恶性脑肿瘤化学治疗ppt课件.ppt

恶性脑肿瘤的化学治疗四川省肿瘤医院内科张智慧Cerebrum and Cerebellum流行病学趋势2005(US)18,500*12,760Incidence 11.47 per 100,000(annual rate)Adjusted 5 yr survival rate(1995-2000)33%adults73%children 2nd leading cause of cancer deaths in persons 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；2,469proceduresPtsCRPRORRM OS(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&ScienceUniversityBloodBrainBarrierandNeuro-OncologyProgram 替尼泊苷联合尼莫司汀治疗转移性脑肿瘤治疗方法：VM26100mg,iv,gtt,D1-3,4周重复ACNU2-3mg/kg,iv,gtt,D1,4-6周重复化疗前20%甘露醇250ml,iv,gtt,DXM10mg,ivACNU共计47周期，平均2.3VM26共计49周期，平均2.5中国癌症杂志Vol9,No2,June,1999替尼泊苷联合尼莫司汀治疗转移性脑肿瘤研究对象男性：11例女性：9例年龄：33-70岁原发肿瘤病理类型：肺癌12例乳腺癌1例恶性淋巴瘤3例鼻咽癌1例滑膜肉瘤1例不明肿瘤2例中国癌症杂志Vol9,No2,June,1999替尼泊苷联合尼莫司汀治疗转移性脑肿瘤 临床表现症状例次头痛13恶心，呕吐11意识改变6肢体肌力感觉异常10颅脑神经受损7共济失调1合计48中国癌症杂志Vol9,No2,June,1999 替尼泊苷联合尼莫司汀治疗转移性脑肿瘤结果：症状缓解率：完全缓解CR：60.4%部份缓解PR：31.6%症状总缓解率：91.7%颅脑CT复查：脑水肿减轻或消失100%(16/16)完全缓解CR10%(2/20)部份缓解PR50%(10/20)总有效率(CR+PR)60%(12/20)颅脑外病灶缩小52.9%(9/17)中国癌症杂志Vol9,No2,June,1999替尼泊苷联合尼莫司汀治疗转移性脑肿瘤结果患者存活时间1-17月，平均6.5月超过6个月者11例中国癌症杂志Vol9,No2,June,1999避开BBB的方式椎管内化疗：主要用于CNS淋巴瘤，脑膜转移肿瘤，白血病的脑膜侵犯。Phase2studyofBCNUandtemozolomideforrecurrentglioblastomamultiforme:NorthAmericanBrainTumorConsortiumstudyNeuro-oncol.2004January;6(1):3337可评价病人数PRSDMTTP(w)PFS-6MS(w)MPFS(w)OS-61Year532211721%341168%26%可评价病人数CRPRMTTP(w)PFS-6(m)42091730.3%Second-linechemotherapywithirinotecanpluscarmustineinglioblastomarecurrentorprogressiveafterfirst-linetemozolomidechemotherapy:aphaseIIstudyoftheGruppoItalianoCooperativodiNeuro-Oncologia(GICNO).JClinOncol.2004Dec1;22(23):4779-862007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-6685959%234043%IngradeIIIpatientsthemedianPFSwas42weeks,the6monthPFSwas61%themedialoverallsurvivalwas60weeksConclusion:The combination of bevacizumab and irinotecan is safe and demonstrates superior activity against malignant gliomas.PhaseIItrialofbevacizumabandirinotecaninthetreatmentofmalignantgliomasAphaseII,randomized,non-comparativeclinicaltrialoftheeffectofbevacizumab(BV)aloneorincombinationwithirinotecan(CPT)on6-monthprogressionfreesurvival(PFS6)inrecurrent,treatment-refractoryglioblastoma(GBM).J Clin Oncol26:2008(May20suppl;abstr2010bBevacizumabplusirinotecaninrecurrentglioblastomamultiformeJClinOncol.2007Oct20;25(30):4722-9可评价病人数PRPFS-6OS-63557%46%77%Phase II trial of irinotecan and thalidomide in adults with recurrent glioblastoma multiforme可评价病人数CRPRSDMPFS(w)MOS(w)1Year3211119133634%Neuro Oncol.2008 Feb 26 Bevacizumabandirinotecanforrecurrentoligodendroglialtumors.Conclusions:Thisregimeniseffectiveinrecurrentoligodendrogliomas,andtheoveralltoleranceisacceptable.ASCO2009,Abstract205425Pts.CRPRM-PFS(d)MOS(d)6-PFS(ms)20%52%17432842%ASCO2009,Abstract20372009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,Abstract204726Pts.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-DNA hyltransferase)2)P-glycoproteinFruehauf,J.P.et al.Clin Cancer Res 2006;12:4523-4532脑胶质瘤和转移性瘤耐药的研究Fruehauf,J.P.et al.Clin Cancer Res 2006;12:4523-4532MGMT methylationstatusasaprognosticfactorinanaplasticastrocytomas.Conclusions:MGMT methylationstatusisanindependentprognosticfactortogetherwithageinAA.Pts.71/80(88.8%)30/71(M)41/71(UM)MGMT methylationM-PFS(ms)48.638p=0.09ASCO2009Abstract2052P-gpexpressioninbraincapillaryendothelialcellssuggeststhatP-gpmayrestrictdrugentryintobraintumorsandthusbeanothermechanismofdrugresistance.K1735cellsK1735cellsMDRThebiologyandmechanismofchemoresistanceofbrainmetastasesTHEUNIVERSITYOFTEXASGRAD.SCH.OFBIOMED.SCI.ATHOUSTON1995BBBD(blood-brain barrier disruption)化疗高渗性、缓激肽衍生物：BBB开放选择性开放血瘤屏障(blood-tumor barrier,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-arterialVersusIntravenousInfusionofACNUforNewlyDiagnosedPatientswithGlioblastomaTocomparetheeffectivenessofintra-arterialACNUwithintravenousACNUinnewlydiagnosedpatientswithsupratentorialglioblastoma.ACNU(80mg/m2)onceevery6weeksconcomitantwithradiotherapy.病人数可评价病人数MS(w)PFS(w)Toxicity8482IA5924-IV5645-Journalofneuro-oncology2000,vol.49,no1,pp.63-702008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/m2 iv 6w重复;,80mg/m2x3 6w重复；CCNU 110mg/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/m2 daily替莫唑胺150-200mg/m2 5/28方案复发/挽救治疗：替莫唑胺5/28方案（初治）Bevacizumab+Irinotecan BCUN;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+Irinotecan BCUN;CCNU;PCV联合原发性CNS肿瘤化疗原则2008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，或联合化疗复发或进展：再次大剂量MTX美罗华+替莫唑胺美罗华；Toptecan 替莫唑胺MVP铂类，大剂量cytarabine,DEX2008年NCCN指南转移性CNS肿瘤化疗原则恶性脑肿瘤是以外科手术、放射治疗为主的综合治疗，传统的化疗药物疗效有限，只能使部分患者受益，伴随着各类新药的诞生，特别是靶向药物和生物酶抑制剂的应用，恶性脑肿瘤的综合治疗已显露出端倪。在恶性脑肿瘤的综合治疗中，肿瘤内科所扮演的角色日显重要。随着精确放射治疗，生物靶区的确立，新型化疗药物和靶向药物的联合应用，恶性脑肿瘤的治疗必将更上新的台阶。结语谢谢