S1治疗胃癌的国外进展课件

替吉奥治疗胃癌的进展

徐建明军事医学科学院307医院肿瘤中心

替吉奥治疗胃癌的进展1试验背景—替吉奥胶囊

替吉奥胶囊（S-1），是日本大鹏药品工业株式会社研制的一种口服氟脲嘧啶类衍生物。1999年在日本上市，在日本已取得胃癌、结直肠癌、头颈癌、肺癌、胰腺癌、乳腺癌、胆管癌等7个适应症。

2005年，S-1获得SFDA批准进行胃癌、结直肠癌、头颈癌临床试验，其中胃癌临床试验已完成，将于近日获得进口批准。结直肠癌于2006年－2007年完成I期临床试验，目前将进一步进行II期探索更佳治疗方案，为III期报批试验做准备。

S-1治疗晚期结直肠癌的疗效：

1994-2001年，单药一线治疗：ORR

16.7%—37.4%，提示S-1单药治疗不亚于奥沙利铂及CPT-11等药（单药疗效7.8～33.3%）

2004-2007年，S-1/LVI/II期临床试验(日本)一线治疗：ORR

57.1%，TTP

203天，疗效良好，值得进一步探索。试验背景—替吉奥胶囊替吉奥胶囊（S-1），是日本大鹏药品工2S-1是一种口服氟尿嘧啶类衍生物，组成：替加氟(FT;5-FU前体药物)：吉美嘧啶(CDHP)：奥替拉西钾(Oxo)=1：0.4：1口服亚叶酸钙(LV)可增强S-1的抗肿瘤活性。

S-1/LV的作用机制S-1是一种口服氟尿嘧啶类衍生物，组成：替加氟(FT;53随机III期临床研究比较S-1单药、S-1+顺铂治疗晚期胃癌(TheSPIRITStrial)SPIRITS:S-1pluscisplatinvsS-1inRCTinthetreatmentofstomachcancerH.Narahara1,W.Koizumi2,T.Hara3,A.Takagane4,T.Akiya5,M.Takagi6,K.Miyashita7,T.Nishizaki8,O.Kobayashi9,S-1AdvancedGastricCancer(AGC)ClinicalTrialGroup;1OsakaMedicalCenterforCancerandCVDiseases,Osaka,JAPAN,2KitasatoUniversityEastHospital,Kanagawa,JAPAN,3KouseirenTakaokaHospital,Toyama,JAPAN,4IwateMedicalUniversity,Iwate,JAPAN,5GunmaPrefecturalCancerCenter,Gunma,JAPAN,6ShizuokaGeneralHospital,Shizuoka,JAPAN,7NationalHospitalOrganizationNagasakiMedicalCenter,Nagasaki,JAPAN,8MatsuyamaRedCrossHospital,Ehime,JAPAN,9KanagawaCancerCenter,Kanagawa,JAPAN.SPIRITSASCO2007:#4514随机III期临床研究比较S-1单药、S-1+顺铂H4背景-1

S-1是:

口服的氟嘧啶类药物，在日本已经广泛用于晚期胃癌.两个单独的II期临床研究表明，单药有效率44-49%，MST207-250天1,21:YSakataetal.EurJCancer1998;34:1715-17202:WKoizumietal.Oncology2000;58:191-7ASCO2007:#4514背景-1S-1是:1:YSakataetal.5背景-2regimenptsRR(%)PFS(M)OS(M)Pvalue(OS)5FUUFT+MMC5FU+CDDP(FP)1057010511.48.634.31.92.43.97.16.07.3NSJCOG92051)1):A.Ohtsuetal.JClinOncol2003;21:54-59FP组比5FU组明显更长的PFS.(P<0.001)

两组的OS无显著差异InJapan,recommendedregimenforAGCwas5-FUaloneASCO2007:#4514背景-2regimenptsRRPFSOSPvalue(O6背景-3JCOG99125-FUS-1CPT-11+CDDPNon-inferiorityBokuetal.ASCO2007abstract#:LBA4513ASCO2007:#4514背景-3JCOG99125-FUS-1CPT-11+CD7背景-4S-1+CDDPPhaseI/IIStudy1)S-140-60mgBIDfor3wksDay1Day8Day15Day22Day29Day36CDDP60mg/m2onDay8S-1regimenPts(RD)RR(%)TTP(Day)MST(Day)S-1+CDDP2576.01623831:WKoizumietal.BrJCancer2003;89:2207-2212S-1给药剂量是依据患者的体表面积(BSA)BSA<1.25:40mgBID1.25-<1.50:50mgBID1.50-<BSA:60mgBIDASCO2007:#4514背景-4S-1+CDDPPhaseI/IIStudy8研究设计AGCNopriorChemo.RS-1aloneS-1:40-60mgBIDfor28daysq6wksS-1+CDDPS-1:40-60mgBIDfor21daysq5wksCDDP:60mg/m2ivonday8

