MCRC治療策略-科內(nèi)講課

轉(zhuǎn)移性結(jié)直腸癌的治療策略根據(jù)不同患者特征制定治療策略Group3

non-resectablemetastases,lessaggressivediseaseIntensivetherapyLessintensivetherapyGroup1PotentiallyresectablemetastasesGroup2non-resectablemetastases,hightumorburden,tumor-relatedsymptomsGroup0ResectablemetastasesNeoadjuvantchemotherapyornot?針對(duì)不同患者應(yīng)有不同的治療目標(biāo)(ESMO)肯定無法切除的MCRC，且腫瘤進(jìn)展緩慢初始不可切除但病灶局限的MCRC肯定無法切除的MCRC,合并巨大腫瘤負(fù)荷或明顯的腫瘤相關(guān)癥狀治愈緩解臨床癥狀延長(zhǎng)總生存期根據(jù)不同治療目標(biāo)設(shè)定治療策略

(ESMO)

臨床特征

具體治療目標(biāo)

治療選擇

肝(±肺)轉(zhuǎn)移

潛在可切除

多個(gè)轉(zhuǎn)移灶

腫瘤進(jìn)展快速

明顯的臨床癥狀

病情可能迅速惡化最大程度縮小腫瘤(RR)控制腫瘤進(jìn)展(PFS)優(yōu)先選擇聯(lián)合方案：聯(lián)合靶向藥物三藥聯(lián)合方案

不可切除的MCRC

無法轉(zhuǎn)化為可切除

無臨床癥狀或快速惡化風(fēng)險(xiǎn)

存在明顯或較多合并癥控制腫瘤的進(jìn)一步增長(zhǎng)控制藥物不良反應(yīng)不追求腫瘤是否縮小單藥續(xù)貫治療或雙藥聯(lián)合方案VanCutsemE,etal.AnnOncol2010;21(Suppl.5):v93–v97;VanCutsemE,etal.AnnOncol2010;21(Suppl.6):vi1–vi10化療方案的評(píng)估5-FU持續(xù)灌注vs5-FU推注:RR與OS占優(yōu)Sixtrials

(1219patients)5-FUBolus5-FU

CI

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

RR占優(yōu)，TTP與OS無差別兩項(xiàng)III期臨床研究（n=1200）HigherRRforcapecitabine

(19%to26%vs15%to16%)Nodifferenceintimetoprogression(TTP)orOSHoffPMetal.JClinOncol2001;19:2282–2292;VanCutsemEetal.JClinOncol2001;19:4097–4106Iri或Oxa聯(lián)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為基礎(chǔ)的聯(lián)合方案療效無明顯差異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;K?hneetal.2003.一線治療mCRC的III期臨床研究

NO169661st-line

(n=2034)NO169672nd-line

(n=627)FOLFOXXELOXFOLFOXXELOXMedianOS,mo19.819.611.912.5MedianPFS,mo8.58.04.84.7RR,%49462017XELOX與FOLFOX在一二線治療療效無明顯差異SaltzJetalClinOncol2008;RothenbergetalJClinOncol2008.三藥聯(lián)合：FOLFOXIRIvs.FOLFIRIHORGstudyFOLFIRI(median19.5months)FOLFOXIRI(median21.5months)p=0.337FOLFIRI(median6.9months)FOLFOXIRI(median8.4months)p=0.17SouglakosJetal.BrJCancer2006PFS與OS：FOLFOXIRI優(yōu)于FOLFIRIGONOtriplechemotherapytrial(n=244)Falconeetal.JClinOncol2007切除率：三藥聯(lián)合優(yōu)于兩藥聯(lián)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;化療方案評(píng)估小結(jié)作為單藥或聯(lián)合化療方案，Cap≈FU兩藥聯(lián)合方案優(yōu)于單藥FOLFIRI≈FOLFOXFOLFOX≈XELOXFOLFOXIRI具有更高的療效，但結(jié)果并不完全一致，可能更多的用于新輔助化療聯(lián)合方案過渡為維持治療（holiday）分子靶向治療-貝伐珠單抗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+貝伐單抗

