惡性腦腫瘤的化學(xué)治療

惡性腦腫瘤的化學(xué)治療1整理課件CerebrumandCerebellum2整理課件流行病學(xué)趨勢(shì)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整理課件流行病學(xué)趨勢(shì)每年以1.2%的速度在增加4整理課件5整理課件CNS原發(fā)腫瘤發(fā)病率BrainTumorFacts&Statistics?2007BrainTumorSociety6整理課件FiveYearSurvivalRatesbyAgeGroupAgeSurvivalRates0-19years63.1%20-44years50.4%45-64years14.2%Over654.9%DataFrom:2002-2003PrimaryBrainTumorsintheUnitedStatesStatisticalReport.FactSheet(1973-1999data).BrainTumorRegistryoftheUnitedStatesCNS原發(fā)腫瘤五年生存率:///factsheet/factsheet.html.7整理課件轉(zhuǎn)移性腦腫瘤〔BrainMetastasesBM〕定義：源自CNS以外組織的腫瘤發(fā)生播散，累及腦組織是成年人群最常見(jiàn)的顱內(nèi)腫瘤，隨全身腫瘤整體治療水平提高和生存延長(zhǎng)，腦轉(zhuǎn)移瘤發(fā)生率不斷上升，實(shí)體瘤患者15%-20%最終會(huì)發(fā)生腦轉(zhuǎn)移。BrainTumorFacts&Statistics8整理課件不同腫瘤發(fā)生鬧轉(zhuǎn)移的比例肺癌乳腺癌惡黑大腸腎原發(fā)灶不明小細(xì)胞非小細(xì)胞50%33%20%50%5%5%15%

多發(fā)性多發(fā)性多發(fā)性單發(fā)單發(fā)混合9整理課件腦轉(zhuǎn)移性腫瘤的發(fā)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整理課件CNS轉(zhuǎn)移性腫瘤發(fā)生率(10倍于原發(fā)腫瘤)原發(fā)腫瘤 例數(shù) %肺 270 48乳腺 82 15黑色素瘤 50 9結(jié)腸 26 5其他原發(fā)瘤 72 13未知原發(fā)瘤 61 10合計(jì) 561 10011整理課件腦轉(zhuǎn)移常見(jiàn)的部位BrainmetsmayoccurinseveralpositionsMeninges/leptomeningesBrainparenchyma(morecommon)80%incerebrum,mostlyingrey-whitematterinterface15%incerebellum5%inbrainstemResultofhaematogenousspreadMediansurvival1-2monthsifuntreated12整理課件ASCO2021Abstract文2068全腦放療轉(zhuǎn)移性腦腫瘤的生存率13整理課件Procedure

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

不同治療模式轉(zhuǎn)移性腦腫瘤的生存時(shí)間14整理課件在盡可能保全重要神經(jīng)功能的前提下,最大限度地手術(shù)切除腫瘤而腫瘤位于重要腦功能區(qū),手術(shù)極度困難而風(fēng)險(xiǎn)又極大者,應(yīng)盡可能進(jìn)行立體定向活組織檢查術(shù)。對(duì)每位病人依據(jù)腫瘤的病理分類和分級(jí)以及腫瘤的分子生物學(xué)特征和病人的免疫狀態(tài)再輔以放療±化療。而手術(shù)、放療、化療三大常規(guī)治療以外的許多新療法,只能作為臨床研究在一些有條件的單位施行,而不能作為一線治療手段。CNS腫瘤治療原那么15整理課件膠質(zhì)瘤的標(biāo)準(zhǔn)化療16整理課件AnnalsofOncology9:589-600,1998Assessmentofmorethan20yearsofchemotherapytrialsisdiscouragingdespiteafewareasofmodestsuccess.Onlypatientswithspecifichistology(oligodendroglioma,anaplasticastrocytoma)andgoodprognosticfactors(youngage,goodperformancestatus)maybenefitfromchemotherapy。17整理課件ChemotherapyinGBMMeta-analysis

