大肠癌肝转移综合治疗进展

Liver Metastases of Colorectal Cancer :Where are we standing in current practice ?,大肠癌肝转移综合治疗进展,郝纯毅 季加孚 北京肿瘤医院外科,我的老婆和丈母娘,Breast cancerWith positiveAxillary lymph nodes,Colorectal cancerWithLiver metastases,Different ? Similar !,1525 patients with primary CRC present with synchronous liver metastasesAn additional 20% will develop metachronous hepatic secondaries 20% are candidates for curative resection of liver metastases,U.S. 150 000 new cases 20 00030 000China 500 000 new cases 70 000100 000,EPIDEMIOLOGY,author year patients op mortality 5 year suvival # (%) (%)Adson 1984 141 2.8 23 Hugues 1986 859 5 33 Nordlinger 1987 80 5 25 Nordlinger 1996 1568 2.3 26 Fong 1999 1001 2.8 37 Yamamoto 1999 96 51Minagawa* 2000 235 0 38 Scheele 2001516 5.8 38,Overall Results of Hepatic Resection for CRC Metastases,Long term results ( French study, n=1985),5 year survivalOverall 26 %Confined to liver 28 %With extra hepatic extension 15 %Positive nodes 12 % Palliative resections 0 %,Overall Survival after Resection (French Study),Liver only,Prognostic Factors after R0-resection (),Demographic features: gender, agePrimary tumor: LN involvement, size, differentiation, staging and location( esp in sychronous metastases)Metastases: multiplicity of lesions and the intrahepatic tumor distribution?Satellite metastases Size of tumor Histopatholigical featuresSynchronous and metachronous metastases,Prognostic Factors after R0-resection (),Therapeutic approachOthers: PS, weight loss, serum albumin , preoperative CEA, tumor ploidy, oncogen/oncosupressor gene expression, etc.Surgeon performing the operation,Prognostic Factors Influencing Survival and Recurrences (French Study),Risk Factors Relative Risk Primary tumor : serosa + 1.4Primary tumor : N+ 1.5Delay (primary to metastase) 3 1.6Resection clearance 5cm 1.3Age 60 yrs 1.2 Plasma CEA 30 ng/ml 2.2,Survival According to Number of Risk Factors,Nordlinger B. Cancer 1996 ; 77:1254-62,*Fong Y. Ann Surg 1999;230:309-321,Survival According to the Number of Metastases,Months,ONE42%,TWO to THREE 30%,MORE than FOUR 23%,Probability of suvival,years from R0 resection,4 metastases (n = 48)13 metastases (n = 425),Scheele et al, 1999,Survival According to the Number of Metastases,P=0.99,1,.8,.6,.4,.2,0,8,6,4,2,0,10,years,Probability of survival,R0 resection (n=490)Disease-free survivalR1/2 resection (n=114),Survival after Liver Resection for CRC Liver Metastases,P=4.9*10-34,vs,29.5%(60),28.3%(57),41.3%(159),35.4%(137),Contraindications to CRC Liver Metastases,Radical(R0) resection not possible but: occasionally justified for symptomatic palliation ( RARE！)Lymph nodes metastases at the liver hilum but: anecdotal success reported by Nakamura, 1992Extrahepatic tumor except for direct invasion of adjacent structures, local recurrence, and a solitary ( 13?）lung metastases, As for any surgical procedure there are patients, and situations, in which the risk of the procedure is too high in relation to the potential benefits.,Factors Contributing to the Improved Results of Liver Metastases of CRC,肝脏外科技术的提高一些新的辅助/姑息治疗手段的出现术前影像诊断技术的改进多中心、大规模临床总结的发表,(回顾性、多中心/非前瞻性随机对照研究）,Preoperative Investigation,The primary tumor siteThe extent of liver involvementThe presence of extrahepatic diseaseMarkers to provide a baseline for follow-up,Preoperative diagnostic studies must be supplemented by thorough intraoperative assessment,Timing Of Liver Resection,a “test of time” ranging from several weeks to 6 months There exists controversy, and no conclusive data are available to support either of the assertions, which allows statement of personal position.Metastasis exceeded 4cm in diameter resect at finding the tumor has already passed the “test of time”Very small lesions wait for a period within 3 months recheck the lesions by ultrasound at 4-week intervals,Technical Aspects of Liver Resection () The prime goal is complete