(n=699)XELOX/FOLFOX4+安慰劑

(n=701)1.00.80.60.40.20月患者比例061218243019.921.2NO16966研究：輕度延長(zhǎng)OS

FOLFOX/XELOX±bevacizumabNO16966：“持續(xù)治療”患者的臨床獲益*預(yù)設(shè)次要分析Saltz,etal.ASCO2007;Saltz,etalJCO2008Bevacizumab一線治療mCRC匯總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中位生存時(shí)間患者人數(shù)A:FOLFOX4+貝伐單抗28612.9B:FOLFOX429110.8C:貝伐單抗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+貝伐單抗C:貝伐單抗B:FOLFOX4E3200研究：延長(zhǎng)OS

FOLFOX4±bevacizumabBevacizumab治療mCRC小結(jié)Bevacizumab聯(lián)合5-FU明確延長(zhǎng)PFSBevacizumab聯(lián)合IFL改善PFS與OSBevacizumab聯(lián)合FOLFIRI需要隨機(jī)對(duì)照研究Bevacizumab聯(lián)合FOLFOX/XELOX改善PFSBevacizumab的治療不受KRAS基因狀態(tài)影響分子靶向治療-西妥昔單抗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，未延長(zhǎng)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單抗一線治療mCRC研究匯總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治療mCRC小結(jié)Cetuximab是目前與FOLFIRI方案聯(lián)合有效改善OS的靶向藥物Cetuximab聯(lián)合改OXA改善RR，部分研究改善PFS治療前推薦常規(guī)進(jìn)行KRAS基因突變檢測(cè)NCCN指南中Cetuximab聯(lián)合FOLFOX或XELOX方案不被推薦根據(jù)不同患者特征制定治療策略Group3

non-resectablemetastases,lessaggressivediseaseIntensivetherapyLessintensivetherapyGroup1PotentiallyresectablemetastasesGroup2non-resectablemetastases,hightumorburden,tumor-relatedsymptomsGroup0ResectablemetastasesNeoadjuvantchemotherapyornot?數(shù)目越多，轉(zhuǎn)移灶越大者新輔助化療獲益40983研究：圍手術(shù)期化療改善PFS隨機(jī)患者肝轉(zhuǎn)移切除患者圍手術(shù)期化療=新輔助化療+輔助化療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歐洲肝膽外科學(xué)組建議ESMO推薦意見具有一項(xiàng)以上高危因素患者應(yīng)接受新輔助化療多個(gè)轉(zhuǎn)移灶最大徑≥5cm異時(shí)性肝轉(zhuǎn)移原發(fā)瘤淋巴結(jié)陽(yáng)性腫瘤標(biāo)記物（CEA）升高<2cm的單發(fā)異時(shí)性轉(zhuǎn)移瘤，可能從直接手術(shù)獲益，但該類病例<10%TML：BEV跨線治療TML（ML18147）：貝伐單抗治療疾病進(jìn)展的患者主要終點(diǎn)：OSBRITE：疾病進(jìn)展后的OS9.5v.19.2個(gè)月標(biāo)準(zhǔn)一線化療+貝伐單抗治療mCRC

(n=820)貝伐單抗5mg/kgq2w或7.5mg/kgq3w+標(biāo)準(zhǔn)二線化療交換至標(biāo)準(zhǔn)二線化療n=410n=410治療直至進(jìn)展RPD(NCT00700102)排除：一線治療<3個(gè)月進(jìn)展的患者治療后進(jìn)展的mCRC使用貝伐單抗的前瞻性、對(duì)照研究TML（ML18147）：貝伐單抗治療疾病進(jìn)展的患者主要終點(diǎn)：OSBRITE：疾病進(jìn)展后的OS9.5v.19.2個(gè)月標(biāo)準(zhǔn)一線化療+貝伐單抗治療mCRC

(n=820)貝伐單抗5mg/kgq2w或7.5mg/kgq3w+標(biāo)準(zhǔn)二線化療交換至標(biāo)準(zhǔn)二線化療n=410n=410治療直至進(jìn)展RPD(NCT00700102)排除：一線治療<3個(gè)月進(jìn)展的患者TML：BEV跨線治療TML：BEV跨線治療MCRC2nd-lineRANDOMIZEAflibercept4mg/kgIV,day1

+FOLFIRIq2weeksPlaceboIV,day1

+FOLFIRIq2weeks1:1DiseaseProgressionDeath

600pts600ptsPrimaryEndpo