肺癌的內(nèi)科治療課件

肺癌的內(nèi)科治療1、戰(zhàn)鼓一響，法律無聲?！?、任何法律的根本；不，不成文法本身就是講道理……法律，也----即明示道理。——愛·科克3、法律是最保險的頭盔?！獝邸た瓶?、一個國家如果綱紀不正，其國風(fēng)一定頹敗?！麅?nèi)加5、法律不能使人人平等，但是在法律面前人人是平等的。——波洛克肺癌的內(nèi)科治療肺癌的內(nèi)科治療1、戰(zhàn)鼓一響，法律無聲?！?、任何法律的根本；不，不成文法本身就是講道理……法律，也----即明示道理?！獝邸た瓶?、法律是最保險的頭盔?！獝邸た瓶?、一個國家如果綱紀不正，其國風(fēng)一定頹敗?！麅?nèi)加5、法律不能使人人平等，但是在法律面前人人是平等的。——波洛克

呼吸病區(qū)：王潔肺癌內(nèi)科治療進展非小細胞肺癌

內(nèi)科治療研究進展NSCLC:NSCLC的流行病學(xué)及診斷分期早期可手術(shù)切除NSCLC的輔助化療局部晚期不可手術(shù)切除NSCLC同步化放療IIIb(胸水)/IV期NSCLC姑息化療分子靶向治療SCLC的全身治療2005EstimatedUSCancerDeaths*ONS=Othernervoussystem.Source:AmericanCancerSociety,2005.Men

295,280Women

275,000

27% Lungandbronchus 15% Breast 10% Colonandrectum 6% Ovary6% Pancreas 4% Leukemia3% Non-Hodgkin

lymphoma 3% Uterinecorpus2% Multiplemyeloma2% Brain/ONS22%AllothersitesLungandbronchus 31%Prostate 10%Colonandrectum 10%Pancreas 5%Leukemia 4%Esophagus 4%Liverandintrahepatic 3%

bileductNon-Hodgkin3%LymphomaUrinarybladder 3%Kidney 3%Allothersites24%高齡肺癌發(fā)病概況肺癌患者年齡70歲占40%加拿大2002年統(tǒng)計男:75-79歲肺癌發(fā)病達高峰女:70-74歲肺癌發(fā)病達高峰意大利：65歲以上肺癌患者大約占60%我國肺癌發(fā)病率40歲以后上升，70歲達高峰鱗癌(30%)男性最常見主要與吸煙相關(guān)（劑量相關(guān)）局部播散傾向痰中較易檢出高表達具有解毒和抗氧化特性的基因編碼蛋白非小細胞肺癌(NSCLC)病理類型腺癌(30-50%)在女性和不吸煙者中最常見的肺癌類型病變常發(fā)于外周全世界發(fā)病率上升高表達與小氣道與免疫相關(guān)的基因編碼蛋白K-ras

突變常見支氣管肺泡癌是其一個亞型大細胞肺癌(10-25%)原始的、未分化細胞病變常發(fā)于外周高度轉(zhuǎn)移傾向NSCLC分期淋巴結(jié)主支氣管對側(cè)淋巴結(jié)遠處器官轉(zhuǎn)移胸壁侵犯IV期0期IA期IIB期IIIB期

NSCLC:

分期及生存Mountain.Chest.1997;1710-1717.StageIStageIIStageIIIStageIV020406080100PercentsurvivorsStageatDiagnosisStIStIIStIIIAStIIIBStIV肺癌

內(nèi)科治療研究進展

NSCLC:

NSCLC的流行病學(xué)及診斷分期早期可手術(shù)切除NSCLC的輔助化療局部晚期不可手術(shù)切除NSCLC同步化放療IIIb(胸水)/IV期NSCLC姑息化療

分子靶向治療SCLC的全身治療NSCLC：復(fù)發(fā)形式期別胸部(%)遠道轉(zhuǎn)移(%)I期T1N01015T2N01030II期T1-2N11240IIIA期N21560背景過去二十年來，非小細胞肺癌采用輔助化療，特別是早期的非小細胞肺癌，由于缺乏有力的證據(jù)，治療效果仍然不明確。第一代的臨床試驗設(shè)計得不完善，使用的藥物有效率不高。第二代的臨床研究以老的化療藥物與鉑類聯(lián)用，但樣本量太小，不足以檢測療效。IALT臨床研究設(shè)計RChemotherapyControlThoracicRadiotherapy60Gy**optional,butpredefinedbyNstageateachcenter

