MCRC治疗策略-科内讲课

转移性结直肠癌的治疗策略根据不同患者特征制定治疗策略Group3

non-resectablemetastases,lessaggressivediseaseIntensivetherapyLessintensivetherapyGroup1PotentiallyresectablemetastasesGroup2non-resectablemetastases,hightumorburden,tumor-relatedsymptomsGroup0ResectablemetastasesNeoadjuvantchemotherapyornot?针对不同患者应有不同的治疗目标(ESMO)肯定无法切除的MCRC，且肿瘤进展缓慢初始不可切除但病灶局限的MCRC肯定无法切除的MCRC,合并巨大肿瘤负荷或明显的肿瘤相关症状治愈缓解临床症状延长总生存期根据不同治疗目标设定治疗策略

(ESMO)

临床特征

具体治疗目标

治疗选择

肝(±肺)转移

潜在可切除

多个转移灶

肿瘤进展快速

明显的临床症状

病情可能迅速恶化最大程度缩小肿瘤(RR)控制肿瘤进展(PFS)优先选择联合方案：联合靶向药物三药联合方案

不可切除的MCRC

无法转化为可切除

无临床症状或快速恶化风险

存在明显或较多合并症控制肿瘤的进一步增长控制药物不良反应不追求肿瘤是否缩小单药续贯治疗或双药联合方案VanCutsemE,etal.AnnOncol2010;21(Suppl.5):v93–v97;VanCutsemE,etal.AnnOncol2010;21(Suppl.6):vi1–vi10化疗方案的评估5-FU持续灌注vs5-FU推注:RR与OS占优Sixtrials

(1219patients)5-FUBolus5-FU

CI

p-valueResponserate,%1422<0.0002Mediansurvival,months11.312.1<0.04Meta-analysisGroupinCancer.JClinOncol1998;16:301–308capecitabinevs5-FUbolus/LV：

RR占优，TTP与OS无差别两项III期临床研究（n=1200）HigherRRforcapecitabine

(19%to26%vs15%to16%)Nodifferenceintimetoprogression(TTP)orOSHoffPMetal.JClinOncol2001;19:2282–2292;VanCutsemEetal.JClinOncol2001;19:4097–4106Iri或Oxa联合5-FU/LV改善生存Median6.7vs4.4months,p<0.001DouillardJYetal.Lancet2000;355:1041–47;deGramontAetal.JClinOncol2000;18:2938–47.Irinotecan-basedregimen:TTPOxaliplatin-basedregimen:PFSMedian8.2vs6.0months,p=0.003Oxa或Iri为基础的联合方案疗效无明显差异Oxaliplatin-basedIrinotecan-basedRR,%5148456349393154MedianPFS,months8.27.98.79.26.77.06.98.5MedianOS,months16.219.719.521.417.414.814.820.1deGramontetal.2000;Grotheyetal.2002;Goldbergetal.2004;deGramontetal.2004;Douillardetal.2000;Saltzetal.2000;Goldbergetal.2004;Köhneetal.2003.一线治疗mCRC的III期临床研究

NO169661st-line

(n=2034)NO169672nd-line

(n=627)FOLFOXXELOXFOLFOXXELOXMedianOS,mo19.819.611.912.5MedianPFS,mo8.58.04.84.7RR,%49462017XELOX与FOLFOX在一二线治疗疗效无明显差异SaltzJetalClinOncol2008;RothenbergetalJClinOncol2008.三药联合：FOLFOXIRIvs.FOLFIRIHORGstudyFOLFIRI(median19.5months)FOLFOXIRI(median21.5months)p=0.337FOLFIRI(median6.9months)FOLFOXIRI(median8.4months)p=0.17SouglakosJetal.BrJCancer2006PFS与OS：FOLFOXIRI优于FOLFIRIGONOtriplechemotherapytrial(n=244)Falconeetal.JClinOncol2007切除率：三药联合优于两药联合

Study

Regimen

nResponserate(%)Resectionrate,allptsSurvival(months)Barone1FOLFIRI40483331.5Alberts2FOLFOX442604026Seium3OCFLalternating30782325.4Masi4FOLFOXIRI74722636.8aAbad5FOLFOXIRI476932>22Ychou6FOLFIRINOX347182(27)b–Souglakos7FOLFOXIRIFOLFIRI137146433410421.519.5Falcone8FOLFOXIRIFOLFIRI122122603415b6b22.616.7aSubpopulationofpatientswhowereresected,bConfirmedR0resections1BaroneCetal.BrJCancer2007;97:1035–1039;2AlbertsSRetal.JClinOncol2005;23:9243–9249;3SeiumYetal.AnnOncol2005;16:762–766;4MasiGetal.AnnSurgOncol2006;13:58-65;5AbadAetal.ActaOncol2008;47:286–292;6YchouMetal.CancerChemotherPharmacol2008;62:195–201;7SouglakosJetal.BrJCancer2006;94:798-8058FalconeAetal.JClinOncol2007;25:1670–1676;化疗方案评估小结作为单药或联合化疗方案，Cap≈FU两药联合方案优于单药FOLFIRI≈FOLFOXFOLFOX≈XELOXFOLFOXIRI具有更高的疗效，但结果并不完全一致，可能更多的用于新辅助化疗联合方案过渡为维持治疗（holiday）分子靶向治疗-贝伐珠单抗5FU/LV+/-bevacizumab:改善OSKabbinavarFF,etal.JClinOncol2005;23:3706-3712.OSestimate 0 10 20 30 40Time(months)Mediansurvival(months):14.6vs17.9

