1、恶性脑肿瘤的化学治疗恶性脑肿瘤的化学治疗1Cerebrum and Cerebellum2流行病学趋势流行病学趋势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 肿瘤肿瘤,正常脑组织暴露化疗药物正常脑组织暴露化疗药物高渗性高渗性BBBBBB开放开放3132Blood brain barrier disruption
2、(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%
3、33A 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 De
4、layed 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 Sodi
5、um 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 StudyNeuro-Oncology Blood-Brain Barrier ProgramOregon He
6、alth&Science UniversityBlood Brain Barrier and Neuro-Oncology Program 34 替尼泊苷联合尼莫司汀治疗转移性脑肿瘤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中国癌症杂志中国癌症杂志Vol9,No2,June,1999Vol9,No2,June,199935替尼泊苷联合尼莫司汀治疗转移性脑肿瘤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：
7、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,199936替尼泊苷联合尼莫司汀治疗转移性脑肿瘤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,199937 替尼泊苷联合尼莫司汀治疗转移性脑肿瘤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
8、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,199938替尼泊苷联合尼莫司汀治疗转移性脑肿瘤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例中国癌症杂志中国癌症杂志Vol9,Vol9,No2,June,1999No2,June,199939避开避开BBBBBB的方式的方式椎管内化疗：椎管内化疗：主要用于主要用于CNSCNS淋巴瘤，脑膜淋巴瘤，脑膜转移肿瘤，白血病的脑膜侵犯。转移肿瘤，白血病
9、的脑膜侵犯。40Phase 2 study of BCNU and temozolomide for recurrent glioblastoma multiforme:North American Brain Tumor Consortium studyNeuro-oncol.2004 January;6(1):3337 可评价病人数可评价病人数PRSDMTTP(w)PFS-6MS(w)MPFS(w)OS-61Year532211721%341168%26%41可评价病人数可评价病人数CRPRMTTP(w)PFS-6(m)42091730.3%Second-line chemotherapy
10、 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 422007年ASCO有关Gliomas的文献有36篇病人数病人数可评价病人数可评价病人数PRMPFS(w)MOS(w)PFS-66
11、85959%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
12、 the treatment of malignant gliomas43A 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
13、2010b44Bevacizumab plus irinotecan in recurrent glioblastoma multiforme J Clin Oncol.2007 Oct 20;25(30):4722-9可评价病人数可评价病人数PRPFS-6OS-63557%46%77%45Phase II trial of irinotecan and thalidomide in adults with recurrent glioblastoma multiforme可评价病人数可评价病人数CRPRSDMPFS(w)MOS(w)1Year3211119133634%Neuro Oncol
14、.2008 Feb 26 46Bevacizumab and irinotecan for recurrent oligodendroglial tumors.Conclusions:This regimen is effective in recurrent oligodendrogliomas,and the overall tolerance is acceptable.ASCO 2009,Abstract 205425Pts.CRPRM-PFS(d)MOS(d)6-PFS(ms)20%52%17432842%47484950515253ASCO 2009,Abstract 203720
15、09年ASCO有关神经系统肿瘤的文献80余篇54A 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 204726Pts.PRSDPD6-PFS(m
16、s)38%35%27%(9pts received bevacizumab)55脑胶质瘤和转移性瘤耐药的研究脑胶质瘤和转移性瘤耐药的研究1)6-1)6-甲基鸟嘌呤甲基鸟嘌呤DNADNA甲基转移酶甲基转移酶 (MGMT)(MGMT)(6-methylguanine-DNA (6-methylguanine-DNA hyltransferasehyltransferase)2)P-glycoprotein2)P-glycoprotein56Fruehauf,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脑胶质瘤和转移性瘤耐药的研究