完全切除NSCLC

ASCO,Chicago,June2,2003

化療方案

順鉑80mg/m2q3weeksx4or100mg/m2q4weeksx3or4or120mg/m2q4weeksx3

+Vp-16100mg/m2x3dayspercycleorNVB30mg/m2weeklyor長春新堿4mg/m2weeklyor長春地辛3mg/m2weekly

結(jié)果

化療 對照

N 932 935中位生存期 50.8months 44.4months中位無病生存期 40.2months 30.5months5-年生存率 44.5% 40.4%5-年無病生存率 39.4% 34.3%總生存期ControlChemotherapyYears164286432602774935181308450624775932Atrisk無病生存ControlChemotherapyYears141244365505655935158272397544684932Atrisk

總結(jié)

5年總生存率提高4.1%（40.4%Vs44.5%）

p<0.03

5年無病生存提高5.1%(34.3%VS39.4%，p<0.003)

致死性毒性0.8%CorrelationbetweenstageandactivityofChemotherapyStageIA-12%IB=32%II=26%IIIA=18%ALPIIALTNCI-CCALGBANITA-positive-negative-nottested早期(I-IIIa)完全切除的NSCLC

基于4組隨機對照研究結(jié)果，對IB-III完全切除的NSCLC,輔助化療是標準的治療方法

ASCO2003 IALT(Lehavalier)ASCO2003 JLCRG(Kato)ASCO2004 JBR10(Winton)ASCO2004 CALGB(Strauss)有待解決的問題選擇哪些患者？選擇何種化療方案？化療的時機？化療周期？分子靶向藥物如何與化療結(jié)合？選擇哪些患者？適應(yīng)癥：1.IB,II,IIIA期患者2.PS評分0-13.高危因素的IA期腫瘤>2cm低分化分子標記物指標－－Dr.Strass的個人觀點禁忌癥：1.IA期2.全肺切除術(shù)？3.年齡>75歲？4.細支氣管肺泡癌5.有合并癥6.術(shù)后恢復(fù)慢化療的時機？

一般術(shù)后4-6周開始化療?；熤芷?？推薦4個化療周期

新輔助治療增加腫瘤的手術(shù)控制率減少腫瘤的微轉(zhuǎn)移

新輔助化療新輔助治療：SWOG9900

泰素225mg/m2卡鉑AUC=6X3cycles

手術(shù)RANDOMIZE手術(shù)StageIB,IIandIIIA(T3N1)N=374/600PrimaryEndpoint:33%improvementintheexpected2.7medianssurvivalforsurgeryalonePistersK,etalASCOAbstract#7012:無疾病進展生存期HR=0.80[0.59-1.07],p=0.140%20%40%60%80%100%01224364860MonthsAfterRegistrationmedianF/U31moSWOG9900總生存

HR=0.84[0.60-1.18],p=0.320%20%40%60%80%100%01224364860MonthsAfterRegistration

SWOG9900Median1yr2yrPreop47mo82%69%Control40mo79%63%MedianFU31months

可切除的N2NSCLC:INT0139TrialCisplatin,50mg/m2IVPBd1,8,29,36Etoposide,50mg/m2IVPBd1-5,29-33ThoracicRT,45Gy(1.8Gy/d),begind1疾病無進展者

手術(shù)繼續(xù)放療至61Gy

鞏固化療cisplatinplusetoposideX2cycles誘導(dǎo)治療AlbainKSetalASCOAbstract#7014CT/RT/S

145/202CT/RT

155/194Logrankp=0.24Hazardratio=0.87(0.70,1.10)%Alive0255075100MonthsfromRandomization01224364860Dead/Total

INT0139UpdateOverallSurvivalMedianFU81months

OverallSurvivalbyPathologicNodalStatusNosurgery(n=38)PathologicN0(n=76)PathologicN1-3,unknown(n=88)p<0.0001%Alive0255075100MonthsfromRandomization020406080100120

INT0139Update肺葉切除的總生存SubsetVSMatchedCT/RTSubset

%Alive0255075100MonthsfromRandomization01224364860///////////////////////logrank

p=0.002CT/RT/S

57/90CT/RT

74/90Dead/TotalMS34mos.22mos.5yrOS36%18%CT/RT/SCT/RT

INT0139MonthsfromRandomization全肺切除的總生存SubsetVSMatchedCT/RTSubset

MS3yrOS5yrOS19mos.36%22%CT/RT/SCT/RT%Alive025507510001224364860//////////29mos.45%24%Dead/TotalCT/RT/S38/51CT/RT42/51logrankp=NS

INT0139Update

部分N2病人可能為外科手術(shù)受益者：外科因素:能行肺葉切除的N2病人腫瘤因素：能淋巴結(jié)完全清掃者有更長的生存期RoleforposttreatmentPET?

