NCCN胃癌治疗指南解读(沈琳)(学习资料)

NCCN胃癌治疗指南的解读

——内科治疗部分

(2010V.2)北京大学临床肿瘤学院北京肿瘤医院消化内科沈琳2025/4/14中国胃癌的发病率和死亡率世界范围内，中国是胃癌发病率最高的国家之一总数:934000,其中

42%发生在中国

(2002)疾病部位

胃窦仍然是最常见部位

胃食管结合部发病率升高的趋势多数患者确诊时已为进展期胃癌，且约70％需要化疗#Kamangaretal,JClinOncol24:2137-50;2006上海

(2002-2004):发病率仍高

:恶性肿瘤中，男性占第二位，女性占第三位疾病部位:胃窦最常见,为

39.88%,小弯为12.68%中国大城市中胃癌的发病率Jsurconcepts＆practice2008,vol13,No124-29北京

(2003-2007)

年度年龄200620072008MFtotalMFtotalMFtotal11~2001100001121~30325448691531~4011122316132910213141~50491665362965614110251~60892711669411101275217961~701021812088391271043614071~80681987802310368249281~9070710212761391~100000000101total32995424303151454384190574≤5094/424(22.2%)102/454(22.5%)149/574(26.0%)近3年来收入院胃癌病例北京大学临床肿瘤学院(2006~2008)AJCC分期 美国 日本中国ⅠA 78% 95%93.7%ⅠB 58% 86% 80.2%Ⅱ 34% 71% 65.7%ⅢA 20% 59% 44.8%ⅢB 8% 35% 23.1%Ⅳ 7% 17%10.8%总计 28% 61.4％

40%>检测大于15个淋巴结Cancer2000,88:921-32

中国胃癌患者预后——5年生存率进展期胃癌需全身治疗中国胃癌发病的特点JSurgConceptsPract2008,Vol.13,No.1：24上海市胃癌发病流行现况早诊率低治疗水平差异大国内高水平的临床研究少，循证医学依据较少更要求规范治疗行为，统一诊疗标准，特别是综合治疗东方国家胃癌预后好于西方的可能原因2010年中国版与2009年相比，主要更新内容RANDOMIZEEradicationgroup(272)9patientslansoprazole30mgBidamoxicillin750mgBid

clarithromycin20mgBid1weeksControlgroup(272)24patientsstandardcareno

treatmentforHP544patientswithearlygastriccancer,either

newlydiagnosedorinpostresectionfollow-upafterendoscopictreatment,allwithHPinfection.UMIN1169临床研究

—Amulti-centre,open-label,randomisedcontrolledtrialmetachronousgastriccancer3-yearfollow-upKazutoshiFukaseetal;Lancet2008;372:392–97(HR:0.353,95%CI0.161-0.775;p=0.009)2009.v.22010.v.2清除幽门螺旋杆菌只要阳性即应治疗如果患者有症状，即应治疗对于根治性胃大部切除术后患者:

检测HP,如阳性给予治疗

但对于全胃切除术后患者，是否根除?对于不可切除的复发转移性胃癌患者，无需清除HP,仅对症支持治疗2010.v.2NCCN胃癌指南更新——中国版2009.v.22010.v.2转移性或局部进展期胃癌-1DCF1ECFECF改良方案

1伊立替康+顺铂

2B奥沙利铂+氟尿嘧啶

(5-FU或卡培他滨)2B伊立替康+氟尿嘧啶(5-FU或

卡培他滨)2BDCF改良方案

2B紫杉醇为基础方案2BDCF1ECF1ECF改良方案

1伊立替康+顺铂

2B奥沙利铂+氟尿嘧啶

(5-FU或卡培他滨)2B伊立替康+氟尿嘧啶(5-FU或卡培他滨)2BDCF改良方案

2B紫杉醇为基础方案2B曲妥珠单抗

12010.v.2NCCN胃癌指南更新

——美国版ToGA试验设计HER2-positive

advancedGC

(n=584)5-FUorcapecitabinea

+cisplatin(n=290)R

aChosenatinvestigator’sdiscretion

GEJ,gastroesophagealjunction5-FUorcapecitabinea

+cisplatin+trastuzumab(n=294)StratificationfactorsadvancedvsmetastaticGCvsGEJmeasurablevsnon-measurableECOGPS0-1vs2capecitabinevs5-FUPhaseIII,randomized,open-label,international,multicenterstudy

