恶性脑肿瘤的化学治疗

恶性脑肿瘤的化学治疗1精选课件CerebrumandCerebellum2精选课件流行病学趋势2005(US) 18,500* 12,760Incidence 11.47per100,000(annualrate)Adjusted5yrsurvivalrate(1995-2000) 33%adults 73%children

2ndleadingcauseofcancerdeathsinpersons<39years(USin2002)JemaletalCA:acancerjournalforclinicians55:10-30,2005.newcases

deaths(estimated)3精选课件流行病学趋势每年以1.2%的速度在增加4精选课件5精选课件CNS原发肿瘤发病率BrainTumorFacts&Statistics©2007BrainTumorSociety6精选课件FiveYearSurvivalRatesbyAgeGroupAgeSurvivalRates0-19years63.1%20-44years50.4%45-64years14.2%Over654.9%DataFrom:2002-2003PrimaryBrainTumorsintheUnitedStatesStatisticalReport.FactSheet(1973-1999data).BrainTumorRegistryoftheUnitedStatesCNS原发肿瘤五年生存率http:///factsheet/factsheet.html.7精选课件转移性脑肿瘤（BrainMetastasesBM）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。BrainTumorFacts&Statistics8精选课件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精选课件脑转移性肿瘤的发生率VariesaccordingtoprimarysiteLung-18-64%Breast-2-21%Colo-rectal-2-12%Melanoma-4-16%Renal-1-8%Thyroid-1-10%Prostate,skin,oropharyngeal-rarelyOverallincidence6-24%10精选课件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 10011精选课件脑转移常见的部位BrainmetsmayoccurinseveralpositionsMeninges/leptomeningesBrainparenchyma(morecommon)80%incerebrum,mostlyingrey-whitematterinterface15%incerebellum5%inbrainstemResultofhaematogenousspreadMediansurvival1-2monthsifuntreated12精选课件ASCO2009Abstract文2068全脑放疗转移性脑肿瘤的生存率13精选课件Procedure

LocalRecur.DistantRecur.Neuro.DeathMediansurvival(wks)WBR50%20%50%15-20Surgery50%40%45%40Surgery+WBR10-20%20%15%40Radiosurgery+WBR15%20%25%55Radiosurgery11%23%

不同治疗模式转移性脑肿瘤的生存时间14精选课件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精选课件胶质瘤的规范化疗16精选课件AnnalsofOncology9:589-600,1998Assessmentofmorethan20yearsofchemotherapytrialsisdiscouragingdespiteafewareasofmodestsuccess.Onlypatientswithspecifichistology(oligodendroglioma,anaplasticastrocytoma)andgoodprognosticfactors(youngage,goodperformancestatus)maybenefitfromchemotherapy。17精选课件ChemotherapyinGBMMeta-analysis

Lancet359:1011,2002MRC2001JClinOnc19:509,2001Largerandomizedtrial(n=674)ingrade3and4astrocytoma-firstlinecomparingradiationaloneversusradiationfollowedbyPCVq6wkxupto12cycles.(1988-97)Nodifferencesinsurvival18精选课件Chemotherapyinadulthigh-gradeglioma:asystematicreviewandmeta-analysisofindividualpatientdatafrom12randomisedtrialsLancet2002;359(9311):1011-8.19精选课件胶质瘤的化疗原则对高级别胶质瘤(WHOⅢ-Ⅳ级)应该常规给予化疗低级别胶质瘤(WHOⅠ-Ⅱ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精选课件InoetalCCR200121精选课件存在于血一脑，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3968μ(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精选课件血脑屏障(BBB)23精选课件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精选课件Temozolomide(TMZ)developmentforgliomaNoveloralcytotoxicagent(imidazotetrazine-relatedtodacarbazine).Rapidabsorptionwith100%bioavailability.GoodCSFpenetration(20-40%)Welltoleratedwithgoodsafetyprofile1999FDAapprovalforanaplasticastrocytoma(secondline)refractorytonitrosoureaandprocarbazine.Ref:JClinOnc17:2762,19992005FDAapprovalforGBM(firstline)Stuppetal.PhaseIIItrialNEJM352:987,2005AthanassiouetalPhaseIIItrialASCO2005Stuppetal.PhaseIItrialJClinOnc20:1375,2002Lanzettaetal.PhaseIItrialAnticancerRes23:5159,2003ClinCancerRes11:6767,200525精选课件能通过BBB的药物亚硝脲类：BCNU,Me-CCNU,ACNU甲基苄肼（Procarbazine)VM-26,TeniposideMTX/CFAra-C,LiposomalAra-cDoxil,IdarubicinDocetaxelTemozolomide,Tamodal26精选课件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精选课件CNS肿瘤的常用化学治疗方案28精选课件间质内化疗: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精选课件BBBD治疗Osmoticopeningoftheblood-brainbarrier.Whenendothelialcellsthatlinecapillarywallsareexposedtoaconcentratedsugarsolution,thecellsshrink,thusopeningthetightjunctionsbetweenthem.(Adaptedfrom:SIRapoport,Blood-BrainBarrierinPhysiologyandMedicine.RavenPress,1976.)Blood-BrainBarrierDisruption(BBBD)治疗30精选课件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Ⅲ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精选课件32精选课件Bloodbrainbarrierdisruption(BBBD)andintra-arterialmethotrexatebasedtherapyfornewlydiagnosedprimaryCNSlymphoma:TheBBBDConsortiumExperience.2007ASCOAnnualMeetingProceedingsPartI.Vol25,No.18S4institutions：1982-2005，177PCNSL