Restagingmediastinoscopy/VATS/EUS?

N2病人是否外科治療需肺癌多學(xué)科討論決定局部晚期（N2）NSCLC

Message:Surgicalresectiondoesnotofferasurvivaladvantageoverradiotherapyinpatientswithclinicallyoperable(INT0319)orinoperable(EORTC8941)stageIIIN2disease.Concurrentchemoradiotherapyisthestandardofcare.Pneumonectomiesshouldbeavoided.

LocallyAdvancedN2LungCancer2005NCCN臨床腫瘤指南

多學(xué)科治療：輔助化療

基于IALT研究，對術(shù)后輔助化療進行修訂√IA期:T1N0不進行輔助治療√IB期:T2N0推薦術(shù)后進行輔助化療√II期:T1-2N1推薦術(shù)后輔助化療或放療(2B)+化療√Ⅲ期術(shù)后可選擇單用化療或放療(2B)+化療2005NCCN臨床腫瘤指南

多學(xué)科治療：輔助化療√對于臨床分期N2陰性而術(shù)后病理分期N2陽性者,術(shù)后可以選擇化療或觀察(2B)或聯(lián)合放化療(2B)√T4N0-1同葉內(nèi)衛(wèi)星結(jié)節(jié)者,術(shù)后需輔助化療√

輔助化療應(yīng)選擇含鉑的二藥聯(lián)合方案術(shù)后輔助化療

基于CALGB9633和BR10研究√對于術(shù)后輔助化療的推薦級別：20042A

20051級

√對IA(T1N0)者完全切除術(shù)后：2004觀察

2005高危者：化療(2B)√化療方案含鉑二藥聯(lián)合方案肺癌

內(nèi)科治療研究進展

NSCLC:

NSCLC的流行病學(xué)及診斷分期早期可手術(shù)切除NSCLC的輔助化療局部晚期不可手術(shù)切除NSCLC同步化放療IIIb(胸水)/IV期NSCLC姑息化療

分子靶向治療SCLC的全身治療

不能手術(shù)局部晚期NSCLC化放療結(jié)合的方式

Sequential:CTàRT

Concurrent:CT/RT

Combinations:CTàCT/RT

CT/RTàCT

LAMP:RandomizedPhaseIIStudyof3ChemoradiationSchedulesforStageIIINSCLC

Arm1:SequentialChemo/XRT:

CarboAUC6+Pac200mg/m2Q3wksx2XRT63Gy/7wksArm2:InductionChemoConcurrentChemoXRT:

CarboAUC6+Pac200mg/m2Q3wksx2XRT63Gy/7wks+weeklyCarboAUC2+Pac45mg/m2

Arm3:ConcurrentChemoXRTConsolidationChemo:

XRT63Gy/7wks+weeklyCarboAUC2+Pac45mg/m2 CarboAUC6+Pac200mg/m2Q3wksx2LAMP:Pre-TreatmentCharacteristics

CTRT CTCT+RT CT+RTCT (N=92) (N=74) (N=92)Age: <70 74(80%) 53(72%) 69(75%)

70+

18(20%)

21(28%)

23(25%)Gender:

Male

63(68%)

54(73%)

62(67%)

Female 29(32%) 20(27%) 30(33%)KPS:

70-80

25(27%)

23(31%)

22(24%)

90-100 67(73%) 51(69%) 70(76%)%WeightLoss

<5% 67(73%) 47(64%) 66(72%)

5-10%

25(27%)

27(36%)

26(28%)Stage: IIIA 33(36%) 28(38%) 35(38%) IIIB 59(64%) 46(62%) 57(62%)

T/CRT

Historical

1yr 59% 58%2yr 31% 31%Median13.0mo 14.5

T/CT/C/RT

Historical1yr 53% 58%2yr22%31%Median12.8mo 14.5mo____----

T/C/RTT/C

Historical1yr 64% 58%2yr 33% 31%Median16.1mo 14.5mo__--Arm1Arm3Arm2

SWOG9504:TreatmentConcurrentChemoradiationPE: Cisplatin50mg/m2IVd1,8,29,36

Etoposide50mg/m2IVd1-5,29-33RT: 45Gy(1.8Gy/fraction)