CentralRandomization

(dynamicbalancing)AdjustmentFactors:

InstitutePSUnresectablevsRecurrentASCO2007:#4514研究设计AGCRS-1aloneS-1+CDDPCen9研究终点PrimaryEndpointOverallSurvivalEstimatedOS(S-1/S-1+CDDP):8/12monthsN=142ineacharmfor90%powertoestablishsuperiorityinOS(Two-sidedlog-ranka=0.05).Followup:2yearsSecondaryEndpointsProgressionFreeSurvivalTimetoTreatmentFailureOverallResponseSafety142ptsineacharmASCO2007:#4514研究终点PrimaryEndpoint142ptsi10入组标准

组织学证实的胃腺癌(unresectable/recurrentgastriccancer)

以前没有化疗PS(ECOGscale)0-2Age20-74

预期生存>3monthsAdequateorganfunction(bonemarrow,liver,renalfunction)

知情同意ASCO2007:#4514入组标准组织学证实的胃腺癌ASCO2007:#451411患者一般状况-1Randomized:305pts(S-1/S-1+CDDP:152/153)betweenMar/2002andNov/2004FAS:298pts(S-1/S-1+CDDP:150/148)No.ofptsS-1S-1+CDDPP-valueGenderM/F116/34108/400.4223Age,yearsMedian(range)62.0(28–74)61.5(33–74)0.8933ECOGPS,0/1/2106/39/5106/38/40.8347Primarylesion-/+58/9253/950.6332ASCO2007:#4514患者一般状况-1Randomized:305pts12患者一般状况-2No.ofptsS-1S-1+CDDPP-valueDiagnosisUnresectableRecurrent11931118301.0000

Adjuvantchemotherapy-/+23/820/100.8069HistologyDiffuseIntestinalUnknown896011034500.0789No.oforgansinvolved1/2/>339/54/5741/36/710.0757Metastasisofperitoneum-/+114/3697/510.0560ASCO2007:#4514患者一般状况-2No.ofptsS-1S-1+CDDP13MonthsEstimatedprobability(%)11.013.0总生存期S-1S-1+CDDPNo.ofpts150148MST11.013.01yrsurvival46.7%54.1%2yrsurvival15.3%23.6%Log-rankp-value:0.0366HR:0.774[95%CI:0.608–0.985]Medianfollow-uptime(M):34.6ASCO2007:#4514MonthsEstimatedprobability(%14无进展生存期Log-rankp-value:<0.0001HR:

0.567[95%CI:0.437–0.734]Estimatedprobability(%)Months6.04.0S-1S-1+CDDPNo.ofpts150148PFS4.06.0ASCO2007:#4514无进展生存期Log-rankp-value:<0.15到治疗失败的时间Log-rankp-value:0.0089HR:

0.699[95%CI:0.536–0.912]Estimatedprobability(%)Months4.83.9S-1S-1+CDDPNo.ofpts150148TTF3.94.8ASCO2007:#4514到治疗失败的时间Log-rankp-value16疗效No.ResponseOverallRRCRPRSDPDNES-11061323434531%S-1+CDDP871461324354%Criteria:RECIST(ExtramuralReview)Fisher’sExactTestp-value:0.0018ASCO2007:#4514疗效No.ResponseOverallRRCRP17药物的副作用-1S-1N=150S-1+CDDPN=148AllGr.N(%)Gr.3/4N(%)AllGr.N(%)Gr.3/4N(%)HaematologicalLeucopenia57(38)3(2)104(70)17(12)Neutropenia63(42)16(11)110(74)59(40)Anemia49(33)6(4)100(68)38(26)Thrombocytopenia27(18)0(0)72(49)8(5)Non-haematologicalT-bil30(20)2(1)36(24)1(1)AST17(11)3(2)15(10)0(0)ALT14(9)1(1)18(12)0(0)ALP8(5)1(1)8(5)1(1)Creatinine3(2)0(0)32(22)0(0)Criteria:NCI-CTCver.2.0ASCO2007:#4514药物的副作用-1S-1S-1+CDDPAllGr.Gr.18药物的副作用-2S-1N=150S-1+CDDPN=148AllGr.N(%)Gr.3/4N(%)AllGr.N(%)Gr.3/4N(%)GeneralFatigue49(33)2(1)84(57)6(4)GastrointestinalAnorexia55(37)9(6)107(72)45(30)Nausea39(26)2(1)99(67)17(12)Vomiting21(14)3(2)54(37)6(4)Diarrhea34(23)5(3)51(35)6(4)Stomatitis32(21)0(0)43(29)1(1)SkinPigmentation60(40)0(0)53(36)0(0)Rash28(19)2(1)32(22)3(2)Hand-footsyndrome18(12)0(0)14(10)0(0)Notreatment-relateddeathwasobservedCriteria:NCI-CTCver.2.0ASCO2007:#4514药物的副作用-2S-1S-1+CDDPAllGr.Gr.19AGC的III期临床研究GroupregimenptsRR(%)PFS(M)OS(M)Pvalue(OS)SPIRITSS-1S-1+CDD06.011.013.00.0366EVanCutsem,etal1)(2006)CFDCF22422125373.7*5.6*8.69.20.02DCunningham,etal2)(2006)ECFEOFECXEOX263245250244414246486.26.56.77.09.99.39.911.2NSYKKang,etal3)(2006)FPX05.69.310.5NS*TTP3)ProcASCO2006;Vol24,No.18S:LBA40181)JClinOncol2006;24:4991–49972)ProcASCO2006;Vol24,No.18S:LBA4017ASCO2007:#4514AGC的III期临床研究GroupregimenptsRRP20结论S-1+CDDP的生存期长于S-1单药S-1中位生存11.0M,

