NCCN胃癌临床实践指南中国版解读-沈琳

NCCN胃癌临床实践指南中国版

解读北京大学临床肿瘤学院北京肿瘤医院消化内科沈琳2008肿瘤学临床实践指南（中国版）2008年第一版胃癌Copyright©2005AmericanCancerSocietyAge-standardizedIncidenceRatesforStomachCancerinworld.FromParkin,D.M.etal.CACancerJClin2005;55:74-108.世界胃癌年龄调整发病率对1990-1992年中国的1/10万人口死因抽样调查资料中胃癌死亡情况进行分析胃癌粗死亡率(crudemortalityrate)25.2/10万（M：32.8/10万，F：17.0/10万），占全部恶性肿瘤死亡的23.2%，恶性肿瘤死亡中第一位。（男性是女性1.9倍）中国胃癌世界人口调整死亡率(mortalityratesadjustedbytheworldpopulation)男性：40.8/10万，女性：18.6/10万，分别是欧美发达国家的4.2-7.9倍，3.8-8.0倍有明显的地区差异和城乡差别。全国抽样调查263个点，胃癌调整死亡率在2.5-153.0/10万之间，Urbanareas:15.3/10万;Ruralareas:24.4/10万，是城市的1.6倍NCCN共识分类1类：基于高水平的证据，NCCN达成共识，推荐应用2A类：基于包括临床经验在内的稍低水平证据，NCCN达成共识，推荐应用。2B类：基于包括临床经验在内的稍低水平证据，NCCN未达成统一共识（但无较大分歧）。3类：NCCN对该建议的适宜性存在较大分歧。除非特别说明，本指南中所有的建议均达成2A类共识。NCCN胃癌临床实践指南

2008第1版指南更新主要变化总结NCCNguidelines----GastricCancerChineseversion1.2008在整个治疗指南中将chemotherapy/RT更改为chemoradiation将salvage改为palliative与2007版类似注意：除了特别指出的情况，所有推荐的治疗都是2A证据的。临床试验：NCCN认为对于任何一个肿瘤病人参加临床实验都获得最佳治疗.要特别鼓励参与临床试验。强调多学科评估和协作！多学科综合治疗模式有益于局部进展期胃癌患者（1类证据）NCCN专家组基本观点：不鼓励单一学科成员单方面进行治疗决策。具备以下条件，可能给局部进展期胃癌患者以最佳的综合治疗：例会形势实用（一周或2周一次），相关学科的机构和个人定期来共同回顾患者的详细资料。每次例会，各相关学科都要积极参与，包括肿瘤外科，肿瘤内科，消化科，放射科，病理科。此外，最好还能包括营养科，社工，护理以及其他支持学科。所有长期的治疗策略要在全面分期检查完成后再进行，最好在所有治疗开始之前。决策前共同回顾原始的医学数据而非单纯阅读报告。多学科团队做出共识推荐并摘要记录在案，对每位患者是有益的。特定患者的主要治疗小组或医生应尊重以及考虑多学科团队所做出的共识推荐。反馈部分患者的治疗随访结果，对整个多学科团队是有效的实例教育方式。在例会期间，正式的定期复习相关文献，对整个多学科团队是高效的教育方式。外科治疗原则NCCNv.1.2008GastricCancer结合淋巴结数目以及累及区域分期JapaneseGastriccancerassociati（JGCA)腹腔细胞学（CY）CY0腹腔细胞学良性或无法确定CY1腹腔细胞学未见癌细胞CYx未作其它远处转移（M）§M0腹膜、肝、腹腔细胞学外无远处转移M1腹膜、肝、腹腔细胞学外有远处转移Mx不清楚分期

N0N1N2N3T1IAIBIIIIIAT2IBIIIIIAT3IIIIIAIIIBT4IIIAIIIBIVH1,P1,CY1,M1RegionalLNGroupAccordingtoLocationofTumorD14d4d4d653D211p12a14v1998a97LD/LSasakoetal:thelong-termoutcomeofsurvival：D2vsD2+,

nostatisticallysignificantdifference69%vs70%,p=0.57,HR:1.03,(95%CI:0.77-1.37).

