大腸癌肝轉(zhuǎn)移綜合治療進展ppt課件

1、Liver Metastases of Colorectal Cancer :Liver Metastases of Colorectal Cancer :Where are we standing in current practice ?Where are we standing in current practice ?大腸癌肝轉(zhuǎn)移綜合治療進展大腸癌肝轉(zhuǎn)移綜合治療進展郝純毅郝純毅 季加孚季加孚 北京腫瘤醫(yī)院外科北京腫瘤醫(yī)院外科Breast cancerBreast cancerWith positiveWith positiveAxillary lymph nodesAxillary l

2、ymph nodesColorectal cancerColorectal cancerWithWithLiver metastasesLiver metastasesDifferent ? Similar !Different ? Similar ! 1525 patients with primary CRC present with synchronous liver metastases An additional 20% will develop metachronous hepatic secondaries 20% are candidates for curative rese

3、ction of liver metastases U.S. 150 000 new cases 20 00030 000China 500 000 new cases 70 000100 000EPIDEMIOLOGYauthor 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 9

4、6 51Minagawa* 2000 235 0 38 Scheele 2001516 5.8 38Overall Results of Hepatic Resection for CRC MetastasesLong 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 Res

5、ection (French Study)Liver onlyOverall Survival- Disease Free Survival(French study)Prognostic Factors after R0-resection () Demographic features: gender, age Primary tumor: LN involvement, size, differentiation, staging and location( esp in sychronous metastases) Metastases: multiplicity of lesions

6、 and the intrahepatic tumor distribution? Satellite metastases Size of tumor Histopatholigical features Synchronous and metachronous metastasesPrognostic Factors after R0-resection ()Therapeutic approachOthers: PS, weight loss, serum albumin , preoperative CEA, tumor ploidy, oncogen/oncosupressor ge

7、ne expression, etc.Surgeon performing the operationPrognostic 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 2.2Su

8、rvival According to Number of Risk Factors Nordlinger B. Cancer 1996 ; 77:1254-620-276%01008060402052103years43-459%5-744%*Fong Y. Ann Surg 1999;230:309-321010080604020602412036Months48ONE42%TWO to THREE 30%MORE than FOUR 23%Probability of suvivalyears from R0 resection1098765432101.9.8.7.6.5.4.3.2.

9、104 metastases (n = 48)13 metastases (n = 425)Scheele et al, 1999Survival According to the Number of MetastasesP=0.99*Jaeck D. Ann Surg Oncol 2002;9:430-8 Survival After Resection Nodes in Liver Pedicle010080604020301260182436N -N + proximalN + distal1.8.6.4.201086420Multiple bilateral (n=79)Multipl

10、e unilateral (n=121)Solitary (n=273)102129462687P=0.25yearsProbability of survivalInfluence of Number and Distribution of CRC MetastasesScheele et al, 1999*Operative mortality excluded*R0 resection1.8.6.4.208642010yearsProbability of survivalR0 resection (n=490)Disease-free survivalR1/2 resection (n

11、=114)Survival after Liver Resection for CRC Liver MetastasesP=4.9*10-34vs29.5%(60)28.3%(57)41.3%(159)35.4%()Contraindications to CRC Liver MetastasesRadical(R0) resection not possible but: occasionally justified for symptomatic palliation ( RARE！)Lymph nodes metastases at the liver hilum but: anecdo

12、tal 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 potent

13、ial benefits.Factors Contributing to the Improved Results of Liver Metastases of CRC肝臟外科技術(shù)的提高肝臟外科技術(shù)的提高一些新的輔助一些新的輔助/姑息治療手段的出現(xiàn)姑息治療手段的出現(xiàn)術(shù)前影像診斷技術(shù)的改良術(shù)前影像診斷技術(shù)的改良多中心、大規(guī)模臨床總結(jié)的發(fā)表多中心、大規(guī)模臨床總結(jié)的發(fā)表(回想性、多中心回想性、多中心/非前瞻性隨機對照研討非前瞻性隨機對照研討Preoperative InvestigationThe primary tumor siteThe extent of liver involvementTh

14、e presence of extrahepatic diseaseMarkers to provide a baseline for follow-upPreoperative diagnostic studies must be supplemented by thorough intraoperative assessmentTiming Of Liver Resection a “test of time ranging from several weeks to 6 months There exists controversy, and no conclusive data are

15、 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

16、Technical Aspects of Liver Resection () The prime goal is complete tumor removal with clear margins and with minimal operative riskSelection of the procedure: anatomical and non-anatomical proceduresParenchymal transectionFinger fracture, ultrasonic/water jet dissectorsInflow occlusion Technical Asp

17、ects of Liver Resection () The prime goal is complete tumor removal with clear margins and with minimal operative riskManagement of the raw surfaceRisks of resectionMortality: 05%, morbidity: 1015%Quality of lifeTherapeutic Options in Case of Tumor RecurrenceUsually occurs within the 1st two years20

18、% 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)2

19、3 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 PatientsAdvances of in the Treatment of Colorectal Cancer1980198519901995200020055-FUIrinotecanCapecitabineOxaliplatinCetuximabBevacizumabpalliative

20、 Ctxadjuvant Ctxneo-adjuvant CtxDo combination therapies offer advantage over 5FU alone?Oxaliplatin based regimens:MOSAIC & N9741NSABP CO-7Irinotecan based regimens:CALGBPETACCMOSAICLVOxaliR*Baxter LV5 infusorsLV5FU2FOLFOX4: LV5FU2 + oxaliplatin 85 mg/mEvery 2 weeks, 12 cycles of treatmentLVLV5-