HR=0.74,p=0.00815-FU/LV/bev5mg(n=249)5-FU/LVorIFL(n=241)14.617.90.00.20.40.60.81.0MedianOSC:18.9monthsCB:18.9monthsCBM:16.4monthsHazardratiosCvsCB:0.86,p=0.2CvsCBM:1.00,p>0.906121824300.00.20.40.60.81.0Time(months)CapecitabineCapecitabine+BevacizumabCapecitabine+Bevacizumab+MitomycinCMAXstudy:Capecitabine+/-bevacizumab:

未改善OSTebbuttNC,etal.JClinOncol2010;28:3191-3198.OSestimateNO2107研究：:改善RR、TTP、OS

IFL±bevacizumabHurwitzH,etal.NEJM2004;350:2335-2342.010203040IFL/placeboIFL/bevTime(months)NRRTTPOSIFL/placebo41235%6.215.6IFL+bev40345%10.620.30.00.20.40.60.81.0OSestimateBICC-CPeriod2:改善OS

FOLFIRI+bevacizumabvsmIFL+bevacizumab1.00.80.60.40.20.0010203040FOLFIRI+bevacizumabmIFL+bevacizumabnOSBeva+FOLFIRI6928monthsBeva+mIFL5719monthsOSestimateTime(months)FuchsCS,etal.JClinOncol2007;25:4779-4786;

FuchsCS,etal.JClinOncol2008;26:689-90.NO16966研究：改善PFS

FOLFOX/XELOX±bevacizumabFOLFOX/XELOX+placebo(n=701)

FOLFOX/XELOX+bevacizumab(n=699) 0 5 10 15 20 25Time(months)HR=0.83[97.5%CI0.72–0.95](ITT)p=0.00231.00.80.60.40.20.08.09.4SaltzLB,etal.JClinOncol2008;26:2013-2019.PFSestimateSaltz,etal.ASCO2007HR=0.89 p=0.0769XELOX/FOLFOX4+贝伐单抗

(n=699)XELOX/FOLFOX4+安慰剂

(n=701)1.00.80.60.40.20月患者比例061218243019.921.2NO16966研究：轻度延长OS

FOLFOX/XELOX±bevacizumabNO16966：“持续治疗”患者的临床获益*预设次要分析Saltz,etal.ASCO2007;Saltz,etalJCO2008Bevacizumab一线治疗mCRC汇总1-Hurwitzetal,NEJM2004;2-Kabbinavaretal.JCO2005;3-MAXstudy:Tebbuttetal;ECCO/ESMO2009;4-NO16966study:Saltzetal.JCO2008;5-StathopoulosetalOncology2010.*Statisticallysignificant;**lowdoseintensityIrinotecanStudyNo.ofpatientsRR%MedianPFS(mo)MedianOS(mo)Median

OS(mo)IFL813356.215.6+4.7

MonthsIFL+bev145*10.6*20.3*Bolus5-FU/LV209155.512.9+4.7MonthsBolus5-FU/LV+bev226*9.2*16.6Capecitabine3135.718.90

MonthsCapecitabine+bev38.5*18.9XELOX/FOLFOX1401388.019.9+1.3MonthsXELOX/FOLFOX+bev4389.4*21.3Bolus5-FU/LV-IRI22235.2?25-3

MonthsBolus5-FU/LV-IRI**+bev536.822中位生存时间患者人数A:FOLFOX4+贝伐单抗28612.9B:FOLFOX429110.8C:贝伐单抗24310.2Giantonio,etal.JCO2007患者的生存比例1.00.80.60.40.20月 0 3 6 9 12 15 18 21 24 27 30 33 36HR=0.75AvsB:p=0.001110.212.910.8A:FOLFOX4+贝伐单抗C:贝伐单抗B:FOLFOX4E3200研究：延长OS

FOLFOX4±bevacizumabBevacizumab治疗mCRC小结Bevacizumab联合5-FU明确延长PFSBevacizumab联合IFL改善PFS与OSBevacizumab联合FOLFIRI需要随机对照研究Bevacizumab联合FOLFOX/XELOX改善PFSBevacizumab的治疗不受KRAS基因状态影响分子靶向治疗-西妥昔单抗CRYSTAL(KRASwt):改善OS,PFS,RR

