惡性腦腫瘤化學治療課件

惡性腦腫瘤的化學治療四川省腫瘤醫院內科張智慧CerebrumandCerebellum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)流行病學趨勢每年以1.2%的速度在增加CNS原發腫瘤發病率BrainTumorFacts&Statistics?2007BrainTumorSocietyFiveYearSurvivalRatesbyAgeGroupAgeSurvivalRates0-19years63.1%20-44years50.4%45-64years14.2%Over654.9%DataFrom:2002-2003PrimaryBrainTumorsintheUnitedStatesStatisticalReport.FactSheet(1973-1999data).BrainTumorRegistryoftheUnitedStatesCNS原發腫瘤五年生存率http:///factsheet/factsheet.html.轉移性腦腫瘤（BrainMetastasesBM）定義：源自CNS以外組織的腫瘤發生播散，累及腦組織是成年人群最常見的顱內腫瘤，隨全身腫瘤整體治療水平提高和生存延長，腦轉移瘤發生率不斷上升，實體瘤患者15%-20%最終會發生腦轉移。BrainTumorFacts&Statistics不同腫瘤發生鬧轉移的比例肺癌乳腺癌惡黑大腸腎原發灶不明小細胞非小細胞50%33%20%50%5%5%15%

多發性多發性多發性單發單發混合腦轉移性腫瘤的發生率VariesaccordingtoprimarysiteLung-18-64%Breast-2-21%Colo-rectal-2-12%Melanoma-4-16%Renal-1-8%Thyroid-1-10%Prostate,skin,oropharyngeal-rarelyOverallincidence6-24%CNS轉移性腫瘤發生率(10倍于原發腫瘤)原發腫瘤 例數 %肺 270 48乳腺 82 15黑色素瘤 50 9結腸 26 5其他已知原發瘤 72 13未知原發瘤 61 10合計 561 100腦轉移常見的部位BrainmetsmayoccurinseveralpositionsMeninges/leptomeningesBrainparenchyma(morecommon)80%incerebrum,mostlyingrey-whitematterinterface15%incerebellum5%inbrainstemResultofhaematogenousspreadMediansurvival1-2monthsifuntreatedASCO2009Abstract文2068全腦放療轉移性腦腫瘤的生存率Procedure

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

不同治療模式轉移性腦腫瘤的生存時間在盡可能保全重要神經功能的前提下,最大限度地手術切除腫瘤而腫瘤位于重要腦功能區,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再輔以放療±化療。而手術、放療、化療三大常規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腫瘤治療原則膠質瘤的規范化療AnnalsofOncology9:589-600,1998Assessmentofmorethan20yearsofchemotherapytrialsisdiscouragingdespiteafewareasofmodestsuccess.Onlypatientswithspecifichistology(oligodendroglioma,anaplasticastrocytoma)andgoodprognosticfactors(youngage,goodperformancestatus)maybenefitfromchemotherapy。ChemotherapyinGBMMeta-analysis

Lancet359:1011,2002MRC2001JClinOnc19:509,2001Largerandomizedtrial(n=674)ingrade3and4astrocytoma-firstlinecomparingradiationaloneversusradiationfollowedbyPCVq6wkxupto12cycles.(1988-97)NodifferencesinsurvivalChemotherapyinadulthigh-gradeglioma:asystematicreviewandmeta-analysisofindividualpatientdatafrom12randomisedtrialsLancet2002;359(9311):1011-8.膠質瘤的化療原則對高級別膠質瘤(WHOⅢ-Ⅳ級)應該常規給予化療低級別膠質瘤(WHOⅠ-Ⅱ級)可以根據手術切除程度、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（安全-高效）InoetalCCR2001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,作為血與CNS之間的 調節界面,對維持CNS內環境恒定有至關重要的作用主要形式:腦毛細血管內皮細胞緊密連接 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的基底膜 內皮細胞內:細胞器,與物質轉運有關的酶類 結構為脂性基架,對大于3968μ(40KD)物質限制通過藥物要求 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)血腦屏障(BBB)腦膠質瘤理想化療藥物的特點有效穿透血腦屏障腦膠質瘤細胞敏感腦腫瘤內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。

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.PhaseIItrialAnticancerRes23:5159,2003ClinCancerRes11:6767,2005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,TamodalCNS腫瘤的化學治療化療方式：1，全身化療：IV；IA2，椎管內化療：穿刺化療；置泵3，間質化療：Ommaya,WaferCNS腫瘤的常用化學治療方案間質內化療: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BBBD治療Osmoticopeningoftheblood-brainbarrier.Whenendothelialcellsthatlinecapillarywallsareexposedtoaconcentratedsugarsolution,thecellsshrink,thusopeningthetightjunctionsbetweenthem.(Adaptedfrom:SIRapoport,Blood-BrainBarrierinPhysiologyandMedicine.RavenPress,1976.)Blood-BrainBarrierDisruption(BBBD)治療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血管內皮細胞收縮 胞間緊密聯接增寬 ↓ 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%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-OncologyProgram