1Bangetal;Abstract4556,ASCO20093807patientsscreened1810HER2-positive(22.1%)来自24个国家3807份肿瘤样本中心实验室检测，3667份肿瘤样本被检810例HER2阳性,总的阳性率22.1%584例HER2阳性患者被随机分为两组进行观察HER2-positivityrate

Europe(23.6%)

Asia(23.5%)

Taiwan5.9%

(n=34)

Australia32.8%

(n=61)

China22.6%±

（n=590）HER2阳性率在欧亚地区是相似的，而在各国家之间有差异HER2阳性率与肿瘤部位和类型有关胃食管结合部腺癌HER2阳性率高肠型胃癌阳性率高，混合型次之，弥漫型最低Primaryendpoint:OSTime(months)2942902772662462232091851731431471171139090647147563243243016211413712665401000No.

atrisk11.113.80.00.10.20.30.40.50.60.70.80.91.0024681012141618202224262830323436EventFC+TFCEvents167

182HR0.7495%CI0.60,0.91pvalue0.0046Median

OS13.8

11.1T,trastuzumabSecondaryendpoint:PFS0246810121416182022242628303234Event2942902582382011821419995626033411728721513393826261614020005.56.7No.

atrisk0.00.10.20.30.40.50.60.70.80.91.0Time(months)FC+TFCEvents226

235HR0.7195%CI0.59,0.85pvalue0.0002Median

PFS6.7

5.5113OSinIHC2+/FISH+orIHC3+(exploratoryanalysis)1.00.80.60.40.20.0363432302826242220181614121086420Time(months)11.816.0FC+TFCEvents120

136HR0.6595%CI0.51,0.83Median

OS16.0

11.8Event0.10.30.50.70.921819840531242011228218196170170141142112122

96100758453653951281000No.

atrisk39202813Secondaryendpoint:

tumorresponserate2.4%5.4%32.1%41.8%34.5%47.3%IntenttotreatORR=CR+PR

CR,completeresponse;PR,partialresponsep=0.0599p=0.0145F+C+trastuzumabF+Cp=0.0017Patients(%)CRPRORRSafety:与对照组比较无明显增加hematologicalAEs%F+C

n=290F+C+trastuzumab

n=294AllGrade3/4AllGrade3/4NeutropeniaFebrileneutropeniaAnemiaThrombocytopenia57321113031035352816275125AE,adverseeventnon-hematologicalAEs%NauseaVomitingFatigueDiarrheaConstipationAstheniaStomatitisWeightdecreaseAbdominalpain6346282832181514147824232216750353726192423167649<14<121Safety:cardiacAEsaMeasuredatbaselineandevery12weeks;MI,myocardialinfarctionCardiacevent,n(%)F+C

(n=290)F+C+trastuzumab

(n=294)AllGrade3/4AllGrade3/4CardiacAEs,total18(6)

9(3)17(6)4(1)Cardiacfailure2(<1)2(<1)1(<1)1(<1)AsymptomaticLVEFdropsa<50%

<50%andby

10%2(1.1)

2(1.1)14(5.9)

11(4.6)CardiacAEsleadingtodeath2(<1)

Cardiacarrest;

cardio-respiratoryarrest2(<1)

AcuteMI;anginaunstableandcardiacfailureCardiacAEsrelatedtotreatment2(<1)2(<1)结论和前景ToGA试验显示trastuzumab联合化疗减少了HER2阳性胃癌患者26%的死亡风险

(HR0.74)延长HER2阳性胃癌患者中位生存期近3月

(11.1to13.8months;p=0.0046)PFS,TTP,ORR,CBR,DoR得到显著性改善化疗加用赫赛汀后，患者耐受性良好，所有安全性指标包括心脏不良反应与对照组比较没有显著差异将成为Her-2阳性晚期胃癌的新的治疗选择2009.v.22010.v.2转移性或局部进展期胃癌DDP+氟尿嘧啶DDP+