S-1+CDDP13.0M

S-1+CDDP耐受性好，无治疗相关的死亡S-1+CDDP方案可以当作AGC的一线治疗方案ASCO2007:#4514结论S-1+CDDP的生存期长于S-1单药AS21N.Boku,S.Yamamoto,K.Shirao,T.Doi,A.Sawaki,W.Koizumi,H.Saito,K.Yamaguchi,A.Kimura,A.Ohtsu

GastrointestinalOncologyStudyGroupofJapanClinicalOncologyGroup

5-FU单药、CPT-11＋顺铂(CP)、S-1单药治疗晚期GC的随机III期临床研究(JCOG9912)N.Boku,S.Yamamoto,K.Shira22背景晚期胃癌无标准化疗方案.III期临床研究(JCOG9205)并未证明，5-FU+CDDP

比5-FU单药延长生存.II期研究表明S-1单药和CPT-11+CDDP疗效好、毒性反应可以接受.(Sakata,EurJCancer1998;Koizumi,Oncology2000;Boku,JClinOncol1999)

(Ohtsu,JClinOncol2003)背景晚期胃癌无标准化疗方案.(Ohtsu,JCli23Primaryendpoint：总生存Secondaryendpoints：到治疗失败的时间(TTF)Non-hospitalizedsurvival(NHS)AdverseEvents(NCI-CTCver.2)Responserate(RECIST,centralreview)

与5-FU持续静滴(5-FUci)比较・CPT-11+CDDP的优效性・S-1的非劣效性研究目的Primaryendpoint：与5-F24InclusionCriteria

1)组织学证实的不能手术切除的或复发的胃腺癌2)能口服药物3)Age:>20,<754)PS(ECOG)：0,1,25)主要脏器功能正常

6)未接受过放化疗

exceptadjuvantchemotherapycompleted6monthsbefore

7)

不一定要有可测量的病灶8)

无严重的腹膜播散

9)WritteninformedconsentInclusionCriteria1)组织学证实的不25S-1

40

mg/m2,po,bid,days1-28q6weeks

Stratifiedby(minimization)・Institution・PS0/1/2・Unresectable/RecurrencewithadjuvantCx/RecurrencewithoutadjuvantCx5-FUciCPT-11+CDDPS-1Randomization800mg/m2/day,ci,days1-5q4weeksCPT-1170mg/m2,div,days1&15CDDP80mg/m2,div,day1q4weeksIII期研究(JCOG9912)Continueduntildiseaseprogression,unacceptabletoxicities,patient’srefusalBSA<1.2580mg/body/day1.25<BSA<1.5100mg/body/day1.5<BSA120mg/body/dayS-140mg/m2,po,bid,days1-26患者一般状况AdjuvantCx-/+Unresectable/Recurrent0/1/2PSM/FGendermedian(range)AgeNo.ofpatients233/1188/46151/80/3175/5964(39-75)234*S-1235/1190/46151/81/4180/5663(32-75)236CPT-11+CDDP233/1189/45152/79/3176/5863(24-75)2345-FUci*

Onepatientwasineligible;adenosquamouscellcarcinoma.患者一般状况AdjuvantCx-/+Unrese27患者肿瘤情况Targetlesion-/+intestinal/diffuseHistologicaltype**