16Gyboost(2Gy/fraction)ConsolidationDocetaxel75mg/m2IVX1cycleDocetaxel75-100mg/m2IVX2cycles(every3weeks)GasparLE,etal.ProcAmSocClinOncol2001;20:315a.(abstr&poster1255)PhaseIISWOGTrial(S9504):ResultsSurvival

Median 27mos[18-43mos]1-yearsurvival 76%[67%-85%]2-yearsurvival 54%[43%-64%]3-yearsurvival 40%[24%-55%]0%20%40%60%80%100%012243648MonthsAfterRegistrationSWOG9504Progression-FreeSurvival MedianNEventsinMonths8356 16100%SWOG9504OverallSurvival0%20%40%60%80%012243648MonthsAfterRegistration MedianNEventsinMonths8345 261YearSurvival:76%2YearSurvival:54%3YearSurvival:40%Gaspar:ASCO2001

SWOG9504(PE/RTTXT)

vsSWOG9019(PE/RTPE):

PatientCharacteristics

SWOG9504

SWOG9019

No.Patients 83 50Medianage 60 58Male/Female 61/22 41/9PS:0-1 78 50

2 5 0Stage:n(%)

T4N0-1 31(37) 18(36)

T4N2 22(27) 12(24)

N3 30(36) 20(40)

SWOG9504(PE/RTTXT)

vsSWOG9019(PE/RTPE):

Survival(medianf/u28mos)

SWOG9504

SWOG9019

MedSurv27mos15mos

[95%CI][18–43mos] [10–22mos]Survivalrates

1year76%[67-85] 58%[44-72]

2year54%[43-64] 34%[21-47]

3year40%[24-55] 17%[7-27]4year39%[]17%GasparLE,etal.ProcAmSocClinOncol2001;20:315a.(abstr&poster1255)CurrentStatusofChemoradiotherapyin

StageIIINSCLCRegimenMST(mos)1yr2yrRTtox(3-4)RT1040%15%10%CT->RT1455%30%25%CT/RT1765%35%50%CT->CT/RT1560%40%35%CT/RT->CT*2678%54%<20%

AdaptedfromPisters:ASCO,2000*S9504

2005NCCN臨床腫瘤指南

多學(xué)科治療：輔助化療√對于臨床分期N2陰性而術(shù)后病理分期N2陽性者,術(shù)后可以選擇化療或觀察(2B)或聯(lián)合放化療(2B)√T4N0-1同葉內(nèi)衛(wèi)星結(jié)節(jié)者,術(shù)后需輔助化療√

輔助化療應(yīng)選擇含鉑的二藥聯(lián)合方案肺癌

內(nèi)科治療研究進展

NSCLC:

NSCLC的流行病學(xué)及診斷分期早期可手術(shù)切除NSCLC的輔助化療局部晚期不可手術(shù)切除NSCLC同步化放療IIIb(胸水)/IV期NSCLC姑息化療

分子靶向治療SCLC的全身治療治療原則控制癥狀提高生活質(zhì)量延長生存期聯(lián)合化療作為NSCLC的一線治療GoodPSPatients1990s:Platinum-basedCTstandard

NSCLCCollaborativeGroupBMJ.1995;311:899-909CurrentASCOGuidelines:Platinumdoubletsornon-platinumdoubletsarestandardforadvancedNSCLCptswithgoodPS

Pfisteretal.JClinOncol.2004;22:330-353AdvancedNSCLC

USFDAApprovedTherapies1994–vinorelbine/cisplatinandvinorelbine1998–gemcitabine/cisplatin1998–paclitaxel/cisplatin1999–docetaxel(afterplatinum)2003–docetaxel/cisplatin2003–gefitnib(afterplatinumanddocetaxel)2004–pemetrexed(afterplatinum)2004–erlotinib(after1priorchemotherapy)