卡培他滨

2A

DDP+5FU2B口服氟尿嘧啶类

2B(老年或体力状况较差者)DDP+氟尿嘧啶

DDP+5FU2B

DDP+

卡培他滨

2A

DDP+

替吉奥胶囊

2A？口服

氟尿嘧啶类

(老年或体力状况较差者)

卡培他滨

2B？

替吉奥胶囊

2B？2010.v.2NCCN指南更新

——中国版RS-1+CDDP

S-1:40-60mg,bidfor21daysq5wksCDDP60mg/m2ivonday8S-1

40-60mg,bid(28daysq6wks)主要研究终点:OS次要研究终点:PFS,TTF,有效率,安全性纳入病例数:298例Evidence:SPIRITSWKoizumi:TheLancetOncology9,215-21,2008入组患者：不可切除/复发性胃癌OS不良反应

(3/4级)S-1/CDDP(%)S-1(%)中性粒细胞减少4011腹泻43粘膜炎10恶心111厌食306结论S-1及S-1+CDDP两组有效率均较高，31%及54%S-1及S-1+CDDP两组中位生存期分别为11.0月及13.0月S-1+CDDP可作为进展期胃癌的标准一线治疗方案phaseIIIRamdomized3-armedstudyofS-1monotherapyversusS-1/CDDP(SP)versus5-FU/CDDP(FP)inpatientswithadvancedgastriccancer(AGC)

(SC-101study)Chinesepatients;Ramdomized;MulticenterComparisonstudyPekingUniversitySchoolofOncologyRS-1S-1:40mg/m2,bid(4weekson/2weeksoff)S-1+CDDP

CDDP:60mg/m2iv(d8)S-1:40mg/m2,bid(3weekson/2weeksoff)5-FU+CDDP

CDDP:20mg/m2iv(d1-5)5FU:600mg/m2civ(d1-5)q4ws.主要研究终点:RR次要研究终点:OS,TTF,不良事件

最终分析患者数:224例Evidence:SC-101Jinetal.ASCO2008#4533

入组患者：不可切除/复发性胃癌Iffailed,canswitchtoS-1S-1SPFPRR24.7%37.8%19.2%SPvsFPp=0.0021有效率FP组41例患者进展后转入S-1组，又达到14.6%有效率

(S-1作为二线化疗)不良反应

(3/4)S-1(%)SP(%)FP(%)中性粒细胞减少3.817.116.2白细胞减少1.313.29.5贫血2.55.35.4血小板减少06.612.2腹泻3.86.60呕吐1.36.60恶心02.65.4OS结论

S-1及SP均安全有效

S-1+DDP可作为中国进展期胃癌一线治疗选择RANDOMIZECS

S-125mg/m2POBIDfor21days,every4wks

Cisplatin75mg/m2IVinfusiononday1,every4wksformax6cycles

CF

5-FU1000mg/m2/24hrsCIfor5days,every4wks

Cisplatin100mg/m2IVinfusiononday1,every4wksformax6cycles

Stratificationfactors:Typeofdisease(locally

advanced;1metastaticsite;

≥2metastaticsites)Prioradjuvanttherapy(y/n)Measurablevs

non-measurablediseaseCenterPrimaryEndpoint: •OverallSurvivalSecondaryEndpoints:

•Progression-FreeSurvival •Safety •TimetoTreatmentFailure •OverallResponseRateClinicalTID:

NCT00400179FLAGSStudyDesign24countries/146centers/1053patients/nonasiantrialLog-rankTest:p=0.1983HazardRatio:0.92(95%CI:0.80,1.05)MedianOverallSurvival:

CS:8.6months

CF:7.9monthsOverallSurvival(FAS)RANDOMIZECS

S-125mg/m2POBIDfor21days,every4wks

Cisplatin75mg/m2IVinfusiononday1,every4wksformax6cycles

CF

5-FU1000mg/m2/24hrsCIfor5days,every4wks

Cisplatin100mg/m2IVinfusiononday1,every4wksformax6cycles

Stratificationfactors:Typeofdisease(locally

advanced;1metastaticsite;

≥2metastaticsites)Prioradjuvanttherapy(y/n)Measurablevs

non-measurablediseaseCenterDose? DDP:75mgvs100mgS-1:25mgvs40mgTTF?