0/1,2/3,4,5Macroscopictype*No.ofpatientsPeritonealmetastasis165/6959/175110/124***5/68/161234S-1102/101/3155/181102/1345/73/155236CPT-11+CDDP160/76100/105/3159/175111/1215/63/1642345-FUci147/87103/90/41No.ofmetastaticsites0,1/2/>3-/+*

JapaneseClassificationofGastricCarcinoma

**

Laurenclassification,nodataavailablein2pts**

1ptwithadenosquamoustypeincluded患者肿瘤情况Targetlesion-/+i28No.ofpatients6个月内Gr.>3AE(1)5.63.83.90.941.505.665.01.312.839.315.51.34.70.40.47.7009.40S-1CPT-11+CDDP5-FUci234236234Treatmentrelateddeath*0.41.30LeukocytesNeutrophilsHemoglobinPlateletsInfectionwithoutneutropeniaInfectionwithGr.3or4neutropeniaFebrileneutropenia*JudgedbyDataandSafetyMonitoringCommitteeNo.ofpatients6个月内Gr.>3AE(291.703.0Stomatitis5.620.56.9Nausea7.79.00.4Diarrhea12.432.912.5Anorexia5.110.31.7Fatigue4.72.64.7AST3.42.63.4ALT4.31.33.0Bilirubin0.92.10Creatinine5.222.66.5Hyponatremia6个月内Gr.>3AE(2)No.ofpatientsS-1CPT-11+CDDP5-FUci2342362341.703.0Stomatitis5.620.56.9Nau30PFS和有效率Responserate-inptswithtargetlesion-5-FUciCPT-11+CDDPS-1CR+PR156849n175181175RR9%38%28%CRandPRwereconfirmedbycentralreview0.0010.62-0.900.754.2M234<0.001-0.57-0.83-95%C.I.-2.9M2340.694.8M236HRMediannP-value†

1224(months)050(%)100†:one-sidedlog-ranktest(superiority)S-15-FUciCPT-11+CDDPPFSPFS和有效率Responserate5-FUciCPT-31<0.0010.59-0.850.714.0M234S-10.014-P-value†0.67-0.98-95%C.I.-2.3M2345-FUci0.813.7M236CPT-11+CDDPHRMediann†:one-sidedlog-ranktest(superiority)到治疗失败的时间1224(months)050(%)100<0.0010.59-0.850.714.0M234S-1032治疗失败的原因OtherDeathRefusalnotrelatedtotoxicityRefusalrelatedtotoxicityToxicitiesDiseaseprogressionContinuingatfinalanalysisNo.ofpatients2108142036S-123491839361430CPT-11+CDDP2366199919915-FUci234治疗失败的原因OtherDeathRefusalnotr33122436(months)050(%)100OverallSurvivalP-value0.034†0.055†-0.68-1.010.70-1.04-95%C.I.-44.0%10.8M2345-FUci0.8347.9%11.4M234S-10.8552.5%12.3M236CPT-11+CDDPHR1-yrMSTn†:one-sidedlog-ranktest(superiority)non-inferiority

<0.001‡:multiplicityadjustedbyHolm’smethodSignificancelevel‡0.050.0250.025122436(months)050(%)OverallS340.0030.62-0.920.769.2M234S-10.027-0.68-1.00-95%C.I.-7.2M2345-FUci0.829.5M236CPT-11+CDDPHRMediannP-value†

†:one-sidedlog-ranktest(superiority)Non-hospitalizedSurvival122436(months)050(%)100=overallsurvivaltime–hospitalizeddays0.0030.62-0.920.769.2M234S-10.35*typeunknownwereexcludedfromtheanalysis生存期的亚组分析

-HazardRatioto5-FUciand95%ConfidenceInterval-HazardratioAge<65(n=372)

>65(n=332)PS0(n=454)1,2(n=250)Unresectable(n=567)Recurrent(n=137)Intestinal(n=323)*Diffuse

(n=379)(-)(n=173)Targetlesion(+)(n=531)No.ofmetsites0,1(n=305)>2(n=399)Peritonealmets(-)(n=472)(+)(n=232)Allrandomized(n=704)CPT-11+CDDPS-1*typeunknownwereexcludedf36生存期的亚组分析P-value†

S-15-FUci122436(months)050(%)1000.0701750.015-175181nP-value†

10.5M9.0M12.1MMST3.8M2.2M4.8MPFS-TargetLesion(+)--TargetLesion(-)-0.1818.1M590.54-13.5M5914.4M55MSTn†:one-sidedlog-ranktest(superiority)S-15-FUciCPT-11+CDDPCPT-11+CDDP050(%)100122436(months)生存期的亚组分析P-value†S-15-FUci122437结论S-1