SasakoM,SanoT,YamamotoS,etal.RandomizedphaseIIItrialofstandardD2versusD2+para-aorticlymphnode(PAN)dissection(D)forclinicallyM0advancedgastriccancer:JCOG9501.JClinOncol2006.24(18S):LBA4015.扩大根治orD2?——循证医学证据D1orD2?——循证医学证据适合于所有胃癌胃切除标本原发性胃癌胃切除标本的检查原发性肿瘤*外科切缘评估†淋巴结评估‡原发性胃癌的组织学类型§Lauren分类，1965日本胃癌研究协会（JRSGC）分类，1981WHO分类，2000病理学分期（pTNM）应包括下列参数：肿瘤的恶性程度（分级）ξ浸润的深度淋巴结的部位、数目及阳性数远端及近端外科切缘状况§胃癌组织学类型Lanren分类（1965）：肠型；弥漫型JRSGC分类（1981）：乳头状型管状型低分化型 粘液型印戒细胞型WHO分类（2000）腺癌肠型弥漫型乳头状腺癌管状腺癌粘液腺癌印戒细胞癌腺鳞癌鳞状细胞癌小细胞癌未分化癌其它ξ胃腺癌组织学分级：高分化；中分化；低分化；未分化病理学分期（pTNM）病理学分期与胃癌预后极其相关，早期胃癌预后极好，5年生存率达90%。建议使用AJCC/UICC分类，在病理报告中N分期可增加标注JRSGC要求的淋巴结部位。病理诊断原则系统化疗原则NEW遵照原始文献报道的药物剂量/方案,合理用药并进行适当调整患者合适的器官功能和体力状况充分考虑化疗的毒性和益处,并始终与患者及家属讨论/交流,并进行患者教育,警示并防治不良反应,避免严重合并症及缩短持续时间患者化疗期间仔细观察,及时治疗合并症,并适当监测患者血液学改变化疗阶段及时评估疗效和长期合并症2007.v.22008.v.1Preoperativechemo-therapyECFcategory1ECFcategory1ECFmodificationcategory1Preoperativechemo-radiationfluoropyrimidine/leucovorin2BFluoropyrimidine-based2BCisplatin-based2BTaxanes-based2BIrinotecan-based2Bpaclitaxel/Docetaxel+fluoropyrimidine(5FU/capecitabine）category2BUpdateof2008.v.1NCCNversion胃癌（占85%）或低位食管癌（15%）N=2505Y38%N=2535Y23%ECF:E50mg/m2C60mg/m2FU200mg/m2/dcivD.Cuuningham2005ASCOabs4001Cunninghametal,NEJM2006Chemo+SurgerySurgeryPatients250253Age6262ToSurgery219(88%)240(95%)PtswithR0resection169(68%)*166(66%)*NopathologiccompleteresponsesCunninghametal,NEJM2006Chemo+SurgerySurgeryPathSize3.1cm5.0cm(p=0.001)T1/T2T3/T452%48%38%62%(p=0.009)N0/1N2/384%16%76%24%(p=0.01)Cunninghametal,NEJM2006OverallSurvivalPatientsatriskLogrankp-value=0.009HazardRatio=0.75

(95%CI0.60-0.93)CSCS250168111795238272531558050311890.00.10.20.30.40.50.60.70.80.91.0Monthsfromrandomization0122436486072149250170253EventsTotalCSCSSurvivalrateN=1135YDFS34%N=1115YDFS21%FP:5-FU800mg/m2d1-5ciDDP100mg/m2d1Q4w随访5.7Y贲门、胃89％食管11％SurgeryChemo+SurgerypN111113R084%73%0.043yDFS25%40%5yDFS21%34%0.003HR0.65V.Boigeetal,ASCO2007abstr4510从12随机试验,2284患者中筛选出2102患者,涉及9个试验,中位随访时间5.3年CT+SvsSHR0.87P=0.003转化为5年绝对生存率提高4%R0切除率67%vs62%p=0.03etal,ASCO2007abstr4512GAST-C1of2:preoperativechemoradiation2008.v.1NCCNguideline：

