恶性脑肿瘤的化疗方案课件.ppt

恶性脑肿瘤的化学治疗,1,编辑版ppt,恶性脑肿瘤的化学治疗1编辑版ppt,Cerebrum and Cerebellum,2,编辑版ppt,Cerebrum and Cerebellum2编辑版ppt,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 39 years (US in 2002)Jemal et al CA: a cancer journal for clinicians 55:10-30, 2005.,new cases deaths (estimated),3,编辑版ppt,流行病学趋势2005 (US) 18,流行病学趋势,每年以1.2%的速度在增加,4,编辑版ppt,流行病学趋势每年以1.2%的速度在增加4编辑版ppt,5,编辑版ppt,5编辑版ppt,CNS原发肿瘤发病率,Brain Tumor Facts & Statistics 2007 Brain Tumor Society,6,编辑版ppt,CNS原发肿瘤发病率Brain Tumor Facts &,CNS原发肿瘤五年生存率,http:/www.cbtrus.org/factsheet/factsheet.html.,7,编辑版ppt,Five Year Survival Rates by Ag,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,8,编辑版ppt,转移性脑肿瘤定义：源自CNS以外组织的肿瘤发生播散，累及脑组,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,9,编辑版ppt,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,脑转移性肿瘤的发生率,Varies according to primary siteLung - 18-64%Breast - 2-21%Colo-rectal - 2-12%Melanoma - 4-16%Renal - 1-8%Thyroid - 1-10%Prostate, skin, oropharyngeal - rarelyOverall incidence 6-24%,10,编辑版ppt,脑转移性肿瘤的发生率Varies according to,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 561 100,11,编辑版ppt,CNS转移性肿瘤发生率原发肿瘤例数 %11编辑,脑转移常见的部位,Brain mets may occur in several positionsMeninges/leptomeningesBrain parenchyma (more common)80% in cerebrum, mostly in grey-white matter interface15% in cerebellum5% in brainstemResult of haematogenous spreadMedian survival 1-2 months if untreated,12,编辑版ppt,脑转移常见的部位12编辑版ppt,ASCO 2009 Abstract文2068,全脑放疗转移性脑肿瘤的生存率,13,编辑版ppt,ASCO 2009 Abstract文2068全脑放疗转移,不同治疗模式转移性脑肿瘤的生存时间,14,编辑版ppt,Procedure Local Recur.Distant,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,15,编辑版ppt,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,胶质瘤的规范化疗,16,编辑版ppt,胶质瘤的规范化疗16编辑版ppt,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。,17,编辑版ppt,Annals of Oncology 9:589-600,Chemotherapy in GBM,Meta-analysis Lancet 359:1011, 2002MRC 2001 J Clin Onc 19:509, 2001Large 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,18,编辑版ppt,Chemotherapy in GBM Meta-analy,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.,19,编辑版ppt,Chemotherapy in adult high-gra,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）,20,编辑版ppt,胶质瘤的化疗原则对高级别胶质瘤(WHO - 级) 应该常,Ino et al CCR 2001,21,编辑版ppt,Ino et al CCR 200121编辑版ppt,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),22,编辑版ppt,存在于血一脑，血一脑脊液及脑一脑脊液之间血脑屏障(BBB)2,血脑屏障(BBB),23,编辑版ppt,血脑屏障(BBB)23编辑版ppt,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。