间,在尽可能保全重要神经功能的前提下, 最大限度地手术切除肿瘤 而肿瘤位于重要脑功能区, 手术极度困难而风险又极大者,应尽可能进行立体定向活组织检查术。 对每位病人依据肿瘤的病理分类和分级以及肿瘤的分子生物学特征和病人的免疫状态再辅以放疗化疗。 而手术、放疗、化疗三大常规治疗以外的许多新疗法, 只能作为临床研究在一些有条件的单位施行, 而不能作为一线治疗手段。,CNS 肿瘤治疗原则,胶质瘤的规范化疗,Annals of Oncology 9:589-600, 1998,Assessment of more than 20 years of chemotherapy trials is discouraging despite a few areas of modest success. Only patients with specific histology (oligodendroglioma, anaplastic astrocytoma) and good prognostic factors (young age, good performance status) may benefit from chemotherapy。,Chemotherapy in GBM,Meta-analysis Lancet 359:1011, 2002 MRC 2001 J Clin Onc 19:509, 2001 Large randomized trial (n=674) in grade 3 and 4 astrocytoma-first line comparing radiation alone versus radiation followed by PCV q 6 wk x up to 12 cycles. (1988-97) No differences in survival,Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials,Lancet 2002;359(9311):1011-8.,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）,Ino et al CCR 2001,存在于血一脑，血一脑脊液及脑一脑脊液之间 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),血脑屏障(BBB),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,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。,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 astrocytoma (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. Phase II trial Anticancer Res 23:5159, 2003,Clin Cancer Res 11:6767, 2005,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,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,CNS肿瘤的常用化学治疗方案,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,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. (Adapted from: SI Rapoport, Blood-Brain Barrier in Physiology and Medicine. Raven Press, 1976.),Blood-Brain Barrier Disruption (BBBD)治疗,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 & Science University Blood Brain Barrier and Neuro-Oncology Program,替尼泊苷联合尼莫司汀治疗转移性脑肿瘤,治疗方法： VM26 100mg,iv,gtt,D1-3,4周重复 ACNU 2-3mg/kg,iv,gtt,D1,4-6周重复 化疗前20%甘露醇250ml,iv,gtt,DXM10mg,iv,ACNU共计47周期，平均2.3 VM26共计49周期，平均2.5,中国癌症杂志Vol9, No2, June,1999,替尼泊苷联合尼莫司汀治疗转移性脑肿瘤,研究对象 男性： 11例 女性： 9例 年龄： 33-70岁 原发肿瘤病理类型： 肺癌 12例 乳腺癌 1例 恶性淋巴瘤 3例 鼻咽癌 1例 滑膜肉瘤 1例 不明肿瘤 2例,中国癌症杂志Vol9, No2, June,1999,替尼泊苷联合尼莫司汀治疗转移性脑肿瘤,临床表现 症状 例次 头痛 13 恶心，呕吐 11 意识改变 6 肢体肌力感觉异常 10 颅脑神经受损 7 共济失调 1 合计 48,中国癌症杂志Vol9, No2, June,1999,替尼泊苷联合尼莫司汀治疗转移性脑肿瘤,结果： 症状缓解率： 完全缓解CR： 60.4% 部份缓解PR： 31.6% 症状总缓解率： 91.7% 颅脑CT复查： 脑水肿减轻或消失 100%(16/16) 完全缓解CR 10%(2/20) 部份缓解PR 50%(10/20) 总有效率(CR+PR) 60%(12/20) 颅脑外病灶缩小 52.9%(9/17),中国癌症杂志Vol9, No2, June,1999,替尼泊苷联合尼莫司汀治疗转移性脑肿瘤,结果 患者存活时间1-17月，平均6.5月 超过6个月者11例,中国癌症杂志Vol9, No2, June,1999,避开BBB的方式,椎管内化疗： 主要用于CNS淋巴瘤，脑膜 转移肿瘤，白血病的脑膜侵犯。,Phase 2 study of BCNU and temozolomide for recurrent glioblastoma multiforme: North American Brain Tumor Consortium study,Neuro-oncol. 2004 January; 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) onc