Paclitaxel/docetaxel+fluoropyrimidine(5-FUorcapecitabine)category2B；RecommendationofChineseversion:Docetaxelmightbechanged;Category2Bto3.Reason:StudyaboutPaclitaxel/5FU+RTisonlyphaseII.Noprospectivestudieshasbeensearchedondocetaxel/5-FU+RT(medline).？Preoperativechemoradiation:phaseIIPhaseIITrialofPreoperativeChemoradiationinPatientsWithLocalizedGastricAdenocarcinoma(RTOG9904):QualityofCombinedModalityTherapyandPathologicResponse——JafferA.AjaniJCO2006：24（24）：3593Phase:IIPatients：43caseswithlocalizedGC(12%IB;37%II;52%III).，20centerMethods:2cysof5FU+CF+DDP——CRT(infusional5FU+weeklypaclitaxel)Resection（5to6weeksafterchemoradiotherapywascompleted.）Result：pathCR：26%R0resection：77%,1year：morepatientswithpathCR(82%)arelivingthanthosewithlessthanpathCR(69%）GAST-C1of2:preoperativechemoradiation2008.v.1NCCNguideline：

Paclitaxel/docetaxel+fluoropyrimidine(5-FU+capecitabine)category2B；RecommendationofChineseversion:Docetaxelmightbechanged;

Category2Bto3.2007.v.22008.v.1Postoperativechemo-therapyECFcategory1（onlywhenpreoperativeECFhasbeenadministered）ECFcategory1ECFmodificationcategory1（onlywhenpreoperativeECFhasbeenadministered）Postoperativechemo-radiationfluoropyrimidine/leucovorin1Fluoropyrimidine-based1Fluoropyrimidine/cisplatin2BECF2BTaxane-based2BFluoropyrimidine(5FUorcapecitabine)category1Updateof2008.v.1NCCNversionPostoperativechemotherapy?StageIB-IV(M0)D0和D1占90%GAST-3:T3,T4oranyT,N1afterR0resection2008.v.1NCCNguideline：RT,45-50.4Gy+concurrent5-FUbasedradiosensitization(preferred)+5-FU±leucovorinorECFifreceivedpreoperatively（category1）RecommendationofChineseversion:AddfootnoteIfD0/D1resection:agreedtheabove;IfD2resection:postoperativechemotherapyrecommended.Evidence：D0/D1operationconsistsmorethan90%inINT0116；2MetaanalysisaboutadjuvantchemotherapyGASC-studyPatients:23trials，4919ptsMethods:Adjuvantchemotherapyarm(ArmA):2441Observationarm(ArmB):2478Results:3ySurvivalrate:60.6%inArmA,53.4%inArmB(RR:0.85,95%CI:0.80–0.90)DFS:ArmBhadashorterDFS(RR:0.88,95%CI:0.77–0.99)Recurrencerate:ArmAhadalowerrecurrencerate(RR:0.78,95%CI:0.710.86)Grade3/4ofAE(myelosuppressionandGI):morefrequentlyinArmA.Conclusion:Adjuvantchemotherapycouldimprovethesurvivalrateanddisease-freesurvivalrateingastriccanceraftercurativeresectionandreducetherelapserate.METAanalysisofAdjuvantchemotherapy1Anupdatedmeta-analysisofadjuvantchemotherapyaftercurativeresectionforgastriccancer——EuropeanJournalofSurgicalOncology(EJSO)

METAanalysisofAdjuvantchemotherapy2Theroleofpostoperativeadjuvantchemotherapyfollowingcurativeresectionforgastriccancer:ameta-analysisShu-LiangZhao;Jing-YuanFang.RenjiHospital,Shanghai,China.CancerInvestigation,May2008,Vol.26Issue3,p317-325,Patients:15trials，3212pts，Methods:Surgery+adjuvantchemotherapyvsSurgeryonlyResults:RRfordeathinthetreatedgroupwas0.90(P=0.0010).

Littleornosignificantbenefitsweresuggestedinsubgroupanalysesbetweendifferentpopulationandregimenseither.Conclusion:Postoperativeadjuvantchemotherapyforgastriccancerconfersslightlysignificantbenefitscomparedtothesurgeryonlygroup.