Lancet359:1011,2002MRC2001JClinOnc19:509,2001Largerandomizedtrial(n=674)ingrade3and4astrocytoma-firstlinecomparingradiationaloneversusradiationfollowedbyPCVq6wkxupto12cycles.(1988-97)Nodifferencesinsurvival18整理課件Chemotherapyinadulthigh-gradeglioma:asystematicreviewandmeta-analysisofindividualpatientdatafrom12randomisedtrialsLancet2002;359(9311):1011-8.19整理課件膠質(zhì)瘤的化療原那么對(duì)高級(jí)別膠質(zhì)瘤(WHOⅢ-Ⅳ級(jí))應(yīng)該常規(guī)給予化療低級(jí)別膠質(zhì)瘤(WHOⅠ-Ⅱ級(jí))可以根據(jù)手術(shù)切除程度、病理類型和基因缺失情況考慮是否化療選擇能通過(guò)血腦屏障的脂溶性、小分子藥物〔平安-高效〕20整理課件InoetalCCR200121整理課件存在于血一腦，血一腦脊液及腦一腦脊液之間 選擇性控制進(jìn)入腦脊液和腦的物質(zhì),作為血與CNS之間的 調(diào)節(jié)界面,對(duì)維持CNS內(nèi)環(huán)境恒定有至關(guān)重要的作用主要形式:腦毛細(xì)血管內(nèi)皮細(xì)胞緊密連接 細(xì)胞之間無(wú)孔隙,“條焊狀〞連接,甚至某種程度重疊 基底部尚有一層連續(xù)的基底膜 內(nèi)皮細(xì)胞內(nèi):細(xì)胞器,與物質(zhì)轉(zhuǎn)運(yùn)有關(guān)的酶類 結(jié)構(gòu)為脂性基架,對(duì)大于3968μ(40KD)物質(zhì)限制通過(guò)藥物要求 分子量小 脂溶性 正常PH時(shí)不電離 不與蛋白結(jié)合血腦屏障(BBB)22整理課件血腦屏障(BBB)23整理課件腦膠質(zhì)瘤理想化療藥物的特點(diǎn)有效穿透血腦屏障腦膠質(zhì)瘤細(xì)胞敏感腦腫瘤內(nèi)維持長(zhǎng)時(shí)間有效濃度骨髓抑制盡量低,毒副作用小可長(zhǎng)期使用CNS腫瘤的化學(xué)治療亞硝脲類藥物較容易通過(guò)血腦屏障，故被視為治療腦腫瘤的首選藥物。

24整理課件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整理課件能通過(guò)BBB的藥物亞硝脲類：BCNU,Me-CCNU,ACNU甲基芐肼〔Procarbazine)VM-26,TeniposideMTX/CFAra-C,LiposomalAra-cDoxil,IdarubicinDocetaxelTemozolomide,Tamodal26整理課件CNS腫瘤的化學(xué)治療化療方式：1，全身化療：IV；IA2，椎管內(nèi)化療：穿刺化療；置泵3，間質(zhì)化療：Ommaya,Wafer

27整理課件CNS腫瘤的常用化學(xué)治療方案28整理課件間質(zhì)內(nèi)化療:可避開(kāi)BBB ※機(jī)理: ▲提高腫瘤局部藥物濃度 ▲減少全身用藥毒副作用

※方法: ▲術(shù)中 ▲術(shù)后避開(kāi)BBB的方式29整理課件BBBD治療Osmoticopeningoftheblood-brainbarrier.Whenendothelialcellsthatlinecapillarywallsareexposedtoaconcentratedsugarsolution,thecellsshrink,thusopeningthetightjunctionsbetweenthem.(Adaptedfrom:SIRapoport,Blood-BrainBarrierinPhysiologyandMedicine.RavenPress,1976.)Blood-BrainBarrierDisruption(BBBD)治療30整理課件A/E:頸動(dòng)脈灌注高滲溶液,迅速改變BBB通透性

20%甘露醇150-250ml,5-10ml/sec BBB血管內(nèi)皮細(xì)胞收縮 胞間緊密聯(lián)接增寬 ↓ 腦組織含水量增加1.0%-1.5% ↓ 4hr恢復(fù)正常

20世紀(jì)80年代用于臨床 尚未Ⅲ期研究證實(shí)近年研究:BBB開(kāi)放無(wú)選擇性,內(nèi)皮細(xì)胞破壞:

正常腦組織>腫瘤,正常腦組織暴露化療藥物↑高滲性BBB開(kāi)放31整理課件32整理課件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整理課件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整理課件

