恶性脑肿瘤的化学治疗.ppt

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1、恶性性脑肿瘤的化学治瘤的化学治疗四川省四川省肿瘤医院内科瘤医院内科张智慧智慧Cerebrum and Cerebellum流行病学趋势流行病学趋势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 肿瘤瘤,正常正常脑组织暴露化暴露化疗药物物高渗性高渗性BBBBBB开放开放Bloodbrainbarrierdisrupt

2、ion(BBBD)andintra-arterialmethotrexatebasedtherapyfornewlydiagnosedprimaryCNSlymphoma:TheBBBDConsortiumExperience.2007ASCOAnnualMeetingProceedingsPartI.Vol25,No.18S4institutions：1982-2005，177PCNSLBBBD/IAMTX；2,469proceduresPtsCRPRORRM OS(y)MPFS(y)PFS-5(y)1771014180.2%40%APhaseIITrialInvolvingPatients

3、withRecurrentPCNSLTreatedwithCarboplatin/BBBD,byAddingRituxan(Rituximab),anantiCD-20Antibody,totheTreatmentRegimenPhaseI/IIStudyofCarboplatin,MelphalanandEtoposidePhosphateinConjunctionwithOsmoticOpeningoftheBlood-BrainBarrierandDelayedIntravenousSodiumThiosulfateChemoprotection,inSubjectswithAnapla

4、sticOligodendrogliomaorOligoastrocytomaPhaseIIClinicalTrialofPatientswithHigh-GradeGliomaTreatedwithIntra-arterialCarboplatin-basedChemotherapy,RandomizedtoTreatmentwithorwithoutDelayedIntravenousSodiumThiosulfateasaPotentialChemoprotectantagainstSevereThrombocytopeniaIntra-arterialMelphalan(L-pheny

5、lalaninemustard)AdministeredinConjunctionwithOsmoticBlood-BrainBarrierDisruptioninPatientswithBrainMalignancies:APhaseIStudyNeuro-OncologyBlood-BrainBarrierProgramOregonHealth&ScienceUniversityBloodBrainBarrierandNeuro-OncologyProgram 替尼泊苷替尼泊苷联合尼莫司汀治合尼莫司汀治疗转移性移性脑肿瘤瘤治疗方法：VM26100mg,iv,gtt,D1-3,4周重复ACN

6、U2-3mg/kg,iv,gtt,D1,4-6周重复化疗前20%甘露醇250ml,iv,gtt,DXM10mg,ivACNUACNU共共计4747周期，平均周期，平均VM26VM26共共计4949周期，平均周期，平均中国癌症中国癌症杂志志Vol9,No2,June,1999Vol9,No2,June,1999替尼泊苷替尼泊苷联合尼莫司汀治合尼莫司汀治疗转移性移性脑肿瘤瘤研究对象男性：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替尼泊苷替尼泊苷联合尼莫司汀治合尼莫司汀治疗转

7、移性移性脑肿瘤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替尼泊苷替尼泊苷联合尼莫司汀治合尼莫司汀治疗转移性移性脑肿瘤瘤结果：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替尼泊苷替尼泊苷联合尼莫司汀治合尼莫司汀治疗

8、转移性移性脑肿瘤瘤结果患者存活时间1-17月，平均月超过6个月者11例中国癌症中国癌症杂志志Vol9,Vol9,No2,June,1999No2,June,1999避开避开BBBBBB的方式的方式椎管内化椎管内化疗：主要用于主要用于CNSCNS淋巴瘤，淋巴瘤，脑膜膜转移移肿瘤，白血病的瘤，白血病的脑膜侵犯。膜侵犯。Phase2studyofBCNUandtemozolomideforrecurrentglioblastomamultiforme:NorthAmericanBrainTumorConsortiumstudyNeuro-oncol.2004January;6(1):3337可评价病

9、人数可评价病人数PRSDMTTP(w)PFS-6MS(w)MPFS(w)OS-61Year532211721%341168%26%可评价病人数可评价病人数CRPRMTTP(w)PFS-6(m)42091730.3%Second-linechemotherapywithirinotecanpluscarmustineinglioblastomarecurrentorprogressiveafterfirst-linetemozolomidechemotherapy:aphaseIIstudyoftheGruppoItalianoCooperativodiNeuro-Oncologia(GICNO

10、).JClinOncol.2004Dec1;22(23):4779-862007年ASCO有关Gliomas的文献有36篇病人数病人数可评价病人数可评价病人数PRMPFS(w)MOS(w)PFS-6685959%234043%In grade III patients the median PFS was 42 weeks,the 6 month PFS was 61%the medial overall survival was 60 weeks Conclusion:The combination of bevacizumab and irinotecan is safe and demo