Postoperativeadjuvantchemotherapy——S1monotherapyAdjuvantchemotherapyforgastriccancerwithS-1,anoralfluoropyrimidine.——Sakuramoto,SNEnglJMed，2007，357：1810-1820

1004cases(stageII/III，D2,3yearsfollowup*S-1monotherapy529casesOS:80.5%OS:70.5%RandomizedphaseIIItrialcomparingS-1monotherapyversussurgeryaloneforstageII/IIIgastriccancerpatients(pts)aftercurativeD2gastrectomy(ACTS-GCstudy).2007Gastrointestinalcancersymposium,sasakoMSurgeryalone530cases*12/2005showedthatHRofdeathforS-1toCwas0.57,trialwasrecommendedtostop.09/2006HRofdeathforS-1was0.68.Conclusions:AdjuvantchemotherapywithS-1forgastriccancerisfeasibleandeffective.ThisregimencanbethestandardtreatmentforstageII/IIIgastriccancerptsaftercurativeD2dissection.ACTS-GCstudyJCOGPostoperativechemoradiationmightbeagoodoptiontocompensatetheinsufficiencyofthesurgerysuchasD0/D1resection.Adjuvantchemotherapyshowssurvivalbenefitcomparedwithsurgeryalone,especiallyafterD2resectionforpatientswithstageIIorhigher.Postoperativeadjuvantchemotherapy

Conclusion:GAST-3：afterR1resection2008.v.1NCCNguideline：RT,45-50.4Gy+concurrent5-FU-basedradiosensitization(preferred)+5-FU±leucovorinRecommendationofChineseversion:

Toadd“Clinicaltrials”asanotheroption.Reason：R1resectionisnotradical,tillnow,nostandardtherapyhasbeenaccepted,itshouldbebettertofindtheappropriateonesbyclinicalstudies.2007.v.22008.v.1Metastaticorlocallyadvancedcancerfluoropyrimidine/leucovorin2BFluoropyrimidine-based2BCisplatin-based2BOxaliplatin-based2BTaxanes-based2BIrinotecan-based2BECF1DCF1ECF1ECFmodification1Irinotecan+cisplatin2BOxaliplatin+fluoropyrimidine(5-FUorcapecitabine)2BDCFmodification2BIrinotecan+fluoropyrimidine(5-FUorcapecitabine)2BUpdateof2008.v.1NCCNversionNoDDP+fluoropyrimidine(5-FUorcapecitabineorS－1)2BNopaclitaxel-basedregimens；V325研究结果TCF(多西紫杉醇、顺铂、5FU)是用于预后较好的患者的一项新的治疗选择Moiseyenkoetal,JCO2007,例数总体缓解疾病进展时间（月）总生存期（月）3—4级毒性TCF221/22737%5.69.2腹泻，感染，中性粒细胞减少症*p=0.01p=0.0004p=0.02CF#4002224/23025%3.78.6胃炎，肾毒性*3－4级毒性包括：81％的非血液学毒性反应，75％的血液学毒性反应中30％伴有中性粒细胞减少性发热CPT-11forAGC——Ⅱ期多中心临床研究

（2003ASCO）FFCD9803法国BoucheOetal.JClinOncol2004;22:4319–27例数RRmTTPmOSLV5FU24513%3.2m6.8mLV5FU2-DDP4427%4.9m9.5mLV5FU2-CPT-114540%6.7m11.3mCPT-11联合5-FU治疗AGC

----III期临床试验（2005ASCO）N=170CPT-1180mg/m2CF500mg/m25FU2000mg/m2civ1/Wx6wN=163CDDP100mg/m2d15FU1000mg/m2/dd1-5Q4WN=333AGCRR54（31.8%）42（25.8%）TTP5.0m4.2m(p=0.088)TTF4.0m3.4m(p=0.002)OS9.0m8.7mp＝0.53M.Dank2005ASCOabs4003REAL-2:疗效（Efficacy）EfficacyECF

N=263ECX

N=250EOF

N=245EOX

N=244P:ECFvsEOXRR(%)41464248

1yearOS(%)

37.740.840.446.8OS(mo)9.99.99.311.20.025Cunninghametal.ASCO2006LBA4017ECFEOFECXEOXGrade3/4non-haematologicaltoxicity,%36423345Grade3/4neutropenia,%42305128p-value