17、57Fruehauf,J.P.et al.Clin Cancer Res 2006;12:4523-453258MGMT 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 methylationM-PFS(ms)48.6 38p=0.09ASC
18、O 2009 Abstract 205259 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.60K1735 cellsK1735 cellsMDRThe biology and mechanism of chemoresistance of brain metastases THE UNIVERSITY OF TEXA
19、S GRAD.SCH.OF BIOMED.SCI.AT HOUSTON 199561BBBD(blood-brain barrier disruption)BBBD(blood-brain barrier disruption)化疗化疗高渗性、缓激肽衍生物：高渗性、缓激肽衍生物：BBBBBB开放开放选择性开放血瘤屏障选择性开放血瘤屏障(blood-tumor barrier,BTB)(blood-tumor barrier,BTB)克服化疗耐药性克服化疗耐药性多药耐药及逆转多药耐药及逆转 MGMTMGMT表达预测化疗疗效，避免无效化疗。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
20、究脑胶质瘤和转移性瘤耐药的研究62联合化疗提高化疗敏感性联合化疗提高化疗敏感性VM-26VM-26和和BCNUBCNU联合显著提高胶质瘤对化疗的敏感性联合显著提高胶质瘤对化疗的敏感性机理：抑制机理：抑制MDR-IMDR-I或或P-P-gpgp过表达过表达PCVPCV方案显著增强多形胶质母细胞瘤对方案显著增强多形胶质母细胞瘤对BCNUBCNU类药制的敏类药制的敏感性感性机理：肿瘤细胞先暴露于烷化剂类药物使瘤机理：肿瘤细胞先暴露于烷化剂类药物使瘤细胞中细胞中AGTAGT（O6-O6-烷基鸟嘌呤烷基鸟嘌呤-DNA-DNA烷基化转酶）烷基化转酶）活性受抑活性受抑 AGTAGT是增强肿瘤细胞对是增强肿瘤
21、细胞对BCNUBCNU类类 药物敏感性的主要药物敏感性的主要靶点靶点63Randomized 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(80
22、mg/m2)once every 6 weeks concomitant with radiotherapy.病人数病人数可评价病人数可评价病人数MS(w)PFS(w)Toxicity8482IA5924-IV5645-Journal of neuro-oncology 2000,vol.49,no1,pp.63-70 6420082008年年NCCNNCCN指南指南成人侵润性低度恶性幕上星形细胞瘤成人侵润性低度恶性幕上星形细胞瘤/少突胶质细胞瘤少突胶质细胞瘤辅助化疗：高剂量替莫唑胺辅助化疗：高剂量替莫唑胺 5/285/28方案方案复发或进展：复发或进展：一线方案：替莫唑胺一线方案：替莫唑胺
23、5/285/28方案（初治）方案（初治）二线方案：二线方案：BCUN210mg/m2 iv 6wBCUN210mg/m2 iv 6w重复重复;,80mg/m2x3 6w;,80mg/m2x3 6w重复；重复；CCNU 110mg/m2 CCNU 110mg/m2 口服口服 6w6w重复；重复；PCVPCV联合化疗联合化疗成人室管膜瘤：复发用成人室管膜瘤：复发用vp-16,vp-16,替莫唑胺替莫唑胺 ，亚硝脲类，铂及联合方案，亚硝脲类，铂及联合方案原发性原发性CNSCNS肿瘤化疗指南肿瘤化疗指南65多形性胶母细胞瘤多形性胶母细胞瘤辅助化疗：辅助化疗：同步替莫唑胺同步替莫唑胺 75mg/m2 d
24、aily75mg/m2 daily替莫唑胺替莫唑胺150-200mg/m2 5/28150-200mg/m2 5/28方案方案复发复发/挽救治疗：挽救治疗：替莫唑胺替莫唑胺 5/285/28方案（初治）方案（初治）Bevacizumab+IrinotecanBevacizumab+Irinotecan BCUN;CCNU;PCVBCUN;CCNU;PCV联合化疗联合化疗间变形星形细胞瘤间变形星形细胞瘤/少突胶质细胞瘤少突胶质细胞瘤辅助化疗：辅助化疗：替莫唑胺或亚硝脲替莫唑胺或亚硝脲复发复发/挽救治疗：挽救治疗：替莫唑胺替莫唑胺 5/285/28方案（初治）方案（初治）Bevacizumab+I
25、rinotecanBevacizumab+Irinotecan BCUN;CCNU;PCVBCUN;CCNU;PCV联合联合原发性原发性CNSCNS肿瘤化疗原则肿瘤化疗原则20082008年年NCCNNCCN指南指南66转移性脑肿瘤局限转移性脑肿瘤局限1-31-3或多发或多发3 3个以上个以上对原发肿瘤有效的药物对原发肿瘤有效的药物替莫唑胺替莫唑胺 5/285/28方案（器官特异性治疗）方案（器官特异性治疗）卡培他宾，大剂量卡培他宾，大剂量MTX(MTX(乳腺癌，淋巴瘤），乳腺癌，淋巴瘤），ToptecanToptecan（肺癌）（肺癌）癌性脑膜炎癌性脑膜炎采用对脑组织穿透能力强的药物；采用对
26、脑组织穿透能力强的药物；椎管内化疗（脂质体椎管内化疗（脂质体cytarabinecytarabine,MTX,MTX，cytarabinecytarabine,ThiotepaThiotepa)大剂量大剂量MTXMTX治疗淋巴瘤性脑膜炎治疗淋巴瘤性脑膜炎原发性中枢神经系统淋巴瘤原发性中枢神经系统淋巴瘤大剂量大剂量MTX3.5g/m2 MTX3.5g/m2 或更高剂量，或联合化疗或更高剂量，或联合化疗复发或进展：复发或进展：再次大剂量再次大剂量MTXMTX美罗华美罗华+替莫唑胺替莫唑胺 美罗华；美罗华；ToptecanToptecan 替莫唑胺替莫唑胺MVPMVP铂类，大剂量铂类，大剂量cyta
27、rabinecytarabine,DEX,DEX20082008年年NCCNNCCN指南指南转移性转移性CNSCNS肿瘤化疗原则肿瘤化疗原则67恶性脑肿瘤是以外科手术、放射治疗为主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。上新的台阶。结结 语语68谢谢谢谢69
