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(wú)聲。——英國(guó)2、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?ài)·科克3、法律是最保險(xiǎn)的頭盔?！獝?ài)·科克4、一個(gè)國(guó)家如果綱紀(jì)不正，其國(guó)風(fēng)一定頹敗。——塞內(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?！蹇朔伟┑膬?nèi)科治療肺癌的內(nèi)科治療1、戰(zhàn)鼓一響，法律無(wú)聲?！?guó)2、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?ài)·科克3、法律是最保險(xiǎn)的頭盔?！獝?ài)·科克4、一個(gè)國(guó)家如果綱紀(jì)不正，其國(guó)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(jìn)展非小細(xì)胞肺癌

內(nèi)科治療研究進(jìn)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(jì)男:75-79歲肺癌發(fā)病達(dá)高峰女:70-74歲肺癌發(fā)病達(dá)高峰意大利：65歲以上肺癌患者大約占60%我國(guó)肺癌發(fā)病率40歲以后上升，70歲達(dá)高峰鱗癌(30%)男性最常見(jiàn)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(dá)具有解毒和抗氧化特性的基因編碼蛋白非小細(xì)胞肺癌(NSCLC)病理類型腺癌(30-50%)在女性和不吸煙者中最常見(jiàn)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(dá)與小氣道與免疫相關(guān)的基因編碼蛋白K-ras

突變常見(jiàn)支氣管肺泡癌是其一個(gè)亞型大細(xì)胞肺癌(10-25%)原始的、未分化細(xì)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(duì)側(cè)淋巴結(jié)遠(yuǎn)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(jìn)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(yuǎn)道轉(zhuǎn)移(%)I期T1N01015T2N01030II期T1-2N11240IIIA期N21560背景過(guò)去二十年來(lái)，非小細(xì)胞肺癌采用輔助化療，特別是早期的非小細(xì)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(yàn)設(shè)計(jì)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(cè)療效。IALT臨床研究設(shè)計(jì)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(zhǎng)春新堿4mg/m2weeklyor長(zhǎng)春地辛3mg/m2weekly

結(jié)果

化療 對(duì)照

N 932 935中位生存期 50.8months 44.4months中位無(wú)病生存期 40.2months 30.5months5-年生存率 44.5% 40.4%5-年無(wú)病生存率 39.4% 34.3%總生存期ControlChemotherapyYears164286432602774935181308450624775932Atrisk無(wú)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(wú)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(jī)對(duì)照研究結(jié)果，對(duì)IB-III完全切除的NSCLC,輔助化療是標(biāo)準(zhǔn)的治療方法

ASCO2003 IALT(Lehavalier)ASCO2003 JLCRG(Kato)ASCO2004 JBR10(Winton)ASCO2004 CALGB(Strauss)有待解決的問(wèn)題選擇哪些患者？選擇何種化療方案？化療的時(shí)機(jī)？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(píng)分0-13.高危因素的IA期腫瘤>2cm低分化分子標(biāo)記物指標(biāo)－－Dr.Strass的個(gè)人觀點(diǎn)禁忌癥：1.IA期2.全肺切除術(shù)？3.年齡>75歲？4.細(xì)支氣管肺泡癌5.有合并癥6.術(shù)后恢復(fù)慢化療的時(shí)機(jī)？

一般術(shù)后4-6周開(kāi)始化療?；熤芷?？推薦4個(gè)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(wú)疾病進(jìn)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(wú)進(jìn)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(zhǎng)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(duì)術(shù)后輔助化療進(jìn)行修訂√IA期:T1N0不進(jìn)行輔助治療√IB期:T2N0推薦術(shù)后進(jìn)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(duì)于臨床分期N2陰性而術(shù)后病理分期N2陽(yáng)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(duì)于術(shù)后輔助化療的推薦級(jí)別：20042A

20051級(jí)

√對(duì)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(jìn)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(duì)于臨床分期N2陰性而術(shù)后病理分期N2陽(yáng)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(jìn)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(zhǎng)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(wú)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(zhǎng)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(zhǎng)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(jí)4級(jí)%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(jí)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(jī)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(jī)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(fèi)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(zhǔn)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(jì)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(jī)III期臨床試驗(yàn)1.JCO2004;2.C.Camps,etal.ProcAmSocClinOncol2003;625.(abstr2514)

非小細(xì)胞肺癌

內(nèi)科治療研究進(jìn)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(diǎn)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(xì)胞凋亡)PI3-K表皮生長(zhǎng)因子受體酪氨酸激酶(EGFR-TK)激活:

癌變的關(guān)鍵驅(qū)動(dòng)因素EGFR-TKEGFR配體RASRAFSOSGRB2PTENAKTSTAT3MEK基因轉(zhuǎn)錄細(xì)胞周期進(jìn)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(jī)、雙盲、全球性研究。在歐洲、日本、南美洲等地進(jìn)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(guó)的30個(gè)試驗(yàn)中心下進(jìn)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?yàn)?00mg/d的療效無(wú)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(jī)對(duì)照III期臨床試驗(yàn)ISEL：Bankground共入組1692NSCLC病人(2003.7.15-2004.8.2)在28個(gè)國(guó)家的210個(gè)中心開(kāi)展其中342例病人(22%)為東方人主要終點(diǎn)指標(biāo)：總體生存期次要終點(diǎn)指標(biāo)（治療失敗時(shí)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(jì)對(duì)東方人進(jìn)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(jìn)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(diǎn)

(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