0.0080.00430.001REAL2:安全性

safetyoutcomesOxaliplatin联合EPI、5-FU/CF治疗

晚期胃癌的临床多中心研究——china用药方法乐沙定100mg/m2d1EPI50mg/m2d1CF200mg/m2d1-35-FU500mg/m2CIVd1-3每3周重复，治疗至少3个周期评价疗效及毒性反应CR2例（5.6%）PR13例（36.1%）SD17例（47.2%）

总有效率41.7%。其中初治患者9/20（45%）复治患者6/16（37.5%）]主要不良反应：骨髓抑制：Ⅲ-ⅣOANC7/36（19.4%），ⅢOPLT3/36（8.3%），ⅢO

Hb4/36（11.1%），ⅢO神经末梢毒性4/36（11.1%），以EPI为基础的三药联合可行！EOX有明显生存优势！ML17032:CAPEvs5-FUinAGC

trialdesignFP

Cisplatin

80mg/m23-houri.v.infusion5-FUc.i.

800mg/m2/day;d1–5q3wXPCisplatin

80mg/m23-houri.v.infusionCapecitabine

1000mg/m2twicedaily;d1–14q3wKPS≥70%18–75yearsAdvancedand/or

metastaticgastriccancer(AGC)≥1measurablelesionNopriortreatmentforAGCR

A

N

D

OM

I

ZA

T

I

O

NSuperiorresponseratewithXPvs.FPConfirmedresponse

%(95%CI)XP

(n=160)FP

(n=156)p-valueOverallresponse41(33–49)29(22–37)0.030Completeresponse230.668Partialresponse39260.019Progressivedisease10180.041ML17032:XPvsFP

progression-freesurvival.HR0.81

EstimatedprobabilityHR=0.81(95%CI:0.63–1.04)ComparedtoHRupperlimit1.25,p=0.00080Months24681012141618202224261.00.80.60.40.20.0PerprotocolanalysisXP(n=139)FP(n=137)MedianPFS

months(95%CI)5.6(4.9–7.3)5.0(4.2–6.3)相似的血液学不良发应

XPvs.FP

%ofpatientsXP

(n=156)FP

(n=155)

Neutropenia3330Leukopenia1417Anemia125Thrombocytopenia66APhaseIITrialofCapecitabineplusDDPinAGC－－China2002.6-2003.5,N=145,Cape1000mg/m2Bidd1-14DDP20mg/m2ivd1-5q3W130ptsevaluable:98M/32FAge:53.7ysResultsCR10(8%)PR48(37%)SD51(39%)PD21(16%)OS12mSafety：grade3-4adverseevent<5%-----2005,2006ASCOfirst-linechemotherapywithfluorouracil,leucovorinandoxaliplatin(FLO)versusfluorouracil,leucovorinandcisplatin(FLP)FLO

F2600mg/m224hinfusion,L200mg/m2,oxaliplatin85mg/m2q2wFLPF2000mg/m224hinfusion,qwL200mg/m2,qwcisplatin50mg/m2,q2w.Total220

ptsMedianage64yrs

Advancedand/or

metastaticgastriccancer(AGC)R

A

N

D

OM

I

ZA

T

I

O

NS.Al-Batran,J.Hartmann,ASCO2006TheprimaryendpointwasTTPSuperiorPerformancewithFLOvs.FLPConfirmedresponse

%(95%CI)FLO(N=98)FLP

(n=102)p-valueOverallresponse34%27%0.012TTP5.73.80.081TTF5.33.10.028S.Al-Batran,J.Hartmann,ASCO2006PhaseIIStudyofS-1±DDPvs5-FU+DDPforGastricCancer(PI:MLJin)C:5-FU+DDPA:S-1B:S-1+DDPrandomizationAssumed180cases，60casesperarm，enrollmentcompletedObjective：RR,TTPPathologicallyconfirmed，unrectable，measurableleasionsEvidence：SC-101study

——2008ASCOmeetingArmNCR+PRTTF(d)OS(d)N%A:S1771924.7*126★267＃B:S-1/CDDP742837.8159433C:5-FU/CDDP731419.2※85★309＃※:ArmBcomparedwithArmC,P<0.05★:ArmBcomparedwithArmAandC,P<0.05＃:ArmBcomparedwithArmAandC,P<0.05*:ArmBcomparedwithArmA,P>0.05Evidence：SC-101study