的生存期明显不劣于5-FUci，毒性较低RR,TTF,NHSandPFS更好

各个亚组的生存期都比5-FUci组长CPT-11+CDDP

生存期并不优于5-FUci，且毒性大导致更多的治疗失败但RR,TTF,NHSandPFS

更好

在TL(+)亚组的生存比5-FUci长

在TL(-)和腹膜转移(+)者的生存更短

S-1shouldbeconsideredforthestandardchemotherapyofunresectableorrecurrentgastriccancer.结论S-1的生存期明显不劣于5-FUci，毒38S-1单药、S-1/CDDP(SP)、5-FU/CDDP(FP)治疗晚期胃癌(AGC)

的随机III期临床试验

(SC-101study)MaolinJin1,YoujianHe2June3rd,20081-BeijingCancerHospital;2-SunYet-SenUniversityCancerCenterASCO2008,ChicagoAbstractNo.#4533;PosterNo.#21S-1单药、S-1/CDDP(SP)、5-FU/CDDP39背景40%初次诊断的胃癌患者是晚期,40％～60％术后复发.AGC无标准治疗方案.S-1治疗GC有效.无论是单药还是SP在日本广泛用于AGC治疗*.S-1在中国无经验,

中国是GC发病率最高的国家之一.*:S-1ismanufacturedandsuppliedbyTaihoPharmaceuticalCo.,Ltd.Tokyo,Japan背景40%初次诊断的胃癌患者是晚期,40％～60％40研究目标Primaryendpoint:

ResponseRate(RR)#1Secondaryendpoint:

TimetoTreatmentFailure(TTF)OverallSurvival(OS)Toxicity/safety#2#1:RECISTguideline,usedIRCevaluationresults.#2:NCCNCTCAEversion3.0研究目标Primaryendpoint:#1:RECIS41研究设计不可切除的晚期或转移性GCCentralrandomization(dynamicbalance)

Stratification：

PerformanceStatus;Numberofmetastaticsites;Gastrectomy

S-15-FU/CDDPS-1/CDDP60patients60patients60patientsIffailed,canswitchtoS-1研究设计不可切除的晚期或转移性GCCentralrand42治疗方案ArmA(S-1):S-1,42days/cycleS-140mg/m2,

Bid,oralRest14daysd1~d28(4weeks)d29~d42(2weeks)ArmB(SP):S-1+CDDP,35days/cycleS-140mg/m2,

Bid,oralRest14daysd1~d21(3weeks)d22~d35(2weeks)CDDP,60mg/m2,d8,infusion×3hrsArmC(FP):5-FU+CDDP,28days/cycle(4weeks)5-FU+CDDPRest23daysd1~d5d6~d28CDDP,20mg/m2,infusion×0.5hr5-FU,600mg/m2,infusion×24hrs治疗方案ArmA(S-1):S-1,42days/43入组标准组织学证实的胃腺癌不可切除,晚期或转移性病灶对转移灶既往未放化疗.辅助和/或新辅助结束6个月以上者可以入选Age18oraboveECOGperformancestatus0to2Adequatehematological,renalandliverfunction入组标准组织学证实的胃腺癌44患者分配230ptsrandomized(Jul.2005~Oct.2006)S-1n=80SPn=76FPn=74FASn=77FASn=74FASn=73Withouttargetlesion,n=1Inclusioncriteriaviolationn=1Withouttargetlesionn=1Withouttargetlesionn=3患者分配230ptsrandomizedS-1SPFPF45一般状况（FAS=224）PatientCharacteristicsS-1(n=77)SP(n=74)FP(n=73)P-valueSexMaleFemale5621551961120.241AgeMeanMedianMin~max56.257.032.0~82.056.156.524.0~80.055.758.033.0~77.00.951BSA(m2)MeanMedianMin~max1.61.61.2~1.91.61.61.3~2.11.61.61.3~1.90.157PS012125312145281350100.922No.ofmetastasticsites1

＞11958116316570.308GastrectomystatusPresentAbsent3938344037360.802Pre-treatedYesNot2849205426470.404ThereisnosignificantdifferencebetweenthethreearmsinFAS.一般状况（FAS=224）PatientCharacte46RR比较(FAS)TreatmentnResponseP-valueaDiff.ofRR(%)bCRPRSDPDNERR(%)95%CIS-1771181525824.7(19/77)d15.6-35.80.06213.2SP741273110537.8(28/74)c,d26.8-49.9————FP7301428181319.2(14/73)c10.9-30.10.02118.7Remarks：a)CMH-test,adjustedbystractifications,two-sidessignificancelevel=2.5%.b)DifferencecomparedwithS-1/CDDParm.