NSCLC:一線化療化療VsBSC？有無最好的鉑類聯(lián)合方案？含鉑方案Vs非鉑方案？卡鉑Vs

順鉑？化療＋靶向治療Vs化療

治療長春瑞濱

30mg/m2，第1、8天每3周+最佳支持治療最佳支持治療(BSC)紫杉醇

200mg/m2第1天每3周+BSC最佳支持治療泰索帝

100mg/m2第1天每3周+BSC最佳支持治療吉西他濱1000mg/m2第1、8和15天每4周+BSC最佳支持治療1.00.80.60.40.2003691215182124長春瑞濱最佳支持治療月概率Log-rankp=0.031.00.80.60.40.2003691215182124紫杉醇最佳支持治療月概率Log-rankp=0.041.00.80.60.40.2003691215182124泰索帝最佳支持治療月概率Log-rankp=0.03吉西他濱最佳支持治療月概率Log-rankp=0.84ECOG1594:StudyDesignStratification:Stage:IIIBvsIVPS:0–1vs2WtLoss:5%vs5%CNSMets:

novsyesArmA:Cisplatin+PaclitaxelPaclitaxel:135mg/m2/24hDay1Cisplatin:75mg/m2day2q3wkArmD:Carboplatin+PaclitaxelPaclitaxel:225mg/m2/3hDay1Carboplatin:AUC6Day1ArmC:Cisplatin+DocetaxelDocetaxel:75mg/m2Day1Cisplatin:75mg/m2Day1ArmB:Cisplatin+GemcitabineGemcitabine:1000mg/m2Days1,8,15Cisplatin:100mg/m2Day1q4wkq3wkq3wkSchillerJH,etal.ProcASCO36thAnnualMeeting.2000;19:abstr2.SchillerJH,etal.NEnglJMed.2002;346:92-98.RANDOMIZEE1594ECOG1594:AnalysisofToxicity2266762115627280102030405060703級4級%泰素/順鉑吉西他濱/順鉑多西紫杉醇/順鉑泰素/卡鉑PS＝2的病人的3-4級毒性發(fā)生百分比

TAX326StudyDesign

（泰素蒂＋鉑類VsNVB+鉑類）R

A

N

D

O

M

I

Z

E

StratifiicationFactors:StageofDiseaseIIIBvs.IVandRegionUS/Canada

SouthAmerica

Europe/LebanonIsrael

SouthAfrica/Australia

NewZealandResponseassessmentevery2cycles泰素蒂75mg/m2IV

卡鉑AUC6

IV

Q3wks(TCb)諾維苯25mg/m2IVD1,8,15&22

順鉑100mg/m2IV

D1Q4wks(VC)泰素蒂75mg/m2IV

順鉑75mg/m2IV

Q3wks（TC）vs.or

TAX326OverallSurvival

Fossellaetal.JClin.Oncol.2003;21:3016-3024.100806040200Survival(%)03691215182124273033Time(months)TCVC100806040200Survival(%)03691215182124273033Time(months)P=.657,adjusted

log-ranktestTCbVC1-ysurvival46%vs41%withVC2-ysurvival21%vs14%withVCMediansurvival:11.3vs10.1moP=.044,adjustedlog-ranktest1-ysurvival38%vs40%withVC2-ysurvival18%vs14%withVCRANDOMIZEProtocolSchemaStratificationWeightlossinprevious6months:

<5%vs≥5%Diseasestage:IIIBwitheffusion,IVBrainmetastases:PresenceorabsenceGemcitabine1000mg/m2d1,8Paclitaxel200mg/m2d1q21daysGemcitabine1000mg/m2d1,8CarboplatinAUC5.5d1q21daysArmA:健擇+卡鉑ArmB:健擇+泰素ArmC:泰素+卡鉑Paclitaxel225mg/m2d1CarboplatinAUC6.0d1q21days

含鉑方案Vs非鉑方案ASCOAbstract#7025

CoalitionTrialSurvivalbyTreatmentArmMeta-Analysis:1-Y生存90年代新化療藥物聯(lián)合作為非鉑方案(N=3,307)d’Addarioetal.JClinOncol.2005;23:2926-2936.卡鉑Vs順鉑

Doesitmatterforadvanceddisease?NSCLC:90年代新化療藥物＋順鉑或卡鉑的隨機研究

NZojwalla,2004RegimenNMedianSurvivalFossellaetal,JCO2003Cis+DocetaxelCarbo+Docetaxel40840611.39.4Roselletal,AnnOnc,2002Cis+PaclitaxelCarbo+Paclitaxel3093099.88.5Schilleretal,NEJM,2002Cis+PaclitaxelCarbo+Paclitaxel2882907.88.1Mazzantietal,LungCa,2003Cis+GemcitabineCarbo+Gemcitabine625810.410.8Zatloukaletal,LungCa,2003Cis+GemcitabineCarbo+Gemcitabine87898.88.0

NSCLC:90年代新化療藥物＋順鉑或卡鉑的隨機研究

NZojwalla,2004MONTHSCarboplatin Cisplatin

N=1152

N=11548.79.8*Noothersuchtrials1992–2003;**2trialswithpaclitaxel,1withdocetaxel,2withgem.Carbovs.CisMeta-analysisOverallsurvivalwithcisplatin-basedcomparedwithcarboplatin-basedchemotherapyHotta,K.etal.JClinOncol;22:3852-38592004Carbovs.CisMeta-analysisOverallsurvivalwithcisplatinplusnewagentscomparedwithcarboplatinplusnewagentsHotta,K.etal.JClinOncol;22:3852-38592004一線化療:

怎樣選擇最好的聯(lián)合方案?

