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1、TargetedTherapyinNon-Small-CellLungCancer非小細胞肺癌的標靶治療胸腔內科施穎銘主要癌症每十萬人口死亡數FryWA,etal.Cancer.1996;77:1953.YearsNSCLC-SurvivalbyStageNSCLCTreatmentEarlystageLocallyadvancedMetastasticSurgeryCT+surgeryCT+RTCCRTSurgery+CTCTTargetIa,IbIIa,IIbIIIaIIIbnocy+effusionIIIbcy+eff
2、usionIVcurativeintentpalliativeintentmetastasectomyThe“FirstGeneration”AgentsMethotrexate,cyclophosphamide,vincristine,anddoxorubicin—wereessentiallyinactiveinNSCLC,despitebeingwidelyusedinthe1970sand1980s.Thorax.58(4):352-6,2003Apr.The“2ndGeneration”AgentsCisplati
3、n,ifosfamide,mitomycin,vindesine,vinblastine,andetoposideinlate1980.Thorax.58(4):352-6,2003Apr.The“3rdGeneration”AgentsPaclitaxel,docetaxel,gemcitabineandvinorelbineemergedinthechemotherapyofNSCLCInthemiddle1990s.Cisplatin-baseddoubletsarethemainstayofchemotherapyf
4、oradvancedNSCLC.Thorax.58(4):352-6,2003Apr.ASCO.NSCLCtreatmentguideline,2003The“4thGeneration”AgentsTargetedtherapyinearly2000s.Thorax.58(4):352-6,2003Apr.TargetValidationThetargetshouldbepresentandfunctionallyabnormalrelativetonormaltissue.Thetargetshouldinfluence
5、tumorbiologymanifestedthroughdifferencesinptoutcome.Interferingwithtargetfunctioninmodelsystemsshouldaltertumorbiology.Interferingwiththetargetintheclinicsshouldalterptsurvivalorreverseclinicalsymptomsassociatedwiththecancerundertreatment.EpidermalGrowthFactorRecep
6、torInhibition(EGFRI)EGFRexpressioninhumantumoursNSCLC40-80%Prostate40-80%Gastric33-74%Headandneck90-100%Breast14-91%Colorectal25-77%Pancreatic30-50%Ovarian35-70%InvasionMetastasisLate-stagediseaseChemotherapyresistanceHormonaltherapyresistancePooroutcomeTumoursshow
7、ing highEGFRexpressionHighexpression generallyassociated withInhibitionoftheEGFRsignalingpathwayMetastasisProliferation/maturationSurvival/apoptosisAngiogenesisMAPKMEKGenetranscriptionCell-cycleprogressionPI3-KRASRAFSOSGRB2PTENAKTSTATKpYMG1SpYpYKEGFRG2HER1Baselga20
8、02Tyrosinekinaseinhibitors(TKIs)Gefitinib(Iressa,艾瑞莎)Erlotinib(Tarceva，得舒緩)IDEAL1&2:designschemaRandomisationIRESSA®250mgoncedailyIRESSA®500mgonc