——2008ASCOmeetingElderlychemo-naïvepts(>=65years)withmeasurablemetastaticorrecurrentgastriccancerarmX(N=46,Medianage=71.0years

)Capecitabine(1,250mg/m2bid,D1-14every3weeks)

armS(N=45,Medianage=70.5years)S-1(40~60mgbidD1-28every6weeks)

randomly10/2004-4/2006

Arandomizedmulti-centerphaseIItrial：

capecitabine(X)versusS-1(S)asfirst-linetreatment

inelderlypatientswithmAGCY.Kang,D.Shin

2007ASCOAnnualMeetingArandomizedstudy:theactivityandsafetyofcapecitabinevsS-1inelderlyptswithAGCphaseII

Y.Kang,

JCO,2007ASCOMeetingsProceedingsPartI.Vol25,No.18S:4546)

Evidence：capecitabinevsS-1

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)Grade3/4(%)1250mg/㎡bidd1-14/3W40-60mg/㎡bidd1-28/6WLeukopenia6.84.8Asthenia07.2Anorexia6.89.5Diarrhea2.30HFS6.80Evidence：capecitabinevsS-1toxity2007.v.22008.v.1Metastaticorlocallyadvancedcancerfluoropyrimidine/leucovorin2BFluoropyrimidine-based2BCisplatin-based2BOxaliplatin-based2BTaxanes-based2BIrinotecan-based2BECF1DCF1ECF1ECFmodification1Irinotecan+cisplatin2BOxaliplatin+fluoropyrimidine(5-FUorcapecitabine)2BDCFmodification2BIrinotecan+fluoropyrimidine(5-FUorcapecitabine)2BUpdateof2008.v.1NCCNversionDDP+fluoropyrimidine(5-FUorcapecitabineorS－1)2BarandomizedphaseIItrialoftheSwissGroupforClinicalCancerResearch.Chemotherapy-naivepatientsECFvsDCvsDCFEvidence1:docetaxel——RothAD,FazioN,etal,JClinOncol.2007Aug1;25(22):3217-23.n=119ECFDCDCFORR25.0%18.5%36.6%MedianOS8.311.010.4neutropeniaG3/434%49%57%QOLsimilararandomizedphaseIIstudyinGermanypatientswithuntreated,advancedgastricadenocarcinoma.Evidence2:docetaxel——Thuss-PatiencePC,KretzschmarA,etal：JClinOncol.2005Jan20;23(3):494-501.

n=90ECFDFORR35.6%37.8%MedianOS9.7m9.5mTTP5.3m5.5marandomizedphaseIItrial106patientsincludedwDCFvswDXwDCF:DOC30mg/m2d1d8;DDP60mg/m2;5-Fu200mg/m2civwDX

DOC30mg/m2d1d8;CAPE1600mg/m2d1-14Evidence3:docetaxel（Weekly）——N.Tebbutt,etal,Asco2007,4528.

wDCFn=50wDXn=56CR+PR%4926Febrileneutropenia%42Gr¾lethargy%104Gr¾diarrhea%107Gr¾stomatitis%222Gr3hand-footSyn%42OSmonths12.810.1Evidence:paclitaxelvsdocetaxelPaclitaxelversusdocetaxelforadvancedgastriccancer:arandomizedphaseIItrialincombinationwithinfusional5-fluorouracil.

——ParkSHetal,AnticancerDrugs.2006Feb;17(2):225-9Phase:II,randomizedPatients：77caseswithmeasurablemetastaticgastriccancer(PFvsDF).Methods:

PXL+5-FuvsDOC+5-FuResult：responserate(42vs33%,P=0.53)overallsurvival(9.9vs9.3m;P=0.42)grade3/4toxicities(68vs85%;P=0.09)Globalqualityoflife:similarpain,dyspnea,constipationanddiarrheafavoredPFConclusion:

BothPFandDFappeartohaveefficacyagainstmetastaticgastriccancer,withdifferent,butacceptable,safetyprofiles.2007.v.22008.v.1Metastaticorlocallyadvancedcancerfluoropyrimidine/leucovorin2BFluoropyrimidine-based2BCisplatin-based