c)OddsRatio:FPvs.SP=0.387(95%CI[0.177~0.847],p=0.0176);d)OddsRatio:S-1vs.SP=0.597(95%CI[0.284-1.256],p=0.1741).nCRPRSDRR41151114.6％(6/41）S-1second-linetreatment41of73ptsswitchedtoS-1monotherapyafterfailedinFPRR比较(FAS)TreatmentnResponseP47OS*UntilJanuary15,2007,224patientswerefollowedup,94died(42%),115alive,15lostfollow-up.**:LogranktestTreatmentnDeathMST(day)95%CIP-value**S323<0.001SP7422433365－——FP7331309238－0.038*FP’ssurvivalinclude41pts’contributionwhoswitchedtoS-1Hazard:S-1vs.SP=2.262(95%CI[1.327-3.856])FPvs.SP=1.908(95%CI[1.089-3.341])OS*UntilJanuary15,2007,2248TTFTreatmentnFailureMedian-TTF(day)95%CIP-value*S-1776212692－1520.008SP7444159146－220——FP73558566－106<0.001Hazard:S-1vs.SP=1.709(95%CI[1.145-2.552])FPvs.SP=2.673(95%CI[1.755-4.071])*:Logranktest.TTFTreatmentnFailureMedian-TTF49药物主要的副作用AETermS-1SPFPn=80n=76n=74G3+G4n(%)G3+G4n(%)G3+G4n(%)Anemia2(2.5)4(5.3)4(5.4)Leucopenia1(1.3)10(13.2)7(9.5)HGBdecreased5(6.3)8(10.5)3(4.1)Lymphocytedecreased7(8.8)4(5.3)5(6.8)Neutropenia3(3.8)13(17.1)12(16.2)PLTdecreased05(6.6)9(12.2)Nausea02(2.6)4(5.4)Vomitting1(1.3)5(6.6)9(12.2)Diarrhea3(3.8)5(6.6)0Anorexia001(1.4)Decreasedappetite2(2.5)01(1.4)Constipation001(1.4)药物主要的副作用AETermS-1SPFPn=80n=7650小结从2005.7月－2006.10月，80ptsinS-1,76ptsinSPand74ptsinFP入组.三组患者的一般状况无显著差异.独立评估委员会评估的结果,RR24.7%inS-1,37.8%inSPand19.2%inFP.SP有效率优于FP(CMHp=0.021).FP组41例患者交替到S-1组后的RR14.6%,说明S-12nd-line治疗有效.SP组的生存明显长于FP组(Log-rankp=0.038)和S-1组(Log-rankp<0.001).S-1/SP/FP最常见的3/4毒性反应(%)

:贫血,2.5/5.3/5.4;白细胞下降,1.3/13.2/9.5;中性粒减少,3.8/17.1/16.2;PLT减少,0/6.6/12.2;恶心,0/2.6/5.4;呕吐,1.3/6.6/12.2;腹泻,3.8/6.6/0.S-1和SP组均能很好耐受.小结从2005.7月－2006.10月，8051结论S-1和SP均有效、耐受性好.SP有可能成为晚期中国胃癌患者的标准治疗方案.结论S-1和SP均有效、耐受性好.52Primaryendpoint:SuperiorityinOSN=1000non-AsianAGCfor1stlinepalliativechemotherapyFLAGSTrial:S-1+CDDPvs5-FU+CDDP5-FU1,000mg/m2/dCIVD1-5Cisplatin100mg/m2ivD1,every4weeksS-125mg/m2pobidD1-21Cisplatin75mg/m2ivD1,every4weeksRAjani,etal.ASCOGI2009Primaryendpoint:Superiority53FLAGS:OSAjani,etal.ASCOGI2009%存活率1009080706050403020100随机后时间（月）0246810121416182022242628303234Log-rankTest:p=0.1983相对危险度:0.92(95%CI:0.80,1.05)中位总生存时间: CS:8.6months CF:7.9monthsCS（顺铂/S1）CF（顺铂/5-Fu）NatriskS-1:5-FU:52147940234127621217212490694836241464005084523853262501991561167956352619128310FLAGS:OSAjani,etal.ASCOGI54FLAGS:PFSAjani,etal.ASCOGI2009%无进展生存率1009080706050403020100Log-rankTest:p=0.9158相对危险度:0.99(95%CI:0.86,1.14) CS:4.8months CF:5.5monthsCS（顺铂/S1）CF（顺铂/5-Fu）0246810121416182022242628521365237152914124171298510508335235149753622161164NatriskS-1:5-FU:随机后时间（月）FLAGS:PFSAjani,etal.ASCOG55FLAGS:3/4度血液学毒性