,24,编辑版ppt,脑胶质瘤理想化疗药物的特点有效穿透血脑屏障CNS肿瘤的化学治,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 profile1999 FDA approval for anaplastic astrocytoma (second line) refractory to nitrosourea and procarbazine. Ref: J Clin Onc 17:2762, 19992005 FDA approval for GBM (first line)Stupp et al. Phase III trial NEJM 352:987, 2005Athanassiou et al Phase III trial ASCO 2005Stupp et al. Phase II trial J Clin Onc 20:1375, 2002Lanzetta et al. Phase II trial Anticancer Res 23:5159, 2003,Clin Cancer Res 11:6767, 2005,25,编辑版ppt,Temozolomide (TMZ) development,能通过BBB的药物,亚硝脲类：BCNU,Me-CCNU,ACNU甲基苄肼（Procarbazine)VM-26,TeniposideMTX/CFAra-C,Liposomal Ara-cDoxil,IdarubicinDocetaxelTemozolomide,Tamodal,26,编辑版ppt,能通过BBB的药物亚硝脲类：BCNU,Me-CCNU,ACN,CNS肿瘤的化学治疗,化疗方式：1，全身化疗：IV；IA2，椎管内化疗：穿刺化疗；置泵3，间质化疗：Ommaya, Wafer,27,编辑版ppt,CNS肿瘤的化学治疗化疗方式：27编辑版ppt,CNS肿瘤的常用化学治疗方案,28,编辑版ppt,CNS肿瘤的常用化学治疗方案28编辑版ppt,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,29,编辑版ppt,间质内化疗: 可避开BBB避开BBB的方式29编辑版ppt,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,30,编辑版ppt,BBBD治疗Osmotic opening of the,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/secBBB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,31,编辑版ppt,A/E: 颈动脉灌注高渗溶液, 迅速改变BBB 通透性高渗性,32,编辑版ppt,32编辑版ppt,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,PtsCRPRORRM OS(y)MPFS(y)PFS-5(y),1771014180.2%3.11.640%,33,编辑版ppt,Blood brain barrier disruption,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 RegimenPhase 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 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 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 Study,Neuro-Oncology Blood-Brain Barrier Program,Oregon Health & Science UniversityBlood Brain Barrier and Neuro-Oncology Program,34,编辑版ppt,A Phase II Trial Involving Pat,替尼泊苷联合尼莫司汀治疗转移性脑肿瘤,治疗方法：VM26100mg,iv,gtt,D1-3,4周重复ACNU2-3mg/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2.3VM26共计49周期，平均2.5,中国癌症杂志Vol9, No2, June,1999,35,编辑版ppt,替尼泊苷联合尼莫司汀治疗转移性脑肿瘤治疗方法：ACNU共计,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,1999,36,编辑版ppt,替尼泊苷联合尼莫司汀治疗转移性脑肿瘤研究对象中国癌症杂志,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,1999,37,编辑版ppt,替尼泊苷联合尼莫司汀治疗转移性脑肿瘤 临床,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CR10%(2/20)部份缓解PR50%(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,1999,38,编辑版ppt,替尼泊苷联合尼莫司汀治疗转移性脑肿瘤结果：中国癌症杂志V,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,1999,39,编辑版ppt,替尼泊苷联合尼莫司汀治疗转移性脑肿瘤结果中国癌症杂志Vol9,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。,40,编辑版ppt,避开BBB的方式椎管内化疗：40编辑版ppt,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PRSDMTTP(w)PFS-6MS(w)MPFS(w)OS-61Year,532211721%341168%26%,41,编辑版ppt,Phase 2 study of BCNU and temo,可评价病人数CRPRMTTP(w)PFS-6(m),42091730.3%,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,编辑版ppt,可评价病人数42Second-line chemothera,2007年ASCO有关Gliomas的文献有36篇,病人数可评价病人数PRMPFS(w)MOS(w)PFS-6,685959%234043%,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,编辑版ppt,2007年ASCO有关Gliomas的文献有36篇病人数68,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,编辑版ppt,A phase II, randomized, non-co,Bevacizumab plus irinotecan in recurrent glioblastoma multiforme,J Clin Oncol. 