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1、RFOLFOX4 x 6 cyclesSurgeryFOLFOX4 x 6 cyclesSurgery 364 patients Potentially resectable(1-4)liver metastases Goal:Improve progression-free survival to demonstrate a 40%increase in median PFS(HR=0.71)with 80%power and 2-sided significance level 5%HR=0.77;CI:0.60-1.00,p=0.041Periop CT28.1%36.2%+8.1%At
2、 3 years(years)01234560102030405060708090100ONNumber of patients at risk:125 171835737228115 1711157443215Surgery onlyOpen Planned Accrual 400FOLFOX6 modified+cetuximab6 cyclesRANDOMIZATIONResectableLiver Metastases from Colorectal Cancer no extrahepatic diseaseWHO PS 0,1No previous chemo for metsFO
3、LFOX6 modified+cetuximab+bevacizumab6 cycles(no bevacizumab in cycle#6)FOLFOX6 modified+cetuximab6 cyclesFOLFOX6 modified+cetuximab+bevacizumab6 cyclesfollow upfollow upSURGERYSURGERYDownsizingsizelocationnumberPalliativeCurativeSurvivalTimeHAI FUDR 0.18 mg/kg+DEX 25 mg over 14 daysEvery 28 days (N=
4、68)5-FU 425 mg/m2+LV 20 mg/m2Daily x 5 every 4 weeks (N=67)RKemeny NE et al.J Clin Oncol 24:1395-1403,2006 HAI 5FU/LVMed OS(months)24.420.0 (p=0.034)THP(months)9.8 7.3 (p=0.034)TEP(months)7.714.8 (p=0.029)RR 47%24%HAI5FU/LVKemeny et al.J Clin Oncol.2006;24:1395.HepaticNonhepaticHAISystemic,P=0.034Ye
5、ars from trial entryProportion hepatic progressionfree012300.20.40.60.81.0012300.20.40.60.81.0HAISystemic,P=0.029Proportion nonhepatic progressionfreeYears from trial entryResection of non-resectable liver metastases after systemic chemotherapyPublished seriesAuthorsLevi FowlerBismuthGiachettiAdamWe
6、inRivoireYear1992199219961999200120012002No Pts98-33038970153131Type ChemoFu-Fol-OxaliFu-FolFu-Fol-Oxali Fu-Fol-Oxali*Fu-Fol-OxaliFu-FolFu-Fol-Oxali No Resect18(19%)1153(16%)77(20%)95(14%)6 (11%)57(43%)5-yr Surv-40%50%39%-Fu-Fol-Oxali:Chronomodulated*Liver only metastasesSurvival after Liver Resecti
7、on of Colorectal MetastasesPaul Brousse Hospital-473 patients(Apr.88-Jul.99)Years20406080100012345678910Survival(%)91%48%30%66%33%23%52%P=0.01Adam R et al.Ann Surg 2004No SurgeryResectable:335Initially non resectable:138Collaboration:Oncologists-Surgeons For Non Resectable Metastases1-Current chemot
8、herapy allows at least 20%of patients to be rescued by liver surgery2-The survival benefit of these patients is substantial (30%and 20%rate at 5 and 10 years)3-Resectability:a new end point for treatment strategyAdam R.et al.,Ann.Surg.Oncol.,2001;8:347-353Chemo:701(80%)14%900800700600500400300200100
9、0Resection:266(31%)86%36%64%95872 patients1988-1996Initially non-resectableNon-resectableResectable14%of 701 CT-treated patients achieved a response permitting resection ChemotherapyPatient status at a mean follow-up of 4.2 years56 dead(59%)39 alive(41%)25 alive disease free(26%)14 alive with diseas
10、e(15%)Survival after primary or secondaryresection of liver metastasesStrictly confidential.For internal use only.Non-promotional material.ACROBATACROBAT 研究设计研究设计FOLFOX+FOLFOX+西妥昔单抗一线治疗西妥昔单抗一线治疗转移性结直肠癌转移性结直肠癌ACROBATACROBAT 研究设计研究设计FOLFOX+FOLFOX+西妥昔单抗一线治疗西妥昔单抗一线治疗转移性结直肠癌转移性结直肠癌(n=43)入组入组入组入组主要终点主要终点主
11、要终点主要终点:RRRRRRRRCetuximabCetuximab(400 mg/m(400 mg/m2 2week 1 and week 1 and 250 mg/m250 mg/m2 2weekly thereafter)weekly thereafter)FOLFOX4 FOLFOX4 方案直至疾病进展或不能耐受毒性方案直至疾病进展或不能耐受毒性次要终点次要终点次要终点次要终点:安全性、安全性、安全性、安全性、耐受性耐受性耐受性耐受性、TTP TTP TTP TTP、OSOSOSOS初筛了初筛了6262例病人例病人(ECOG PS 0(ECOG PS 0?2);52(84%)2);52
12、(84%)例是有例是有EGFREGFR过度表达的转移性过度表达的转移性病人病人;43;43例入组例入组(安全性和疗效均可评估安全性和疗效均可评估)+E Diaz-Rubio et al,2005 ASCO Abs 3535Strictly confidential.For internal use only.Non-promotional material.ACROBATACROBAT 研究有效率高达研究有效率高达8181ACROBATACROBAT 研究有效率高达研究有效率高达81819 9 例病人例病人(21%)(21%)获得了二次手术获得了二次手术R0 R0(完全切除完全切除):7(17
13、%):7(17%)E Diaz-Rubio et al,2005 ASCO Abs 353587 87?99%99%98%98%4141疾病控制疾病控制(OR+SD)(OR+SD)66 66?91%91%81%81%3434总有效率总有效率(CR+PR)(CR+PR)7 7?31%31%17%17%7 7疾病稳定疾病稳定(SD)(SD)55 55?84%84%71%71%3030部分缓解部分缓解(PR)(PR)3 3?23%23%10%10%4 4完全缓解完全缓解(CR)(CR)可信区间可信区间95%CI95%CI百分比百分比病例数病例数N=42N=42Peeters et al.Eur J
14、Cancer 2005;Supplement 3:Abstract 664StratificationCenterPS 0/1 vs 2Adj.CtxRFOLFIRICPT-11 180 mg/m2 d1LV100 mg/m2 d1,25-FU400 mg/m2 bolus d1,25-FU600 mg/m2 22h inf d1,2q 2 wks x 12 cyclesFOLFOXIRICPT-11 165 mg/m2 d1Oxali 85 mg/m2 d1LV200 mg/m2 d15-FU 3200 mg/m2 48h inf d1q 2 wks x 12 cyclesFalcone e
15、t al.,ASCO4026,JCO 2007*externally reviewed:67%2nd line FOLFOXFalcone.,ASCO4026,JCO 2007*CMH testn=599/groupn=599/groupn=134/n=122p=0.0034*odds ratio 3.0 95%CI:1.4-6.5 FOLFIRI alone ERBITUX+FOLFIRINo residual tumor in patients with liver metastasesITT populationLiver-limited disease populationVan Cu
16、tsem et al,ASCO 2007 Patients with steatohepatitis had an increased 90-day mortality compared with patients who did not have steatohepatitis(P=0.001)*Comparison of each group vs no chemotherapy.Vauthey et al.J Clin Oncol.2006;24:2065.Vasodilation&CongestionPeliosis:Hemorrhagic Centrilobular Necrosis Nodular Regenerative Hyperplasia Vascular Changes in Liver Post Systemic Chemotherapy Aloia et al,J Clin Oncol 24:4983,2006Hepatic atrophy&sinusoidal congestionCollaboration Oncologists-Surgeons for