療效與生存?

生活質(zhì)量?

毒性?病人的基礎(chǔ)狀態(tài)?費用?WeeklyPaclitaxel

withCarboplatin

FollowedbyMaintenancePaclitaxelvs.Observation

forAdvancedNSCLCArm3Arm2Arm1Paclitaxel150mg/m2+CarboplatinAUC=2(weeklyfor6wks,2wksoff),thenPaclitaxel100mg/m2+CarboplatinAUC=2(weeklyfor6wks,2wksoff)*Paclitaxel100mg/m2+CarboplatinAUC=2(weeklyfor3wks,4thwkoff)*Paclitaxel100mg/m2(weeklyfor3wks,4thwkoff)+CarboplatinAUC=6(d1)*SCHEMABelanietal,JCO21:2933-39,2003*PatientswithCR,PRorSDrandomizedtopaclitaxel70mg/m2/wkorobservation

WeeklyPaclitaxelwithCarboplatin

FollowedbyMaintenancePaclitaxelvs.ObservationforAdvancedNSCLCEfficacy/Toxicity

Arm1

Arm2Arm3MedianSurvivalTime 49wks 31wks40wks(p=0.077vs1)(p<0.45vs1)

MedianTTP 30wks 21wks27wks(p=0.01vs1)(p<0.73vs1)

1-yr.Survival 47% 31% 41%(p<0.01vs1)(p<0.20vs1)

Neutropeniagrade4 22% 8% 19%Thrombocytopeniagrade4 5% 2% 1%Neuropathygrade3 5%3% 13%

Belanietal,JCO21:2933-39,2003STRATIFYECOGPS0&1vs2StageIIIBvsIVRANDOMIZEWeeklyPaclitaxel100mg/m2/weekx3CarboplatinAUC=6(Cycleduration4weeks,Total4cycles)StandardPaclitaxel225mg/m23CarboplatinAUC=6day1(Cycleduration3weeks,Total4cycles)TAXMEN12:PhaseIIIStudySchema*MaintenanceTherapyPaclitaxel70mg/m2/week3weekson,1weekoffUntilDiseaseProgression*ForpatientswithCR/PRorSDonbotharmsTaxmen12:Kaplan-MeierEstimates

PatientSurvival1.00.90.80.70.60.50.40.30.20.10.0081624324048566472808896104112120128136144152160WeeklyStandardProportionofPatientsWhoSurvivedTime(Weeks)Message:

Firstsetofevidencesuggestingwearemoving towardcustomizedchemotherapyinlungcancer.

Dilemma:

Willpredictivemarkersofresponsetotheoriginaltreatmenttranslateintoasurvivalbenefitintheeraofsecondandthirdlinetherapies?Finally MTwithwklypaclitaxeldemonstratessignificantimprovementinsurvival(76.6wkswithMTvs.49.6wkswithoutMT,P=0.016)---Role? Canthisconceptbevalidatedwithotheragents?

MetastaticLungCancerMessage:Aplatinumoranon-platinumdoubletisthestandardofcareforthefirstlinetreatmentofgoodperformancestatuspatients.Dilemma:

WhowillswitchtoanonplatinumregimeningoodPSpatients!!!!

OvershadowedbyefficacyofChemotherapy/Bevacizumabcombinationinselectpatientswithnon-squamouscarcinoma

MetastaticLungCancerFDA批準的NSCLC二線治療藥物DocetaxelPemetrexedErlotinibNSCLC

二線治療：泰素蒂

VsBSCShepherdetal2000

中位生存期(月)

1年

生存率(%) Logrank:p=0.01泰素蒂75mg/m2(n=55)最好的支持治療(n=49)036912151821累計的概率0.00.20.40.60.81.0

泰素蒂75mg/m27.537最好的支持治療

4.612月Hanna1Camps2

Alimta和泰索帝及泰索帝單藥3周和每周方案的肺癌2線隨機III期臨床試驗1.JCO2004;2.C.Camps,etal.ProcAmSocClinOncol2003;625.(abstr2514)

