恶性脑肿瘤的化学治疗.ppt

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,2019(US)18,500*12,760Incidence11.47per100,000(annualrate)Adjusted5yrsurvivalrate(2019-2000)33%adults73%children2ndleadingcauseofcancerdeathsinpersons肿瘤,正常脑组织暴露化疗药物,高渗性BBB开放,Bloodbrainbarrierdisruption(BBBD)andintra-arterialmethotrexatebasedtherapyfornewlydiagnosedprimaryCNSlymphoma:TheBBBDConsortiumExperience.,2019ASCOAnnualMeetingProceedingsPartI.Vol25,No.18S,4institutions：1982-2019，177PCNSL,BBBD/IAMTX；2,469procedures,PtsCRPRORRMOS(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:APhaseIStudy,Neuro-OncologyBlood-BrainBarrierProgram,OregonHealth6(1):3337,可评价病人数PRSDMTTP(w)PFS-6MS(w)MPFS(w)OS-61Year,532211721%341168%26%,可评价病人数CRPRMTTP(w)PFS-6(m),42091730.3%,Second-linechemotherapywithirinotecanpluscarmustineinglioblastomarecurrentorprogressiveafterfirst-linetemozolomidechemotherapy:aphaseIIstudyoftheGruppoItalianoCooperativodiNeuro-Oncologia(GICNO).,JClinOncol.2019Dec1;22(23):4779-86,2019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-6,685959%234043%,IngradeIIIpatientsthemedianPFSwas42weeks,the6monthPFSwas61%themedialoverallsurvivalwas60weeksConclusion:Thecombinationofbevacizumabandirinotecanissafeanddemonstratessuperioractivityagainstmalignantgliomas.,PhaseIItrialofbevacizumabandirinotecaninthetreatmentofmalignantgliomas,AphaseII,randomized,non-comparativeclinicaltrialoftheeffectofbevacizumab(BV)aloneorincombinationwithirinotecan(CPT)on6-monthprogressionfreesurvival(PFS6)inrecurrent,treatment-refractoryglioblastoma(GBM).,JClinOncol26:2019(May20suppl;abstr2019b,Bevacizumabplusirinotecaninrecurrentglioblastomamultiforme,JClinOncol.2019Oct20;25(30):4722-9,可评价病人数PRPFS-6OS-6,3557%46%77%,PhaseIItrialofirinotecanandthalidomideinadultswithrecurrentglioblastomamultiforme,可评价病人数CRPRSDMPFS(w)MOS(w)1Year,3211119133634%,NeuroOncol.2019Feb26,Bevacizumabandirinotecanforrecurrentoligodendroglialtumors.,Conclusions:Thisregimeniseffectiveinrecurrentoligodendrogliomas,andtheoveralltoleranceisacceptable.,ASCO2009,Abstract2054,25Pts.CRPRM-PFS(d)MOS(d)6-PFS(ms),20%52%17432842%,ASCO2009,Abstract2037,2009年ASCO有关神经系统肿瘤的文献80余篇,AphaseIIstudyofXL184inpatients(pts)withprogressiveglioblastomamultiforme(GBM)infirstorsecondrelapse.,Conclusions:XL184atadoseof175mgPOqd,hasdemonstratedsubstantialactivityinptswithprogressiveorrecurrentGBM.,ASCO2009,Abstract2047,26Pts.PRSDPD6-PFS(ms),38%35%27%,(9ptsreceivedbevacizumab),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-glycoprotein,Fruehauf,J.P.etal.ClinCancerRes2019;12:4523-4532,脑胶质瘤和转移性瘤耐药的研究,Fruehauf,J.P.etal.ClinCancerRes2019;12:4523-4532,MGMTmethylationstatusasaprognosticfactorinanaplasticastrocytomas.,Conclusions:MGMTmethylationstatusisanindependentprognosticfactortogetherwithageinAA.,Pts.71/80(88.8%),30/71(M)41/71(UM),MGMTmethylation,M-PFS(ms),48.638,p=0.09,ASCO2009Abstract2052,P-gpexpressioninbraincapillaryendothelialcellssuggeststhatP-gpmayrestrictdrugentryintobraintumorsandthusbeanothermechanismofdrugresistance.,K1735cells,K1735cells,MDR,Thebiologyandmechanismofchemoresistanceofbrainmetastases,THEUNIVERSITYOFTEXASGRAD.SCH.OFBIOMED.SCI.ATHOUSTON2019,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,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,RandomizedComparisonofIntra-arterialVersusIntravenousInfusionofACNUforNewlyDiagnosedPatientswithGlioblastoma,Tocomparetheeffectivenessofintra-arterialACNUwithintravenousACNUinnewlydiagnosedpatientswithsupratentorialglioblastoma.,ACNU(80mg/m2)onceevery6weeksconcomitantwithradiotherapy.,病人数可评价病人数MS(w)PFS(w)Toxicity,8482,IA5924-,IV5645-,Journalofneuro-oncology2000,vol.49,no1,pp.63-70,2019年NCCN指南,成人侵润性低度恶性幕上星形细胞瘤/少突胶质细胞瘤辅助化疗：高剂量替莫唑胺5/28方案复发或进展：一线方案：替莫唑胺5/28方案（初治）二线方案：BCUN210mg/m2iv6w重复;,80mg/m2x36w重复；CCNU110mg/m2口服6w重复；PCV联合化疗成人室管膜瘤：复发用vp-16,替莫唑胺，亚硝脲类，铂及联合方案,原发性CNS肿瘤化疗指南,多形性胶母细胞瘤辅助化疗：同步替莫唑胺75mg/m2daily替莫唑胺150-200mg/m25/28方案复发/挽救治疗：替莫唑胺5/28方案（初治）Bevacizumab+IrinotecanBCUN;CCNU;PCV联合化疗间变形星形细胞瘤/少突胶质细胞瘤辅助化疗：替莫唑胺或亚硝脲复发/挽救治疗：替莫唑胺5/28方案（初治）Bevacizumab+IrinotecanBCUN;CCNU;PCV联合,原发性CNS肿瘤化疗原则,2019年NCCN指南,转移性脑肿瘤局限1-3或多发3个以上对原发肿瘤有效的药物替莫唑胺5/28方案（器官特异性治疗）卡培他宾，大剂量MTX(乳腺癌，淋巴瘤），Toptecan（肺癌）癌性脑膜炎采用对脑组织穿透能力强的药物；椎管内化疗（脂质体cytarabine,MTX，cytarabine,Thiotepa)大剂量MTX治疗淋巴瘤性脑膜炎原发性中枢神经系统淋巴瘤大剂量MTX3.5g/m2或更高剂量，或