11、nstrates superior activity against malignant gliomas.PhaseIItrialofbevacizumabandirinotecaninthetreatmentofmalignantgliomasAphaseII,randomized,non-comparativeclinicaltrialoftheeffectofbevacizumab(BV)aloneorincombinationwithirinotecan(CPT)on6-monthprogressionfreesurvival(PFS6)inrecurrent,treatment-re

12、fractoryglioblastoma(GBM).J Clin Oncol26:2008(May20suppl;abstr2010bBevacizumabplusirinotecaninrecurrentglioblastomamultiforme JClinOncol.2007Oct20;25(30):4722-9可评价病人数可评价病人数PRPFS-6OS-63557%46%77%Phase II trial of irinotecan and thalidomide in adults with recurrent glioblastoma multiforme可评价病人数可评价病人数C

13、RPRSDMPFS(w)MOS(w)1Year3211119133634%Neuro Oncol.2008 Feb 26 Bevacizumabandirinotecanforrecurrentoligodendroglialtumors.Conclusions:This regimen is effective in recurrent oligodendrogliomas,and the overall tolerance is acceptable.ASCO2009,Abstract205425Pts.CRPRM-PFS(d)MOS(d)6-PFS(ms)20%52%17432842%A

14、SCO2009,Abstract20372009年ASCO有关神经系统肿瘤的文献80余篇AphaseIIstudyofXL184inpatients(pts)withprogressiveglioblastomamultiforme(GBM)infirstorsecondrelapse.Conclusions:XL184at a dose of 175 mg PO qd,has demonstrated substantial activity in ptswith progressive or recurrent GBM.ASCO2009,Abstract204726Pts.PRSDPD6-

15、PFS(ms)38%35%27%(9ptsreceivedbevacizumab)脑胶胶质瘤和瘤和转移性瘤耐移性瘤耐药的研究的研究1)6-1)6-甲基鸟嘌呤甲基鸟嘌呤DNADNA甲基转移酶甲基转移酶 (MGMT)(MGMT)(6-methylguanine-DNA hyltransferase)(6-methylguanine-DNA hyltransferase)2)P-glycoprotein2)P-glycoproteinFruehauf,J.P.et al.Clin Cancer Res 2006;12:4523-4532脑胶胶质瘤和瘤和转移性瘤耐移性瘤耐药的研究的研究Fruehauf

16、,J.P.et al.Clin Cancer Res 2006;12:4523-4532MGMT methylationstatusasaprognosticfactorinanaplasticastrocytomas.Conclusions:MGMT methylation status is an independent prognostic factor together with age in AA.Pts.71/80(88.8%)30/71(M)41/71(UM)MGMT methylationM-PFS(ms)48.638ASCO2009Abstract2052P-gpexpres

17、sioninbraincapillaryendothelialcellssuggeststhatP-gpmayrestrictdrugentryintobraintumorsandthusbeanothermechanismofdrugresistance.K1735cellsK1735cellsMDRThebiologyandmechanismofchemoresistanceofbrainmetastasesTHEUNIVERSITYOFTEXASGRAD.SCH.OFBIOMED.SCI.ATHOUSTON1995BBBD(blood-brainbarrierdisruption)BBB

18、D(blood-brainbarrierdisruption)化化疗高渗性、高渗性、缓激激肽衍生物：衍生物：BBBBBB开放开放选择性开放血瘤屏障性开放血瘤屏障(blood-tumorbarrier,BTB)(blood-tumorbarrier,BTB)克服化克服化疗耐耐药性性多多药耐耐药及逆及逆转MGMTMGMT表达表达预测化化疗疗效，避免无效化效，避免无效化疗。脑胶胶质瘤和瘤和转移性瘤耐移性瘤耐药的研究的研究联合化合化疗提高化提高化疗敏感性敏感性VM-26VM-26和和BCNUBCNU联合合显著提高胶著提高胶质瘤瘤对化化疗的敏感性的敏感性机理：抑制机理：抑制MDR-IMDR-I或或P-g

19、pP-gp过表达表达PCVPCV方案方案显著增著增强多形胶多形胶质母母细胞瘤胞瘤对BCNUBCNU类药制的敏制的敏感性感性机理：机理：肿瘤瘤细胞先暴露于胞先暴露于烷化化剂类药物使瘤物使瘤细胞中胞中AGTAGT（O6-O6-烷基基鸟嘌呤呤-DNA-DNA烷基化基化转酶）活性受抑活性受抑AGTAGT是增是增强肿瘤瘤细胞胞对BCNUBCNU类 药物敏感性的主要物敏感性的主要靶点靶点RandomizedComparisonofIntra-arterialVersusIntravenousInfusionofACNUforNewlyDiagnosedPatientswithGlioblastomaToc