替尼泊苷聯(lián)合尼莫司汀治療轉(zhuǎn)移性腦腫瘤治療方法：VM26

100mg,iv,gtt,D1-3,4周重復(fù)ACNU

2-3mg/kg,iv,gtt,D1,4-6周重復(fù)化療前20%甘露醇250ml,iv,gtt,DXM10mg,ivACNU共計(jì)47周期，平均2.3VM26共計(jì)49周期，平均2.5中國(guó)癌癥雜志Vol9,No2,June,199935整理課件替尼泊苷聯(lián)合尼莫司汀治療轉(zhuǎn)移性腦腫瘤

研究對(duì)象 男性： 11例 女性： 9例 年齡： 33-70歲

原發(fā)腫瘤病理類型： 肺癌 12例 乳腺癌 1例 惡性淋巴瘤 3例 鼻咽癌 1例 滑膜肉瘤 1例 不明腫瘤 2例中國(guó)癌癥雜志Vol9,No2,June,199936整理課件替尼泊苷聯(lián)合尼莫司汀治療轉(zhuǎn)移性腦腫瘤 臨床表現(xiàn) 病癥 例次 頭痛 13 惡心，嘔吐 11 意識(shí)改變 6 肢體肌力感覺(jué)異常 10 顱腦神經(jīng)受損 7 共濟(jì)失調(diào) 1 合計(jì) 48中國(guó)癌癥雜志Vol9,No2,June,199937整理課件

替尼泊苷聯(lián)合尼莫司汀治療轉(zhuǎn)移性腦腫瘤結(jié)果：病癥緩解率：完全緩解CR： 60.4%部份緩解PR： 31.6%病癥總緩解率： 91.7%顱腦CT復(fù)查：腦水腫減輕或消失 100%(16/16)完全緩解CR 10%(2/20)部份緩解PR 50%(10/20)總有效率(CR+PR) 60%(12/20)顱腦外病灶縮小 52.9%(9/17)中國(guó)癌癥雜志Vol9,No2,June,199938整理課件替尼泊苷聯(lián)合尼莫司汀治療轉(zhuǎn)移性腦腫瘤結(jié)果患者存活時(shí)間1-17月，平均6.5月超過(guò)6個(gè)月者11例中國(guó)癌癥雜志Vol9,No2,June,199939整理課件避開(kāi)BBB的方式椎管內(nèi)化療： 主要用于CNS淋巴瘤，腦膜轉(zhuǎn)移腫瘤，白血病的腦膜侵犯。40整理課件Phase2studyofBCNUandtemozolomideforrecurrentglioblastomamultiforme:NorthAmericanBrainTumorConsortiumstudyNeuro-oncol.2004January;6(1):33–37可評(píng)價(jià)病人數(shù)PRSDMTTP(w)PFS-6MS(w)MPFS(w)OS-61Year532211721%341168%26%41整理課件可評(píng)價(jià)病人數(shù)CRPRMTTP(w)PFS-6(m)42091730.3%Second-linechemotherapywithirinotecanpluscarmustineinglioblastomarecurrentorprogressiveafterfirst-linetemozolomidechemotherapy:aphaseIIstudyoftheGruppoItalianoCooperativodiNeuro-Oncologia(GICNO).JClinOncol.2004Dec1;22(23):4779-8642整理課件2007年ASCO有關(guān)Gliomas的文獻(xiàn)有36篇病人數(shù)可評(píng)價(jià)病人數(shù)PRMPFS(w)MOS(w)PFS-6685959%234043%IngradeIIIpatientsthemedianPFSwas42weeks,the6monthPFSwas61%themedialoverallsurvivalwas60weeksConclusion:Thecombinationofbevacizumabandirinotecanissafeanddemonstratessuperioractivityagainstmalignantgliomas.PhaseIItrialofbevacizumabandirinotecaninthetreatmentofmalignantgliomas43整理課件AphaseII,randomized,non-comparativeclinicaltrialoftheeffectofbevacizumab(BV)aloneorincombinationwithirinotecan(CPT)on6-monthprogressionfreesurvival(PFS6)inrecurrent,treatment-refractoryglioblastoma(GBM).JClinOncol26:2021(May20suppl;abstr2021b44整理課件Bevacizumabplusirinotecaninrecurrentglioblastomamultiforme