Ajani,etal.ASCOGI2009患者比例(%)706050403020100贫血中性粒细胞减少血小板减少白细胞减少中性粒细胞减少性发热*********CSCF**P<0.01FLAGS:3/4度血液学毒性Ajani,etal56FLAGS:肝肾相关毒性Ajani,etal.ASCOGI2009患者比例(%)50454035302520151050肌酐>1.5xULN肌酐清除率<50mL/min肾相关不良事件(所有分级)肾损害胆红素>1.5xULN肝相关不良事件(所有分级)肝功能损害肾毒性肝毒性******CSCF*P<0.05**P<0.01*FLAGS:肝肾相关毒性Ajani,etal.ASC57FLAGS:结论与顺铂/5-Fu相比，顺铂/S1并不提高OS次要终点指标：有效性：顺铂/S1与顺铂/5-Fu无差异顺铂/S1在安全性上比顺铂/5-Fu更好.然而，顺铂/S1方案中顺铂剂量是顺铂/5-Fu方案的75%，且S-1剂量也低于日本研究的剂量Ajani,etal.ASCOGI2009FLAGS:结论与顺铂/5-Fu相比，顺铂/S1并不提高O58Sakuramotoetal.NEnglJMed2007;357:1810-20Sakuramotoetal.NEnglJMed59研究目标探讨II/III胃癌D2术后，S-1单药辅助治疗的有效性PrimaryendpointOverallsurvivalSecondaryendpointsRelapse-freesurvivalSafetyofS-1Sakuramotoetal.NEnglJMed2007;357:1810-20研究目标探讨II/III胃癌D2术后，S-1单药辅助治60入组标准组织学证实的胃癌D≥2术后术后分期II/III(Japaneseclassification)R0resection(curabilityAorB)NegativeperitonealcytologyAge20-80years既往未做辅助治疗AdequateorganfunctionWritteninformedconsentSakuramotoetal.NEnglJMed2007;357:1810-20入组标准组织学证实的胃癌Sakuramotoetal.61研究设计Curativegastrectomy(D2)CentralRandomization(dynamicbalancing)Adjustmentfactors:stage*(II,IIIA,IIIB),Institutionwithin6weeksaftersurgeryS-180-120mg/day**4wksadministrationwith2wksoffineachcoursefor12monthsSurgeryalone(Nofurthertherapy)*JapaneseClassificationofGastricCarcinoma,13thed,1999**Bodysurfacearea(m2) <1.25 80mg/day 1.25-<1.5 100mg/day >=1.5 120mg/daySakuramotoetal.NEnglJMed2007;357:1810-20研究设计Curativegastrectomy(D2)C62统计学考虑5-yearOSforsurgeryalone=70%ImprovementbyS-1atahazardratioof0.7(5yOS:77.9%)Followup:5yearsTwo-sidedα=0.05,statisticalpower=80%

485patientsineachgroup*CalculatedbythemethodofFreedmanTwointerimanalyses1and3yearsaftercompletionoftheenrollmentAlphaspendingfunction:O’Brien&FlemingtypeSakuramotoetal.NEnglJMed2007;357:1810-20统计学考虑5-yearOSforsurgeryalo63AccrualOpened :October2001Closed :December2004Randomized :1059pts