21、FU infusion*5-FU infusion*LVLV5-FU infusion*5-FU infusion*D1D1D2D25-FU bolus5-FU bolus5-FU bolus5-FU bolusN9741RNSABP C-07 Completed phase III trial 158 NSABP institutionsRFLOX (Eloxatin + LV + 5-FU i.v.)Bolus FL (LV + 5-FU i.v.)Stage IIIIIRoswell Park regimen (5-FU per week x 6, 2 weeks rest, three

22、 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 CRCOral Capecitabine1,000mg/m2 ,BidRepeat at day 22Daz-Rubio E et al. Ann Oncol 2002;13:55865Day

23、 1(pm)15(am)Eloxatin 130mg/m2 (2-hour infusion)1815RESTDayMetastases from Colorectal Cancer before FOLFOX after FOLFOX12 cycles)right lobectomy + cryo. on left lobeInfusional 5-FU/LV Backbones600600400400LV5FU2 q2wks2400400sLV5FU2 q2wks2400vsLV5FU2 q2wks2600AIO weeklyxxxxOxaliplatinIrinotecanFOLFOX4

24、85(mg/m2)FOLFOX6100(mg/m2)FOLFOX7130(mg/m2)FUFOX50(mg/m2)“Douillard180 (mg/m2)FOLFIRI180(mg/m2)FUFIRI80(mg/m2)2000D1D2Resection rates after FOLFOX in initially un-operable patientsStudyGiacchettiGiacchettiAdamAlbertsTournigand Resected 51%32%13.6%35.7%21.0%R0 resection38%21%13.6%28.5%12.6%5-yr survi

25、val50% 35%54%Proportion SurvivingSurvival Time (years)29%34%50%34%19%27%1098765432101.9.8.7.6.5.4.3.2.10Resectable (n = 425)Initially nonresectable (n = 95)Bismuth et al, 1996Survival after Primary or Secondary Resection of Liver MetastasesOxaliplatin combinations as first-line therapy in advanced C

26、RC22.350.70.000116530.000114.716.2n.s.6.29.00.0001FU/LV inf.FOLFOX4 p-valueDe Gramont,JCO 8/ 2000#42019.919.4n.s.6.18.70.048FU/LV inf.FOLFOXp-valueGiacchetti,JCO 1/ 2000#20022.649.10.000116.119.7n.s.5.37.80.0001FU/ LV Bolus (Mayo)FUFOXp-valueGrothey,ASCO 2002#252RR(%)OS(mos)PFS (mos)ProtocolAuthorIr

27、inotecan combinations as first-line therapy in advanced CRC31490.00121390.00114.117.40.0314.46.70.001FU/ LV inf.“Douillardp-valueDouillard,Lancet 3/2000#33812.614.80.044.37.00.004FU/ LV bolus (Mayo)IFLp-valueSaltz,NEJM 9/2000 #45731.554.21719.516.2Capecitabine / IrinotecanXELIRI1CAPIRI2IFL3FOLFIRI4P

28、atients (n)5279264145RR (%)42413133Median TTP(months)7.17.16.96.5Median OS(months)Not yetreported1714.817.41Patt YZ et al. ASCO 2003 (Abst 1130)2Grothey A et al. ASCO 2003 (Abst 295) 3Goldberg R et al. ASCO 2003 (Abst 1009)4Douillard JY et al. Lancet 2000;355:10417 5-FU/ LV + Oxaliplatin as Neo-adju

29、vant Treatment in Metastatic CRCGiacchetti et al., Ann Oncol 1999 151 patients with initially unresectable liver metastases Primary Ctx with Oxaliplatin + 5FU/LV 51% of patients underwent secondary liver resection74 non-operable pts58 pts: macroscopicallycomplete resection77 operated pts012345678902

30、0406080100yearsOverall survival(%)Secondary Surgery: FROM CARE TO CURENew Goals in the Treatment of Advanced CRC020406080100Overall survival (% of pts)TimeCtx = ProlongationCtx + Surgery = Cure?Dose-to-Grade 3 Neurotox N9741010203040506070809010005001000150020002500Cumulative Oxaliplatin Dose (mg/m2

31、)% Neurotox FreeMonoclonal Antibodies in OncologyCan we further improve results with biologicals? Anti-EGFR : Cetuximab (C-225) Anti-VEGF : BevacizumabThe Angiogenic Switch1-2 mmAngiogenic SwitchSmall tumor Nonvascular “DormantLarger tumor Vascular Metastatic potential.Maturation factors presentNorm

32、al and Tumor VasculatureNormal Blood VesselsTumor Blood VesselsReduced integrin expressionLess dependent on cell survival factors.Less permeableLeakyPreferential expression of v3 v5 & 51 integrinsFewer pericytesGrowth and survival factors (eg, VEGF) present.Supporting pericytes presentFuture of

33、Adjuvant Therapy in CRC Integration of new therapeutics Oxaliplatin and Irinotecan Capecitabine as substitute for 5-FU/LV? Bevacizumab and Cetuximab Individualization of therapy Prognostic factors Predictive parameters Pharmacogenomics!?Prognostic FactorsAchievements and Goals in CRCBSC 1980s5-FU/LV

34、 1990s5-FU/LV/Irino 20005-FU/LV/Oxali 2000FOLFOX/ FOLFIRIFUFOX 200206121824(mos)medianOSall 3 drugs+ molecular Tx?What is the future adjuvant therapy in colon cancer ?PresentPatientsABAll patients receivestandard therapy AClinical trials Survival benefit in AFuturePatientsPrognostic/predictive factorsPharmacogenomicsABCDIndividualized adjuvant therapyNON-COLORECTAL METASTASES()Noncolorectal neuroendocrine (NCNE) metastasesA real R0 resection appears possibleA palliative cytoreductive resection is justified