非小細胞肺癌

內(nèi)科治療研究進展

NSCLC的流行病學(xué)及診斷分期輔助化療同步化放療姑息化療一線化療二線/三線化療分子靶向治療化療預(yù)防TargetedTherapy:Validatesthe“TargetedTherapy”developmentstrategyBut,thusfar,offermarginalbenefit抗腫瘤生物靶點治療(臨床)EGFRHER2TKgefitinib/erolinib(NSCLC)EGFR單抗(人)Herceptin(乳癌/Chemo協(xié)同),C225(結(jié)直腸癌,乳癌,NSCLC)VEGF單抗Avastin(結(jié)直腸癌,NSCLC)存活

(抗細胞凋亡)PI3-K表皮生長因子受體酪氨酸激酶(EGFR-TK)激活:

癌變的關(guān)鍵驅(qū)動因素EGFR-TKEGFR配體RASRAFSOSGRB2PTENAKTSTAT3MEK基因轉(zhuǎn)錄細胞周期進展DNAMycMycCyclinD1JunFosPPMAPK增生/成熟放化療耐藥性血管形成轉(zhuǎn)移Balabanetal1996;Akimotoetal1999;Wells1999;Woodburn1999;

Hanahan2000;Raymondetal2000CyclinD1pYpYpYGefitinib(IRESSATM,ZD1839)PhaseIImonotherapytrials

inadvancednon-small-cell

lungcancer(NSCLC)IDEAL1(Trial16)

IDEAL2(Trial39)IDEAL=IRESSADoseEvaluationinAdvancedLungCancerIDEAL1&2:designschemaGefitinib250mgoncedailyGefitinib500mgoncedaily

Received

1or2(IDEAL1)

or>2(IDEAL2)

previous

chemotherapy

regimensContinuegefitinibuntildisease

progressionorunacceptabletoxicityPrimaryendpointsPatientsResponserate(bothtrials)Safetyprofile(IDEAL1)Symptomrelief(IDEAL2)IDEAL1–globaltrialincludingJapan,Europe,Australia,andSouthAfrica(JPN=209)IDEAL2–USAtrialNatale&Zaretsky2002

RANDOMIZEDDGefitinib(Iressa)治療晚期NSCLC的研究(IDEAL-1,2)IDEAL：IressaDoseEvaluationinAdvancedLungCancer

IDEAL-1：該研究是一隨機、雙盲、全球性研究。在歐洲、日本、南美洲等地進行，比較不同劑量的Irassa治療晚期NSCLC。IDEAL-2：Iressa作為三線藥物單藥治療晚期NSCLC的研究。該研究在美國的30個試驗中心下進行。Gefitinib作為三線藥物治療

晚期NSCLC的研究SeminOncol.2003;30(1Suppl1):30-85154疾病控制率(％)1918有效率（％）500mg/d250mg/dIDEAL-1N＝2103543癥狀改善率(％)912有效率（％）500mg/d250mg/dIDEAL-2N＝216Gefitinib作為三線藥物治療

晚期NSCLC的Ⅱ期研究Oncologist.2003;8(4):303-6.

7.04.58.9中位有效期(月)10.67.913.6有效率（％）兩組合并(n=142)500mg/d(n=76)250mg/d(n=66)結(jié)論：Gefitinib用于鉑類和多西紫杉醇治療失敗的晚期NSCLC病人，推薦結(jié)論是250mg/d。因為500mg/d的療效無增加，但毒性更大。ISEL:IRESSAsurvivalevaluationinlungcancer(Trial709)曾接受1-2種化療方案的晚期NSCLC患者接受吉非替尼(易瑞沙)與最佳支持治療并安慰劑隨機對照III期臨床試驗ISEL：Bankground共入組1692NSCLC病人(2003.7.15-2004.8.2)在28個國家的210個中心開展其中342例病人(22%)為東方人主要終點指標：總體生存期次要終點指標（治療失敗時間，客觀緩解和生活質(zhì)量），2005年2月的安全性情況預(yù)先設(shè)計對東方人進行亞組分析IRESSA

(250mg/day)1oend-pointSurvival2oend-pointsTTFORRQoL,symptomsSafetyExploratoryend-pointTumourbiomarkeranalysis(egEGFR)1692patientsin210centersacross28countriesRandomized(2:1ratio)Placebo