•3.8moinbotharms •SecondlineTherapy:29.6%vs33.3%(CSvsCF) •OverallResponseRate:29.1%vs31.9%•SafetyFLAGS?StudyDesign!•Subgroupanalysis?AdvancedGastricCancerS-1MonotherapyforpatientswithpoorconditionPatientsBackgroundTrialDesignAuthorJournalNRegimenRRTTPOSWithperitonealdisseminationCaseReportOsugietal.OncolRep.200218S-180mg/m2/day,d1-28,q6wNANA8.4moWithpoorperformancestatusPhaseIIJeungetal.BrJCancer.200752S-170mg/m2/day,d1-14,q3w12%2.5mo7.6moWithlowrenalfunctionetc.PostMarketingSurveyNagashimaetal.GastricCancer.20053,801S-180mg/m2/day,d1-28,q6wNANA8.3moAdvancedGastricCancerS-1MonotherapyforelderlypatientsTrialDesignAuthorJournalNRegimenRRTTPOSPKtrialFujitaetal.DrugMetabDispos.200910S-180mg/m2/day,d1-28,q6wNANANAPhaseIIKoizumietal.CancerChemotherPharmacol.200931S-180mg/m2/day,d1-28,q6w(AdjustedbyCreatinineClearance)21.2%3.9mo15.7moRandomizedPhaseIILeeetal.BrJCancer.200891·Cape2500mg/m2/day,d1-14,q3w·S-180mg/m2/day,d1-28,q6w27.2%28.9%4.7mo4.2mo9.5mo8.2moRetrospectiveStudySeoletalJpnJClinOncol.200972·Cape2500mg/m2/day,d1-14

CDDP70mg/m2d1,q3w·S-1100-120mg/day,d1-14

CDDP70mg/m2d1,q3w55.0%40.6%5.9mo5.4mo10.2mo9.6moEvidence：phaseIIIML17032:XPvsFP

KangYKAnnOncol.2009Jan20.666-673SuperiorORRwithXPvs.FPConfirmedresponse

%(95%CI)XP

(n=160)FP

(n=156)p-valueOverallresponse41(33–49)29(22–37)0.030SuperiorPFSwithXPvsFPEstimatedprobabilityHR=0.81(95%CI:0.63–1.04)ComparedtoHRupperlimit1.25,p=0.00081.00.80.60.40.20.0XP(n=139)FP(n=137)MedianPFS

months(95%CI)5.6(4.9–7.3)5.0(4.2–6.3)纳入141例患者(中位年龄Age:53.7ys)化疗方案:Cape1000mg/m2Bidd1-14DDP20mg/m2ivd1-5q3W

WHO评价疗效

CTCv2.0评价不良反应有效率CR3(2.1%)PR48(34.0%)SD51(36.2%)PD39(27.6%)mOS:12.0m,ORR:36.2%安全性：3/4AE<5%Evidence：中国胃癌XP临床II期研究

金懋林等.中华肿瘤杂志2008Dec;30(12):940-3结论卡培他滨

联合小剂量分次给予顺铂

一线治疗进展期胃癌安全有效。Meta-analysisofREAL2andML17032trials

inadvancedoesophago-gastriccancerEvidence:Meta-analysisofREAL2andML17032TrailscomparingCapectabinewith5-Fluorouracil(5-FU)inAdvancedOesophage-gastriccancerAFCOkines,etal.AnnOncol.2009Sep;20(9):1529-34.Epub2009May27.卡培他滨

组5FU组HRPmOS(95%CI)(d)322(300-343)285(265-305)0.87(0.77-0.98)0.027mPFS(95%CI)(d)199(180-217)182(167-197)0.91(0.81-1.02)0.0925ORR(95%CI)(%)45.638.4OR:1.38(1.10-1.73)0.006结论卡培他滨为基础联合化疗方案较5-FU为基础方案治疗进展期胃癌总生存期及有效率。Evidence：卡培他滨

对比

S-1ArandomisedmulticentrephaseIItrialof卡培他滨

vsS-1asfirst-linetreatmentinelderlypatientswithmetastaticorrecurrentunresectablegastriccancer.