替尼泊苷聯合尼莫司汀治療轉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,1999替尼泊苷聯合尼莫司汀治療轉移性腦腫瘤中國癌癥雜志Vol9,No2,June,1999替尼泊苷聯合尼莫司汀治療轉移性腦腫瘤

臨床表現 癥狀 例次 頭痛 13

惡心，嘔吐 11

意識改變 6

肢體肌力感覺異常 10

顱腦神經受損 7

共濟失調 1

合計 48中國癌癥雜志Vol9,No2,June,1999

替尼泊苷聯合尼莫司汀治療轉移性腦腫瘤結果：癥狀緩解率：完全緩解CR： 60.4%部份緩解PR： 31.6%癥狀總緩解率： 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,1999替尼泊苷聯合尼莫司汀治療轉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,1999避開BBB的方式椎管內化療： 主要用于CNS淋巴瘤，腦膜轉移腫瘤，白血病的腦膜侵犯。Phase2studyofBCNUandtemozolomideforrecurrentglioblastomamultiforme:NorthAmericanBrainTumorConsortiumstudyNeuro-oncol.2004January;6(1):33–37可評價病人數PRSDMTTP(w)PFS-6MS(w)MPFS(w)OS-61Year532211721%341168%26%可評價病人數CRPRMTTP(w)PFS-6(m)42091730.3%Second-linechemotherapywithirinotecanpluscarmustineinglioblastomarecurrentorprogressiveafterfirst-linetemozolomidechemotherapy:aphaseIIstudyoftheGruppoItalianoCooperativodiNeuro-Oncologia(GICNO).JClinOncol.2004Dec1;22(23):4779-862007年ASCO有關Gliomas的文獻有36篇病人數可評價病人數PRMPFS(w)MOS(w)PFS-6685959%234043%PhaseIItrialofbevacizumabandirinotecaninthetreatmentofmalignantgliomasAphaseII,randomized,non-comparativeclinicaltrialoftheeffectofbevacizumab(BV)aloneorincombinationwithirinotecan(CPT)on6-monthprogressionfreesurvival(PFS6)inrecurrent,treatment-refractoryglioblastoma(GBM).JClinOncol26:2008(May20suppl;abstr2010bBevacizumabplusirinotecaninrecurrentglioblastomamultiformeJClinOncol.2007Oct20;25(30):4722-9可評價病人數PRPFS-6OS-63557%46%77%PhaseIItrialofirinotecanandthalidomideinadultswithrecurrentglioblastomamultiforme可評價病人數CRPRSDMPFS(w)MOS(w)1Year3211119133634%NeuroOncol.2008Feb26

Bevacizumabandirinotecanforrecurrentoligodendroglialtumors.Conclusions:Thisregimeniseffectiveinrecurrentoligodendrogliomas,andtheoveralltoleranceisacceptable.ASCO2009,Abstract205425Pts.CRPRM-PFS(d)MOS(d)6-PFS(ms)20%52%17432842%ASCO2009,Abstract20372009年ASCO有關神經系統腫瘤的文獻80余篇AphaseIIstudyofXL184inpatients(pts)withprogressiveglioblastomamultiforme(GBM)infirstorsecondrelapse.ASCO2009,Abstract204726Pts.PRSDPD6-PFS(ms)38%35%27%(9ptsreceivedbevacizumab)腦膠質瘤和轉移性瘤耐藥的研究1)6-甲基鳥嘌呤DNA甲基轉移酶(MGMT)(6-methylguanine-DNAhyltransferase)2)P-glycoproteinFruehauf,J.P.etal.ClinCancerRes2006;12:4523-4532腦膠質瘤和轉移性瘤耐藥的研究Fruehauf,J.P.etal.ClinCancerRes2006;12:4523-4532MGMTmethylationstatusasaprognosticfactorinanaplasticastrocytomas.Conclusions:MGMTmethylationstatusisanindependentprognosticfactortogetherwithageinAA.Pts.71/80(88.8%)30/71(M)41/71(UM)MGMTmethylationM-PFS(ms)48.638p=0.09ASCO2009Abstract2052P-gpexpressioninbraincapillaryendothelialcellssuggeststhatP-gpmayrestrictdrugentryintobraintumorsandthusbeanothermechanismofdrugresistance.K1735cellsK1735cellsMDRThebiologyandmechanismofchemoresistanceofbrainmetastasesTHEUNIVERSITYOFTEXASGRAD.SCH.OFBIOMED.SCI.ATHOUSTON1995BBBD(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

MGMT表達預測化療療效，避免無效化療。腦膠質瘤和轉移性瘤耐藥的研究聯合化療提高化療敏感性RandomizedComparisonofIntra-arterialVersusIntravenousInfusionofACNUforNewlyDiagnosedPatientswithGlioblastomaTocomparetheeffectivenessofintra-arterialACNUwithintravenousACNUinnewlydiagnosedpatientswithsupratentorialglioblastoma.ACNU(80mg/m2)onceevery6weeks