惡性腦腫瘤的化學治療

惡性腦腫瘤的化學治療1整理課件CerebrumandCerebellum2整理課件流行病學趨勢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整理課件流行病學趨勢每年以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的顱內(nèi)腫瘤，隨全身腫瘤整體治療水平提高和生存延長，腦轉(zhuǎn)移瘤發(fā)生率不斷上升，實體瘤患者15%-20%最終會發(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)灶不明小細胞非小細胞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結腸 26 5其他原發(fā)瘤 72 13未知原發(fā)瘤 61 10合計 561 10011整理課件腦轉(zhuǎn)移常見的部位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,最大限度地手術切除腫瘤而腫瘤位于重要腦功能區(qū),手術極度困難而風險又極大者,應盡可能進行立體定向活組織檢查術。對每位病人依據(jù)腫瘤的病理分類和分級以及腫瘤的分子生物學特征和病人的免疫狀態(tài)再輔以放療±化療。而手術、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)瘤的標準化療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)瘤的化療原那么對高級別膠質(zhì)瘤(WHOⅢ-Ⅳ級)應該常規(guī)給予化療低級別膠質(zhì)瘤(WHOⅠ-Ⅱ級)可以根據(jù)手術切除程度、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,對維持CNS內(nèi)環(huán)境恒定有至關重要的作用主要形式:腦毛細血管內(nèi)皮細胞緊密連接 細胞之間無孔隙,“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)皮細胞內(nèi):細胞器,與物質(zhì)轉(zhuǎn)運有關的酶類 結構為脂性基架,對大于3968μ(40KD)物質(zhì)限制通過藥物要求 分子量小 脂溶性 正常PH時不電離 不與蛋白結合血腦屏障(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有效穿透血腦屏障腦膠質(zhì)瘤細胞敏感腦腫瘤內(nèi)維持長時間有效濃度骨髓抑制盡量低,毒副作用小可長期使用CNS腫瘤的化學治療亞硝脲類藥物較容易通過血腦屏障，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腫瘤的常用化學治療方案28整理課件間質(zhì)內(nèi)化療:可避開BBB ※機理: ▲提高腫瘤局部藥物濃度 ▲減少全身用藥毒副作用

※方法: ▲術中 ▲術后避開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恢復正常

20世紀80年代用于臨床 尚未Ⅲ期研究證實近年研究:BBB開放無選擇性,內(nèi)皮細胞破壞:

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ACNU

2-3mg/kg,iv,gtt,D1,4-6周重復化療前20%甘露醇250ml,iv,gtt,DXM10mg,ivACNU共計47周期，平均2.3VM26共計49周期，平均2.5中國癌癥雜志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 意識改變 6 肢體肌力感覺異常 10 顱腦神經(jīng)受損 7 共濟失調(diào) 1 合計 48中國癌癥雜志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)移性腦腫瘤結果患者存活時間1-17月，平均6.5月超過6個月者11例中國癌癥雜志Vol9,No2,June,199939整理課件避開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可評價病人數(shù)PRSDMTTP(w)PFS-6MS(w)MPFS(w)OS-61Year532211721%341168%26%41整理課件可評價病人數(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Gliomas的文獻有36篇病人數(shù)可評價病人數(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可評價病人數(shù)PRPFS-6OS-63557%46%77%45整理課件PhaseIItrialofirinotecanandthalidomideinadultswithrecurrentglioblastomamultiforme可評價病人數(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有關神經(jīng)系統(tǒng)腫瘤的文獻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開放 選擇性開放血瘤屏障(blood-tumorbarrier,BTB)克服化療耐藥性 多藥耐藥及逆轉(zhuǎn)MGMT表達預測化療療效，防止無效化療。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)瘤對化療的敏感性 ※機理：抑制MDR-I或P-gp過表達PCV方案顯著增強多形膠質(zhì)母細胞瘤對BCNU類藥制的敏感性 ※機理：腫瘤細胞先暴露于烷化劑類藥物使瘤 細胞中AGT〔O6-烷基鳥嘌呤-DNA烷基化轉(zhuǎn)酶〕活性受抑 AGT是增強腫瘤細胞對BCNU類藥物敏感性的主要靶點63整理課件RandomizedComparisonofIntra-arterialVersusIntravenousInfusionofACNUforNewlyDiagnosedPatientswithGlioblastomaTocomparetheeff