tumor removal with clear margins and with minimal operative risk,Selection of the procedure: anatomical and non-anatomical proceduresParenchymal transectionFinger fracture, ultrasonic/water jet dissectorsInflow occlusion,Technical Aspects of Liver Resection () The prime goal is complete tumor removal with clear margins and with minimal operative risk,Management of the raw surfaceRisks of resectionMortality: 05%, morbidity: 1015%Quality of life,Therapeutic Options in Case of Tumor Recurrence,Usually occurs within the 1st two years20% is possible for the 2nd R0 resection, and the 5-year survival is comparable to the 1st R0 resection Similar results obtained after subsequent resection of lung metastases These data warrant a close follow-up policy after the 1st R0 resection!,number mortality morbidity 5 year survivalTutle (1997)23 0 22% 32%Adam (1997)64 0 26%Yamamoto (1999)90 0 31%Imamura (2000)20 0 18% 22%Nordlinger (1996) 143 1 25% 16%,Survival After Re-resection in Recurrent Patients,Advances of in the Treatment of Colorectal Cancer,1980,1985,1990,1995,2000,2005,5-FU,Irinotecan,Capecitabine,Oxaliplatin,Cetuximab,Bevacizumab,Therapeutic concepts,palliative Ctx,adjuvant Ctx,neo-adjuvant Ctx,Do combination therapies offer advantage over 5FU alone?,Oxaliplatin based regimens:MOSAIC & N9741NSABP CO-7Irinotecan based regimens:CALGBPETACC,MOSAIC,LV,Oxali,*Baxter LV5 infusors,LV5FU2,FOLFOX4: LV5FU2 + oxaliplatin 85 mg/m,Every 2 weeks, 12 cycles of treatment,LV,LV,5-FU infusion*,5-FU infusion*,LV,LV,5-FU infusion*,5-FU infusion*,D1,D1,D2,D2,5-FU bolus,5-FU bolus,5-FU bolus,5-FU bolus,IROXCPT-11:200 mg/m2 d1 q 3 wksOxaliplatin: 85 mg/m2 d1 q 3 wks,IFLCPT-11:125 mg/m2/wk x 4 wks, q 6 wks5FU:500 mg/m2/wk x 4 wks, q 6 wksLV: 20 mg/m2/wk x 4 wks, q 6 wks,FOLFOX 4 Oxaliplatin: 85 mg/m2 d1 q 2 wks5-FU:400 b/600 CI mg/m2 d1, 2 q 2 wksLV:200 mg/m2 d1, 2 q 2 wks,N9741,R,NSABP C-07,Completed phase III trial158 NSABP institutions,R,FLOX (Eloxatin + LV + 5-FU i.v.),Bolus FL (LV + 5-FU i.v.),Stage IIIII,Roswell Park regimen (5-FU per week x 6, 2 weeks rest, three cycles; 24 weeks total),Roswell Park regimen (5-FU per week x 6, 2 weeks rest, three cycles; 24 weeks total) + Eloxatin 85mg/m2/2hrs i.v.,Smith R, et al. Proc Am Soc Clin Oncol 2003;22 (abst 1181),XELOX in CRC,Oral Capecitabine1,000mg/m2 ,Bid,Repeat at day 22,Daz-Rubio E et al. Ann Oncol 2002;13:55865,Day 1(pm)15(am),Eloxatin 130mg/m2 (2-hour infusion),1,8,15,REST,Day,Metastases from Colorectal Cancer,before FOLFOX after FOLFOX（12 cycles),right lobectomy + cryo. on left lobe,Infusional 5-FU/LV Backbones,600,600,400,400,LV5FU2 q2wks,2400,400,sLV5FU2 q2wks,2400,vsLV5FU2 q2wks,2600,AIO weekly,x,x,x,x,Oxaliplatin,Irinotecan,FOLFOX485(mg/m2),FOLFOX6100(mg/m2),FOLFOX7130(mg/m2),FUFOX50(mg/m2),“Douillard”180 (mg/m2),FOLFIRI180(mg/m2),FUFIRI80(mg/m2),2000,D1,D2,Resection rates after FOLFOX in initially un-operable patients,54%,Proportion Surviving,Survival Time (years),29%,34%,50%,34%,19%,27%,Resectable (n = 425)Initially nonresectable (n = 95),Bismuth et al, 1996,Survival after Primary or Secondary Resection of Liver Metastases,Oxaliplatin combinations as first-line therapy in advanced CRC,22.350.70.0001,16530.0001,14.716.2n.s.,6.29.00.0001,FU/LV inf.FOLFOX4 p-value,De Gramont,JCO 8/ 2000#420,19.919.4n.s.,6.18.70.048,FU/LV inf.FOLFOXp-value,Giacchetti,JCO 1/ 2000#200,22.649.10.0001,16.119.7n.s.,5.37.80.0001,FU/ LV Bolus (Mayo)FUFOXp-value,Grothey,ASCO 2002#252,RR(%),OS(mos),PFS (mos),Protocol,Author,Irinotecan combinations as first-line therapy in advanced CRC,31490.001,21390.001,14.117.40.031,4.46.70.001,FU/ LV inf.“Douillard”p-value,Douillard,Lancet 3/2000#338,12.614.80.04,4.37.00.004,FU/ LV bolus (Mayo)IFLp-value,Saltz,NEJM 9/2000 #457,31.554.290% tumor mass reduction appears possible The increased operative risk in patients with carcinoid heart disease has to be considered!,NON-COLO