恶性脑肿瘤的化学治疗--张智慧

恶性脑肿瘤的化学治疗四川省肿瘤医院内科张智慧CerebrumandCerebellum流行病学趋势2005(US)18,500*12,760Incidence11.47per100,000(annualrate)Adjusted5yrsurvivalrate(1995-2000)33%adults73%children2ndleadingcauseofcancerdeathsinpersons39years(USin2002)JemaletalCA:acancerjournalforclinicians55:10-30,2005.newcasesdeaths(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BrainTumorFacts&Statistics©2007BrainTumorSocietyFiveYearSurvivalRatesbyAgeGroupAgeSurvivalRates0-19years63.1%20-44years50.4%45-64years14.2%Over654.9%DataFrom:2002-2003PrimaryBrainTumorsintheUnitedStatesStatisticalReport.FactSheet(1973-1999data).BrainTumorRegistryoftheUnitedStatesCNS原发肿瘤五年生存率（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&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VariesaccordingtoprimarysiteLung-18-64%Breast-2-21%Colo-rectal-2-12%Melanoma-4-16%Renal-1-8%Thyroid-1-10%Prostate,skin,oropharyngeal-rarelyOverallincidence6-24%CNS转移性肿瘤发生率(10倍于原发肿瘤)原发肿瘤例数%肺27048乳腺8215黑色素瘤509结肠265其他已知原发瘤7213未知原发瘤6110合计561100脑转移常见的部位BrainmetsmayoccurinseveralpositionsMeninges/leptomeningesBrainparenchyma(morecommon)80%incerebrum,mostlyingrey-whitematterinterface15%incerebellum5%inbrainstemResultofhaematogenousspreadMediansurvival1-2monthsifuntreatedASCO2009Abstract文2068全脑放疗转移性脑肿瘤的生存率ProcedureLocalRecur.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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AnnalsofOncology9:589-600,1998Assessmentofmorethan20yearsofchemotherapytrialsisdiscouragingdespiteafewareasofmodestsuccess.Onlypatientswithspecifichistology(oligodendroglioma,anaplasticastrocytoma)andgoodprognosticfactors(youngage,goodperformancestatus)maybenefitfromchemotherapy。ChemotherapyinGBMMeta-analysisLancet359:1011,2002MRC2001JClinOnc19:509,2001Largerandomizedtrial(n=674)ingrade3and4astrocytoma-firstlinecomparingradiationaloneversusradiationfollowedbyPCVq6wkxupto12cycles.(1988-97)NodifferencesinsurvivalChemotherapyinadulthigh-gradeglioma:asystematicreviewandmeta-analysisofindividualpatientdatafrom12randomisedtrialsLancet2002;359(9311):1011-8.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）InoetalCCR2001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)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)developmentforgliomaNoveloralcytotoxicagent(imidazotetrazine-relatedtodacarbazine).Rapidabsorptionwith100%bioavailability.GoodCSFpenetration(20-40%)Welltoleratedwithgoodsafetyprofile1999FDAapprovalforanaplasticastrocytoma(secondline)refractorytonitrosoureaandprocarbazine.Ref:JClinOnc17:2762,19992005FDAapprovalforGBM(firstline)Stuppetal.PhaseIIItrialNEJM352:987,2005AthanassiouetalPhaseIIItrialASCO2005Stuppetal.PhaseIItrialJClinOnc20:1375,2002Lanzettaetal.PhaseIItrialAnticancerRes23:5159,2003ClinCancerRes11:6767,2005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,TamodalCNS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,WaferCNS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Osmoticopeningoftheblood-brainbarrier.Whenendothelialcellsthatlinecapillarywallsareexposedtoaconcentratedsugarsolution,thecellsshrink,thusopeningthetightjunctionsbetweenthem.(Adaptedfrom:SIRapoport,Blood-BrainBarrierinPhysiologyandMedicine.RavenPress,1976.)Blood-BrainBarrierDisruption(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/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Bloodbrainbarrierdisruption(BBBD)andintra-arterialmethotrexatebasedtherapyfornewlydiagnosedprimaryCNSlymphoma:TheBBBDConsortiumExperience.2007ASCOAnnualMeetingProceedingsPartI.Vol25,No.18S4institutions：1982-2005，177PCNSLBBBD/IAMTX；2,469proceduresPtsCRPRORRMOS(y)MPFS(y)PFS-5(y)1771014180.2%3.11.640%APhaseIITrialInvolvingPatientswithRecurrentPCNSLTreatedwithCarboplatin/BBBD,byAddingRituxan(Rituximab),anantiCD-20Antibody,totheTreatmentRegimenPhaseI/IIStudyofCarboplatin,MelphalanandEtoposidePhosphateinConjunctionwithOsmoticOpeningoftheBlood-BrainBarrierandDelayedIntravenousSodiumThiosulfateChemoprotection,inSubjectswithAnaplasticOligodendrogliomaorOligoastrocytomaPhaseIIClinicalTrialofPatientswithHigh-GradeGliomaTreatedwithIntra-arterialCarboplatin-basedChemotherapy,RandomizedtoTreatmentwithorwithoutDelayedIntravenousSodiumThio