2007 Oct 20;25(30):4722-9,可评价病人数PRPFS-6OS-6,3557%46%77%,45,编辑版ppt,Bevacizumab plus irinotecan in,Phase II trial of irinotecan and thalidomide in adults with recurrent glioblastoma multiforme,可评价病人数CRPRSDMPFS(w)MOS(w)1Year,3211119133634%,Neuro Oncol. 2008 Feb 26,46,编辑版ppt,Phase II trial of irinotecan a,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.CRPRM-PFS(d)MOS(d)6-PFS(ms),20%52%17432842%,47,编辑版ppt,Bevacizumab and irinotecan for,48,编辑版ppt,48编辑版ppt,49,编辑版ppt,49编辑版ppt,50,编辑版ppt,50编辑版ppt,51,编辑版ppt,51编辑版ppt,52,编辑版ppt,52编辑版ppt,53,编辑版ppt,53编辑版ppt,ASCO 2009,Abstract 2037,2009年ASCO有关神经系统肿瘤的文献80余篇,54,编辑版ppt,ASCO 2009,Abstract 20372009年AS,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.PRSDPD6-PFS(ms),38%35%27%,(9pts received bevacizumab),55,编辑版ppt,A phase II study of XL184 in p,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,56,编辑版ppt,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,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,57,编辑版ppt,Fruehauf, J. P. et al. Clin Ca,Fruehauf, J. P. et al. Clin Cancer Res 2006;12:4523-4532,58,编辑版ppt,Fruehauf, J. P. et al. Clin Ca,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,编辑版ppt,MGMT methylation status as a p,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,编辑版ppt,P-gp expression in brain capi,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,编辑版ppt,K1735 K1735 MDRThe biology and,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,62,编辑版ppt,脑胶质瘤和转移性瘤耐药的研究62编辑版ppt,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,63,编辑版ppt,联合化疗提高化疗敏感性VM-26和BCNU联合显著提高胶质瘤,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,8482,IA5924-,IV5645-,Journal of neuro-oncology2000,vol.49,no1,pp.63-70,64,编辑版ppt,Randomized Comparison of Intra,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,65,编辑版ppt,2008年NCCN指南成人侵润性低度恶性幕上星形细胞瘤/少突,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联合化疗间变形星形细胞瘤/少突胶质细胞瘤辅助化疗：替莫唑胺或亚硝脲复发/挽救治疗：替莫唑胺 5/28方案（初治）Bevacizumab+Irinotecan BCUN; CCNU ;PCV联合,原发性CNS肿瘤化疗原则,2008年NCCN指南,66,编辑版ppt,多形性胶母细胞瘤原发性CNS肿瘤化疗原则2008年NCCN指,转移性脑肿瘤局限1-3或多发3个以上对原发肿瘤有效的药物替莫唑胺 5/28方案（器官特异性治疗）卡培他宾，大剂量MTX(乳腺癌，淋巴瘤），Toptecan（肺癌）癌性脑膜炎采用对脑组织穿透能力强的药物；椎管内化疗（脂质体cytarabine, MTX， cytarabine, Thiotepa )大剂量MTX治疗淋巴瘤性脑膜炎原发性中枢神经系统淋巴瘤大剂量MTX3.5g/m2 或更高剂量，或联合化疗复发或进展：再次大剂量MTX美罗华+替莫唑胺 美罗华；Toptecan 替莫唑胺MVP铂类，大剂量cytarabine, DEX,2008年NCCN指南,转移性CNS肿瘤化疗原则,67,编辑版ppt,转移性脑肿瘤局限1-3或多发3个以上2008年NCCN指南转,恶性脑肿瘤是以外科手术、放射治疗为主的综合治疗，传统的化疗药物疗效有限，只能使部分患者受益，伴随着各类新药的诞生，特别是靶向药物和生物酶抑制剂的应用，恶性脑肿瘤的综合治疗已显露出端倪。在恶性脑肿瘤的综合治疗中，肿瘤内科所扮演的角色日显重要。随着精确放射治疗，生物靶区的确立，新型化疗药物和靶向药物的联合应用，恶性脑肿瘤的治疗必将更上新的台阶。,结 语,68,编辑版ppt,恶性脑肿瘤是以外科手术、放射治疗为主的综合治疗，传统的化疗,谢谢,69,编辑版ppt,谢谢69编辑版ppt,