(S-1:529,Surgeryalone:530)Eligible :1034pts(S-1:515,Surgeryalone:519)Institutions :109JapaneseinstitutionsSakuramotoetal.NEnglJMed2007;357:1810-20AccrualOpened :October2001S64一般状况(1)(Allrandomized)S-1(n=529)SurgeryOnly(n=530)Sex–no.(%)Male367(69.4)369(69.6)Female162(30.6)161(30.4)Age–no.(%)<60199(37.6)195(36.8)60-69193(36.5)215(40.6)70-80137(25.9)120(22.6)Median(Range):yr63(27-80)63(33-80)Sakuramotoetal.NEnglJMed2007;357:1810-20一般状况(1)(Allrandomized)S-1Sur65一般状况(2)(Allrandomized)S-1(n=529)SurgeryOnly(n=530)T–no.(%)T11(0.2)0T2289(54.6)286(54.0)T3225(42.5)232(43.8)T414(2.6)12(2.3)N,Japaneseclassification–no.(%)N051(9.6)64(12.1)N1296(56.0)281(53.0)N2182(34.4)185(34.9)N300No.oflymph-nodemetastasis–no.(%)051(9.6)64(12.1)1-6331(62.6)325(61.3)7-15117(22.1)113(21.3)≧1630(5.7)28(5.3)Sakuramotoetal.NEnglJMed2007;357:1810-20一般状况(2)(Allrandomized)S-1Sur66一般状况(3)(Allrandomized)S-1(n=529)SurgeryOnly(n=530)Stage,Japaneseclassification–no.(%)II236(44.6)238(44.9)IIIA202(38.2)207(39.1)IIIB90(17.0)85(16.0)IV1(0.2)0Stage,TNMclassification–no.(%)IB1(0.2)0II264(49.9)282(53.2)IIIA170(32.1)157(29.6)IIIB54(10.2)56(10.6)IV40(7.6)35(6.6)Sakuramotoetal.NEnglJMed2007;357:1810-20一般状况(3)(Allrandomized)S-1Sur67一般状况(4)(Allrandomized)S-1(n=529)SurgeryOnly(n=530)Typeoflymph-nodedissection–no.(%)D101(0.2)D2501(94.7)497(93.8)D328(5.3)32(6.0)Typeofgastrectomy–no.(%)Total220(41.6)201(37.9)Distal301(56.9)316(59.6)Proximal4(0.8)11(2.1)Others4(0.8)2(0.4)Sakuramotoetal.NEnglJMed2007;357:1810-20一般状况(4)(Allrandomized)S-1Sur68依从性:S-1PeriodCompliance(n=517)3months87.4%6months77.9%9months70.8%12months65.8%Reasonsfordiscontinuationby12monthsPatient’swithdrawal(adverseeventsetc.) 71ptsDoctor’sdecision(adverseeventsorcomplications) 72ptsRelapseorsecondcancer 27ptsSakuramotoetal.NEnglJMed2007;357:1810-20依从性:S-1PeriodCompliance(n=569不良事件(1)S-1(n=517)SurgeryOnly(n=526)Grade3Grade4Grade3Grade4Luekopenia6(1.2%)02(0.4%)0Anemia6(1.2%)03(0.6%)1(0.2%)Thrombocytopenia1(0.2%)02(0.4%)0AST9(1.7%)017(3.2%)1(0.2%)ALT6(1.2%)016(3.0%)1(0.2%)Totalbilirubin7(1.4%)1(0.2%)5(1.0%)1(0.2%)Creatinine001(0.2%)1(0.2%)*NCI-CTC(Ver.2.0)Sakuramotoetal.NEnglJMed2007;357:1810-20不良事件(1)S-1SurgeryOnlyGrade370不良事件(2)S-1(n=517)SurgeryOnly(n=526)Grade3Grade4Grade3Grade4Stomatitis1(0.2%)000Anorexia30(5.8%)1(0.2%)8(1.5%)3(0.6%)Nausea19(3.7%)-6(1.1%)-Vomiting6(1.2%)07(1.3%)3(0.6%)Diarrhea16(3.1%)01(0.2%)0Rash5(1.0%)02(0.4%)0Fatigue3(0.6%)03(0.6%)0*NCI-CTC(Ver.2.0)Sakuramotoetal.NEnglJMed2007;357:1810-20不良事件(2)S-1SurgeryOnlyGrade371第一次中期分析FirstinterimanalysiswascarriedoutonJune2006,usingthefollow-updataofDecember2005(Medianfollow-up:2.0yrs)O’Brien-Flemingstoppingboundary:p=0.0011OverallsurvivalAllrandomized :p=0.0016Eligible :p=0.0008Relapse-freesurvival :p=0.0002Predictivepower(OS) :99.3%Sakuramotoetal.NEnglJMed2007;357:1810-20第一次中期分析Firstinterimanalysis72DSMC推荐OnJune20th,2006,afterrigorousdiscussion,theDSMCconcludedthatthetreatmentwaseffectiveandrecommendedtotheinvestigatorstostopthestudyandopenthesurvivalresultsusingthefollow-updatauptoJune30th,2006.O’Brien-Flemingstoppingboundary:p=0.0011OverallsurvivalAllrandomized :p=0.0016Eligible :p=0.0008Relapse-freesurvival :p=0.0002Theinvestigatorsacceptedtherecommendation.

FinalanalysiswascarriedoutonNovember24th,2006.Sakuramotoetal.NEnglJMed2007;357:1810-20DSMC推荐OnJune20th,2006,aft73总生存3-yearOS-S-1 80.1%

-Surgeryonly 70.1%HR=0.68[0.52-0.87]p=0.003(stratifiedlog-ranktest)012345050100OverallSurvival(%)5295305155043703521961634640YearssinceRandomizationNo.atriskS-1SurgeryonlySakuramotoetal.NEnglJ