BBBD/IAMTX

；2,469proceduresPtsCRPRORRMOS(y)MPFS(y)PFS-5(y)1771014180.2%3.11.640%33精选课件APhaseIITrialInvolvingPatientswithRecurrentPCNSLTreatedwithCarboplatin/BBBD,byAddingRituxan(Rituximab),anantiCD-20Antibody,totheTreatmentRegimenPhaseI/IIStudyofCarboplatin,MelphalanandEtoposidePhosphateinConjunctionwithOsmoticOpeningoftheBlood-BrainBarrierandDelayedIntravenousSodiumThiosulfateChemoprotection,inSubjectswithAnaplasticOligodendrogliomaorOligoastrocytomaPhaseIIClinicalTrialofPatientswithHigh-GradeGliomaTreatedwithIntra-arterialCarboplatin-basedChemotherapy,RandomizedtoTreatmentwithorwithoutDelayedIntravenousSodiumThiosulfateasaPotentialChemoprotectantagainstSevereThrombocytopeniaIntra-arterialMelphalan(L-phenylalaninemustard)AdministeredinConjunctionwithOsmoticBlood-BrainBarrierDisruptioninPatientswithBrainMalignancies:APhaseIStudyNeuro-OncologyBlood-BrainBarrierProgramOregonHealth&ScienceUniversity

BloodBrainBarrierandNeuro-OncologyProgram34精选课件

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,ivACNU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,199935精选课件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,199936精选课件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精选课件

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,199938精选课件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,199939精选课件避开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精选课件Phase2studyofBCNUandtemozolomideforrecurrentglioblastomamultiforme:NorthAmericanBrainTumorConsortiumstudyNeuro-oncol.2004January;6(1):33–37可评价病人数PRSDMTTP(w)PFS-6MS(w)MPFS(w)OS-61Year532211721%341168%26%41精选课件可评价病人数CRPRMTTP(w)PFS-6(m)42091730.3%Second-linechemotherapywithirinotecanpluscarmustineinglioblastomarecurrentorprogressiveafterfirst-linetemozolomidechemotherapy:aphaseIIstudyoftheGruppoItalianoCooperativodiNeuro-Oncologia(GICNO).JClinOncol.2004Dec1;22(23):4779-8642精选课件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-6685959%234043%IngradeIIIpatientsthemedianPFSwas42weeks,the6monthPFSwas61%themedialoverallsurvivalwas60weeksConclusion:Thecombinationofbevacizumabandirinotecanissafeanddemonstratessuperioractivityagainstmalignantgliomas.PhaseIItrialofbevacizumabandirinotecaninthetreatmentofmalignantgliomas43精选课件AphaseII,randomized,non-comparativeclinicaltrialoftheeffectofbevacizumab(BV)aloneorincombinationwithirinotecan(CPT)on6-monthprogressionfreesurvival(PFS6)inrecurrent,treatment-refractoryglioblastoma(GBM).JClinOncol26:2008(May20suppl;abstr2010b44精选课件Bevacizumabplusirinotecaninrecurrentglioblastomamultiforme

JClinOncol.2007Oct20;25(30):4722-9可评价病人数PRPFS-6OS-63557%46%77%45精选课件PhaseIItrialofirinotecanandthalidomideinadultswithrecurrentglioblastomamultiforme可评价病人数CRPRSDMPFS(w)MOS(w)1Year3211119133634%NeuroOncol.2008Feb26

46精选课件Bevacizumabandirinotecanforrecurrentoligodendroglialtumors.Conclusions:Thisregimeniseffectiveinrecurrentoligodendrogliomas,andtheoveralltoleranceisacceptable.ASCO2009,Abstract205425Pts.CRPRM-PFS(d)MOS(d)6-PFS(ms)20%52%17432842%47精选课件48精选课件49精选课件50精选课件51精选课件52精选课件53精选课件ASCO2009,Abstract20372009年ASCO有关神经系统肿瘤的文献80余篇54精选课件AphaseIIstudyofXL184inpatients(pts)withprogressiveglioblastomamultiforme(GBM)infirstorsecondrelapse.Conclusions:XL184atadoseof175mgPOqd,hasdemonstratedsubstantialactivityinptswithprogressiveorrecurrentGBM.ASCO2009,Abstract204726Pts.PRSDPD6-PFS(ms)38%35%27%(9ptsreceivedbevacizumab)55精选课件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-DNAhyltransferase)2)P-glycoprotein56精选课件Fruehauf,J.P.etal.ClinCancerRes2006;12:4523-4532脑胶质瘤和转移性瘤耐药的研究57精选课件Fruehauf,J.P.etal.ClinCancerRes2006;12:4523-453258精选课件MGMTmethylationstatusasaprognosticfactorinanaplasticastrocytomas.Conclusions:MGMTmethylationstatusisanindependentprognosticfactortogetherwithageinAA.Pts.71/80(88.8%)30/71(M)41/71(UM)MGMTmethylationM-PFS(ms)48.638p=0.09ASCO2009Abstract205259精选课件P-gpexpressioninbraincapillaryendothelialcellssuggeststhatP-gpmayrestrictdrugentryintobraintumorsandthusbeanothermechanismofdrugresistance.60精选课件K1735cellsK1735cellsMDRThebiologyandmechanismofchemoresistanceofbrainmetastasesTHEUNIVERSITYOFTEXASGRAD.SCH.OFBIOMED.SCI.ATHOUSTON199561精选课件BBBD(blood-brainbarrierdisruption)化疗 高渗性、缓激肽衍生物：BBB开放 选择性开放血瘤屏障(blood-tumorbarrier,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精选课件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精选课件RandomizedComparisonofIntra-arterialVersusIntravenousInfusionofACNUforNewlyDiagnosedPatientswithGlioblastomaTocomparetheeffectivenessofintra-arterialACNUwithintraveno