JClinOncol.2007Oct20;25(30):4722-9可評(píng)價(jià)病人數(shù)PRPFS-6OS-63557%46%77%45整理課件PhaseIItrialofirinotecanandthalidomideinadultswithrecurrentglioblastomamultiforme可評(píng)價(jià)病人數(shù)CRPRSDMPFS(w)MOS(w)1Year3211119133634%NeuroOncol.2021Feb2646整理課件Bevacizumabandirinotecanforrecurrentoligodendroglialtumors.Conclusions:Thisregimeniseffectiveinrecurrentoligodendrogliomas,andtheoveralltoleranceisacceptable.ASCO2021,Abstract205425Pts.CRPRM-PFS(d)MOS(d)6-PFS(ms)20%52%17432842%47整理課件48整理課件49整理課件50整理課件51整理課件52整理課件53整理課件ASCO2021,Abstract20372021年ASCO有關(guān)神經(jīng)系統(tǒng)腫瘤的文獻(xiàn)80余篇54整理課件AphaseIIstudyofXL184inpatients(pts)withprogressiveglioblastomamultiforme(GBM)infirstorsecondrelapse.Conclusions:XL184atadoseof175mgPOqd,hasdemonstratedsubstantialactivityinptswithprogressiveorrecurrentGBM.ASCO2021,Abstract204726Pts.PRSDPD6-PFS(ms)38%35%27%(9ptsreceivedbevacizumab)55整理課件腦膠質(zhì)瘤和轉(zhuǎn)移性瘤耐藥的研究1)6-甲基鳥(niǎo)嘌呤DNA甲基轉(zhuǎn)移酶(MGMT)(6-methylguanine-DNAhyltransferase)2)P-glycoprotein56整理課件Fruehauf,J.P.etal.ClinCancerRes2006;12:4523-4532腦膠質(zhì)瘤和轉(zhuǎn)移性瘤耐藥的研究57整理課件Fruehauf,J.P.etal.ClinCancerRes2006;12:4523-453258整理課件MGMTmethylationstatusasaprognosticfactorinanaplasticastrocytomas.Conclusions:MGMTmethylationstatusisanindependentprognosticfactortogetherwithageinAA.Pts.71/80(88.8%)30/71(M)41/71(UM)MGMTmethylationM-PFS(ms)48.638p=0.09ASCO2021Abstract205259整理課件P-gpexpressioninbraincapillaryendothelialcellssuggeststhatP-gpmayrestrictdrugentryintobraintumorsandthusbeanothermechanismofdrugresistance.60整理課件K1735cellsK1735cellsMDRThebiologyandmechanismofchemoresistanceofbrainmetastasesTHEUNIVERSITYOFTEXASGRAD.SCH.OFBIOMED.SCI.ATHOUSTON199561整理課件BBBD(blood-brainbarrierdisruption)化療 高滲性、緩激肽衍生物：BBB開(kāi)放 選擇性開(kāi)放血瘤屏障(blood-tumorbarrier,BTB)克服化療耐藥性 多藥耐藥及逆轉(zhuǎn)MGMT表達(dá)預(yù)測(cè)化療療效，防止無(wú)效化療。腦膠質(zhì)瘤和轉(zhuǎn)移性瘤耐藥的研究62整理課件聯(lián)合化療提高化療敏感性VM-26和BCNU聯(lián)合顯著提高膠質(zhì)瘤對(duì)化療的敏感性 ※機(jī)理：抑制MDR-I或P-gp過(guò)表達(dá)PCV方案顯著增強(qiáng)多形膠質(zhì)母細(xì)胞瘤對(duì)BCNU類藥制的敏感性 ※機(jī)理：腫瘤細(xì)胞先暴露于烷化劑類藥物使瘤 細(xì)胞中AGT〔O6-烷基鳥(niǎo)嘌呤-DNA烷基化轉(zhuǎn)酶〕活性受抑 AGT是增強(qiáng)腫瘤細(xì)胞對(duì)BCNU類藥物敏感性的主要靶點(diǎn)63整理課件RandomizedComparisonofIntra-arterialVersusIntravenousInfusionofACNUforNewlyDiagnosedPatientswithGlioblastomaTocomparetheeff