Y.Kang,BrJCancer.2008Aug19;99(4):584-90.PhaseIIXeloda(n=44)S-1(n=45)Regimen1250mg/㎡bidd1-14/3W40-60mg/㎡bidd1-28/6WCR(%)01(2.2%)PR(%)13(29.5)12(26.7)mOS(mo)10.07.9mTTP(mo)4.84.2mTTF(mo)4.43Xeloda(n=44)S-1(n=45)¾级

(%)1250mg/㎡bidd1-14/3W40-60mg/㎡bidd1-28/6W中性粒细胞减少6.84.8乏力07.2厌食6.89.5腹泻2.30手足综合征6.80Evidence：卡培他滨

vsS-1:不良反应

Y.Kang,BrJCancer.2008Aug19;99(4):584-90.Capecitabine+cisplatin(n=40)S-1+cisplatin(n=32)Regimen1250mg/㎡bidd1-14DDP:70mg/㎡,q3W50-60mgbidd1-14DDP:70mg/㎡,q3WpRR(%)55%40.6%0.246mOS(mo)10.29.60.343mTTP(mo)5.95.40.6403/4HFS37%6%＜0.05diarrhea32%25%＜0.05两组中其他血液学及非血液学毒性发生率相似对比XP和SP的回顾性研究YoungMiSeoletal.JpnJclinOncol2009:39(1)43-48doi:10.1093/jjco/hynl192009.v.22010.v.2转移性或局部进展期胃癌DDP+氟尿嘧啶DDP+

卡培他滨

2A

DDP+5FU2B口服氟尿嘧啶类

2B(老年或体力状况较差者)DDP+氟尿嘧啶

DDP+5FU2B

DDP+

卡培他滨

2A

DDP+

替吉奥胶囊

2A口服

氟尿嘧啶类

(老年或体力状况较差者)

卡培他滨

2B

替吉奥胶囊

2B2010.v.2NCCN指南更新

——中国版2010.v.2NCCN指南——中国版胃癌（占85%）或低位食管癌（15%）N=2505Y38%N=2535Y23%ECF:E50mg/m2C60mg/m2FU200mg/m2/dcivCunninghametal,NEJM2006PatientsatriskLogrankp-value=0.009HazardRatio=0.75

(95%CI0.60-0.93)CSCS250168111795238272531558050311890.00.10.20.30.40.50.60.70.80.91.0Monthsfromrandomization0122436486072149250170253EventsTotalCSCSSurvivalratePatients：3809ptsMethods:12RCTfromJan.1998toDec.20074fromJapan,4fromItaly,2fromFrance,1fromSpainorPolandT1wasexcluded,onlyD1ormorewasincludedSurgeryalonegroup(1913pts)vsCT+surgerygroup(1896pts)BritishJournalofSurgery,Jan,2009;96:26-33Results:ThepooledHRforOSwas0·78(95CI0·71to0·85)infavourofchemotherapy.

Subgroupanalysisshowedthattheadvantageofchemotherapywasnotinfluencedby

depthoftumourinfiltrationstatusoflymphnodemetastasistypeoflymphadenectomygeographicaldistributionofpatientsrouteofdrugadministrationMeta-analysisshowssurvivalbenefitofadjuvantchemotherapygroup.Favourschemotherapy+surgeryFavourssurgeryaloneRS-1S-1:40-60mgBIDfor28daysq6wksfor1year分层因素

:

不同中心

II/IIIA/IIIB期*

主要研究终点

总生存期

次要研究终点

无复发生存

安全性*JapaneseClassificationofGastricCarcinoma,13thed,1999Evidence:ACTS-GC研究设计SSakuramoto:NEnglJMed357,1810-20,2007总生存期不良反应S-1(n=517)单纯手术(n=526)Grade3Grade4Grade3Grade4粒细胞减少6(1.2%)02(0.4%)0贫血6(1.2%)03(0.6%)1(0.2%)AST升高9(1.7%)017(3.2%)1(0.2%)T-bil升高7(1.4%)1(0.2%)5(1.0%)1(0.2%)肌酐升高001(0.2%)1(0.2%)厌食30(5.8%)1(0.2%)8(1.5%)3(0.6%)恶心19(3.7%)-6(1.1%)-腹泻16(3.1%)01(0.2%)0皮疹5(1.0%)02(0.4%)0疲乏3(0.6%)03(0.6%)0*NCI-CTC(Ver.2.0)Evidence:ACTS-GCstudyresultSSakuramoto:NEnglJMed357,1810-20,2007StageII012345050100232233230226186178100882527(years)No.atriskTS-1Surgery3年OS-TS-1

90.7%--Surgeryalone

82.1%HR=0.59[0.36-0.99]p=0.042(log-ranktest)01234505010023123321520716114385681919(years)3yRFS-TS-1

83.7%-surgeryalone

72.1%HR=0.55[0.36-0.83]p=0.004(log-ranktest)OverallsurvivalRelapse-freesurvival(%)StageIIIA01234505010019420319119613613267591814(years)No.atriskTS-1surgery3yearOS-TS-1

77.4%--surgery

62.0%HR=0.66[0.45-0.97]p=0.032(log-ranktest)0123450501001942031761701111025247117(years)3yearRFS-TS-1

69.1%--surgery

56.5%HR=0.64[0.45-0.90]p=0.009(log-ranktest)OverallsurvivalRelapse-freesurvival(%)StageIIIB01234505010089838576595434251010(years)No.atriskTS-1Surgery3yOS-TS-1

63.4%--surgery

56.6%HR=0.73[0.45-1.18]p=0.192(log-ranktest)012345050100898376604335261756(years)3yRFSTS-1

49.9%--surgery

38.3%HR=0.69[0.46-1.04]p=0.075(log-ranktest)OverallsurvivalRelapse-freesurvival(%)无统计学差异！52Evidence:ACTS-GC亚组分析SSakuramoto:NEnglJMed357,1810-20,20072010.v.2NCCN胃癌指南更新

——更新EGJadenocarcinomauT3/4NxM0

因入组太慢，提前终止试验。Nov2000-Dec2005CTCRTRCROSStrial结果32%PCRCROSStrial结果鳞癌患者占23%，腺癌为74%最佳支持治疗—肿瘤部位慢性出血姑息化疗或放化疗?mOS：6.7mvs2.4mp=0.08该研究为回顾性研究，观察梗阻、疼痛、出血等多种症状的缓解放疗虽可缓解症状，CRT优于RT的趋势

考虑的选择:

联合放化疗

？

姑息性放疗？姑息性化疗？

(关于是否增加姑息性化疗的征询:

收到9位专家的书面反馈意见,6人同意,3人不同意)最佳支持治疗–梗阻脚注1:梗阻可分为消化道梗阻及胆道梗阻。脚注2:恶性肠梗阻患者的治疗请参照NCCN姑息治疗中PAL16-17相关章节

置入胆道内支架或

PTCD(经皮肝穿刺胆管引流)2A最佳支持治疗–腹水恶性腹水无症状，参照胃癌的系统化疗GAST-C有症状• 腹水引流

• 腹腔化疗联合全身化疗

---5FU,顺铂,紫杉醇,MMC2A• 腹腔持续热灌注化疗，IPCH？纳入患者33例晚期胃癌合并恶性腹腔积液患者方法及结果同时静脉(50mg/m(2)及腹腔给以紫杉醇

(20mg/m(2)，

d1、8,S-1口服80mg/m(2)/d，14天23(70%)例患者

腹水量减少>50%，8例腹水完全消失

每周静脉及腹腔给予紫杉醇

联合S-1治疗晚期胃癌合并恶性腹水.

KitayamaJ,IshigamiHetal.Oncology.2010;78(1):40-46.Epub2010Mar3.纳入病例胃癌伴有腹腔内播散病灶或腹水细胞学阳性患者方法及结果方法:同前

1年生存率78%.18例有可测病灶患者中，评价疗效示有效率为56%21例恶性腹水患者中13例

(62%)腹水消失。

每周静脉及腹腔给予紫杉醇

联合