+BSCCT,chemotherapy;BSC,bestsupportivecare;EGFR,epidermalgrowthfactorreceptor;TTF,timetotreatmentfailure;ORR,objectiveresponserate;QoL,qualityoflifePatientsLocallyadvancedormetastaticNSCLC1or2prior

CTregimensIntoleranttomostrecentCTregimenorprogression<90daysoflastCTcycleISELtrialdesign0246810121416Time(months) Atrisk: 1692134787748525210431Median,months1-yearsurvival,%Log–rankHR(95%CI),0.89(0.77,1.02);p=0.087

Coxregressionanalysis,p=0.030

IRESSA5.627Placebo5.1210.00.20.40.60.81.0Proportion

survivingIRESSAPlaceboCI,confidenceinterval;HR,hazardratioMedianfollow-up:7months(range3–15);58%deathsISEL:survivalintheoverallpopulationMedian,months1-yearsurvival,%Log–rankHR(95%CI),0.84(0.68,1.03);p=0.089

Coxregressionanalysis,p=0.033 IRESSA6.330Placebo5.418Time(months) Atrisk: 81266944626214566181IRESSAPlacebo02468101214160.00.20.40.60.81.0Proportion

survivingISEL:Survivalinthe

AdenocarcinomaPopulation169210515392781294917IRESSAPlacebo

IRESSAPlaceboCoxanalysis

(95%CI)Log–rankOddsratio

(95%CI)MedianTTF,

months3.02.60.82(0.73,0.92)

p=0.0006p=0.002–ORR,

%(n)8.0(77/959)1.3(6/480)–

–7.28(3.1,16.9)

p<0.0001TTF(months) Atrisk: 02468101214160.00.20.40.60.81.0Proportion

without

treatment

failureISEL:significantimprovementinTTFandORRReasonsfortreatmentfailurePatients(%)

IRESSA Placebo6050403020100腫瘤進展（客觀）癥狀加重不良事件其他FactorspredictingGafitinibSensitivityIressaTMpackageinsertLynch:NEJM2004

GGCGGGCCAAACTGCTGGGTGCG

100EGFRproteinexpressionbyimmunohistochemistryEGFRgenecopynumberbyFISHEGFRMutationalstatusSelectionofPatientsforEGFRInhibitors5/5patientswhorespondedtogefitinibhadEGFRmutations4/4patientswhoprogressedongefitinibhadnoEGFRmutationsPaez:ScienceExpressRep2004.CharacteristicAdenocarcinomaOtherNSCLCFemaleMaleJapaneseAmerican%withMutation(n)

21%(15/70)2%(1/49)20%(1/45)9%(7/74)26%(15/58)2%(1/61)Isabathandashoweralwaysbetterthaneitheralone?

貝伐單抗（Bevacizumab）+Chemotherapy晚期NSCLC:靶向治療聯(lián)合化療有歷史意義的一步？

RANDOMIZEEligibility:NopriorRxStageIIIBorIV

Non-SqCCaECOGPS0-1NoCNSmets卡鉑:AUC=6泰素:200mg/m2Q3weeks卡鉑:AUC=6泰素:200mg/m2貝伐單抗:15mg/kgQ3weeks

ECOGTrial(E4599):rhuMabVEGF(貝伐單抗Bevacizumab)在晚期NSCLC(Non-Squamous)Sandler:LBA,ASCO05Samplesizeof842patientsfor80%powertodetecta25%improvementinmediansurvival(8to10mos.)病人特點

(eligiblepatients)90%91%Caucasian50%58%Male40%38%ECOGPS043%44%Age6528%28%Priorwt.loss5%91%91%Measurabledisease13%14%StageIIIBN=424N=431

PCBPC

非血液學(xué)毒性

PC(%n) PCB(%n)

Grade3 Grade3 p-valueHemorrhage（出血） 3(0.7) 19(4.5) <.001

Hemoptysis 1(0.2) 8(1.9) 0.04 CNS 0 4(1.0) 0.03 GI 2(0.5) 5(1.2) NS Other 1(0.2) 4(1.0) NSHypertension（高血壓） 3(0.7) 25(6.0) <.001VenousThrombosis（） 13(3.0) 16(3.8) NSArterialThrombosis 4(1.0) 8(1.9) NS

6mo. 1yr 33% 6% 55% 15%

ECOGTrial(E4599):rhuMabVEGF(Bevacizumab)inAdvancedNSCLC(Non-Squamous)ResponseCategory(Patients)PC(383)PCB(391)CR0.3%1.3%PR9%24