FOLFIRI±CetuximabVanCutsemE,etal.JClinOncol(inpress)OS0.00.20.40.60.81.0180612245430364248Time(months)ERBITUX+FOLFIRI(n=316)FOLFIRI(n=350)2023.5HR=0.796Responserate(%)010203040506070FOLFIRI

(n=350)

ERBITUX

+FOLFIRI(n=316)57.339.7p<0.0001PFSTime(months)0.00.20.40.60.81.01204816209.98.4ERBITUX+FOLFIRI(n=316)FOLFIRI(n=350)HR=0.696OPUS:改善PFS,RR，未延长OS

FOLFOX±CetuximabBokemeyerC,etal.AnnOncol2011(EpubJan12);BokemeyerC,etal.ASCOGI2010(AbstractNo428)

Responserate(%)010203040506070FOLFOX

(n=97)

ERBITUX

+FOLFOX

(n=82)5734p=0.00270.00.20.40.60.81.0061218243036Time(months)ERBITUX+

FOLFOX4(n=82)FOLFOX4(n=97)OS18.522.8HR=0.8551.00.80.60.40.20.0048121620Time(months)PFS7.28.3ERBITUX+

FOLFOX4(n=82)FOLFOX4(n=97)HR=0.567抗EGFR单抗一线治疗mCRC研究汇总ERBITUX(CRYSTAL)Panitumumab(PRIME)ERBITUX(OPUS)ERBITUX(COIN)Endpointsignificantly

superiorwithmAbvs

CTcomparatorOS

XXXPFS

X

RR

X

Curativeresectionrates

X

XVanCutsemE,etal.ASCOGI2010(AbstractNo.281);DouillardJ-Y,etal.JClinOncol2010;28:4697–4705;

BokemeyerC,etal.AnnOncol2011(EpubJan12);MaughanT,etal.ASCOGI2010(AbstractNo.402)Cetuximab治疗mCRC小结Cetuximab是目前与FOLFIRI方案联合有效改善OS的靶向药物Cetuximab联合改OXA改善RR，部分研究改善PFS治疗前推荐常规进行KRAS基因突变检测NCCN指南中Cetuximab联合FOLFOX或XELOX方案不被推荐根据不同患者特征制定治疗策略Group3

non-resectablemetastases,lessaggressivediseaseIntensivetherapyLessintensivetherapyGroup1PotentiallyresectablemetastasesGroup2non-resectablemetastases,hightumorburden,tumor-relatedsymptomsGroup0ResectablemetastasesNeoadjuvantchemotherapyornot?数目越多，转移灶越大者新辅助化疗获益40983研究：围手术期化疗改善PFS随机患者肝转移切除患者围手术期化疗=新辅助化疗+辅助化疗40983研究：未能改善OSHR=0.87;CI:

0.66-1.14,p=0.303LV5FU+Oxaliplatin

PeriopCT+8.7monthsinmedianOS+4.1%

At5yearsSurgeryonly63.7M55M52.4.%48.3%5欧洲肝胆外科学组建议ESMO推荐意见具有一项以上高危因素患者应接受新辅助化疗多个转移灶最大径≥5cm异时性肝转移原发瘤淋巴结阳性肿瘤标记物（CEA）升高<2cm的单发异时性转移瘤，可能从直接手术获益，但该类病例<10%TML：BEV跨线治疗TML（ML18147）：贝伐单抗治疗疾病进展的患者主要终点：OSBRITE：疾病进展后的OS9.5v.19.2个月标准一线化疗+贝伐单抗治疗mCRC

(n=820)贝伐单抗5mg/kgq2w或7.5mg/kgq3w+标准二线化疗交换至标准二线化疗n=410n=410治疗直至进展RPD(NCT00700102)排除：一线治疗<3个月进展的患者治疗后进展的mCRC使用贝伐单抗的前瞻性、对照研究TML（ML18147）：贝伐单抗治疗疾病进展的患者主要终点：OSBRITE：疾病进展后的OS9.5v.19.2个月标准一线化疗+贝伐单抗治疗mCRC

(n=820)贝伐单抗5mg/kgq2w或7.5mg/kgq3w+标准二线化疗交换至标准二线化疗n=410n=410治疗直至进展RPD(NCT00700102)排除：一线治疗<3个月进展的患者TML：BEV跨线治疗TML：BEV跨线治疗MCRC2nd-lineRANDOMIZEAflibercept4mg/kgIV,day1

+FOLFIRIq2weeksPlaceboIV,day1

+FOLFIRIq2weeks1:1DiseaseProgressionDeath

600pts600ptsPrimaryEndpo