20、omparetheeffectivenessofintra-arterialACNUwithintravenousACNUinnewlydiagnosedpatientswithsupratentorialglioblastoma.ACNU(80mg/m2)onceevery6weeksconcomitantwithradiotherapy.病人数病人数可评价病人数可评价病人数MS(w)PFS(w)Toxicity8482IA5924-IV5645-Journalofneuro-oncology2000,vol.49,no1,pp.63-7020082008年年NCCNNCCN指南指南成人侵成

21、人侵润性低度性低度恶性幕上星形性幕上星形细胞瘤胞瘤/少突胶少突胶质细胞瘤胞瘤辅助化助化疗：高：高剂量替莫量替莫唑胺胺5/285/28方案方案复复发或或进展：展：一一线方案：替莫方案：替莫唑胺胺5/285/28方案（初治）方案（初治）二二线方案：方案：BCUN210mg/m2iv6wBCUN210mg/m2iv6w重复重复;,80mg/m2x36w;,80mg/m2x36w重复；重复；CCNU110mg/m2CCNU110mg/m2口服口服6w6w重复；重复；PCVPCV联合化合化疗成人室管膜瘤：复成人室管膜瘤：复发用用vp-16,vp-16,替莫替莫唑胺胺，亚硝硝脲类，铂及及联合方案合方案原原

22、发性性CNSCNS肿瘤化瘤化疗指南指南多形性胶母多形性胶母细胞瘤胞瘤辅助化助化疗：同步替莫同步替莫唑胺胺75mg/m2daily75mg/m2daily替莫替莫唑胺胺150-200mg/m25/28150-200mg/m25/28方案方案复复发/挽救治挽救治疗：替莫替莫唑胺胺5/285/28方案（初治）方案（初治）Bevacizumab+IrinotecanBevacizumab+IrinotecanBCUN;CCNU;PCVBCUN;CCNU;PCV联合化合化疗间变形星形形星形细胞瘤胞瘤/少突胶少突胶质细胞瘤胞瘤辅助化助化疗：替莫替莫唑胺或胺或亚硝硝脲复复发/挽救治挽救治疗：替莫替莫唑胺胺5

23、/285/28方案（初治）方案（初治）Bevacizumab+IrinotecanBevacizumab+IrinotecanBCUN;CCNU;PCVBCUN;CCNU;PCV联合合原原发性性CNSCNS肿瘤化瘤化疗原原则20082008年年NCCNNCCN指南指南转移性移性脑肿瘤局限瘤局限1-31-3或多或多发3 3个以上个以上对原原发肿瘤有效的瘤有效的药物物替莫替莫唑胺胺5/285/28方案（器官特异性治方案（器官特异性治疗）卡培他卡培他宾，大，大剂量量MTX(MTX(乳腺癌，淋巴瘤），乳腺癌，淋巴瘤），ToptecanToptecan（肺癌）（肺癌）癌性癌性脑膜炎膜炎采用采用对脑组织穿

24、透能力穿透能力强的的药物；物；椎管内化椎管内化疗（脂（脂质体体cytarabine,MTXcytarabine,MTX，cytarabine,Thiotepa)cytarabine,Thiotepa)大大剂量量MTXMTX治治疗淋巴瘤性淋巴瘤性脑膜炎膜炎原原发性中枢神性中枢神经系系统淋巴瘤淋巴瘤大大剂量或更高量或更高剂量，或量，或联合化合化疗复复发或或进展：展：再次大再次大剂量量MTXMTX美美罗华+替莫替莫唑胺胺 美美罗华；ToptecanToptecan替莫替莫唑胺胺MVPMVP铂类，大，大剂量量cytarabine,DEXcytarabine,DEX20082008年年NCCNNCCN指

25、南指南转移性移性CNSCNS肿瘤化瘤化疗原原则恶性性脑肿瘤是以外科手瘤是以外科手术、放射治、放射治疗为主主的的综合治合治疗，传统的化的化疗药物物疗效有限，只能使效有限，只能使部分患者受益，伴随着各部分患者受益，伴随着各类新新药的的诞生，特生，特别是是靶向靶向药物和生物物和生物酶抑制抑制剂的的应用，用，恶性性脑肿瘤的瘤的综合治合治疗已已显露出端倪。在露出端倪。在恶性性脑肿瘤的瘤的综合治合治疗中，中，肿瘤内科所扮演的角色日瘤内科所扮演的角色日显重要。随着精重要。随着精确放射治确放射治疗，生物靶区的确立，新型化，生物靶区的确立，新型化疗药物和物和靶向靶向药物的物的联合合应用，用，恶性性脑肿瘤的治瘤的治疗必将更必将更上新的台上新的台阶。结 语谢谢