肝癌综合治疗.ppt

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1、肝癌的综合治疗Multidisciplinary Strategies to Management of HCC,背景,绝大多数（80-90）的HCC合并肝硬化HCC治疗策略应考虑对肿瘤作用，并避免肝功能损害HCC的分期系统也应同时考虑肿瘤因素，和肝功能损害的严重性至今尚未有公认的HCC的分期系统肝癌的BCLC分期系统目前在西方国家应用较广，对治疗有指导意义。,HCC的BCLC分期系统和治疗推荐,Liver transplant,PEI/RF,Curative treatments,TACE,HCC,Single,Increased,Associateddiseases,Normal,No,Y

2、es,No,Yes,Terminalstage,PST 0-2,Child-Pugh A-B,Multinodular,PST 0,Portal invasion,N1,M1,Sorafenib,Portal pressure/bilirubin,3 nodules 3 cm,Intermediate stage,PST 2,Child-Pugh C,Very early stage,Single 2 cm,Early stage,Single or 3 nodules 3 cm,PST 0,Advanced stage,Portal invasion,N1,M1,PST 1-2,PST 0,

3、Child-Pugh A,Resection,Symptomatic(unless LT),Llovet JM,et al.J Natl Cancer Inst.2008;100:698-711.Bruix J,et al.Hepatology.2005;42:1208-1236.,Surgical treatments:applicable overall to 30%of HCC at first diagnosis and 2%to 5%of recurrent HCC,HCC的BCLC分期系统和治疗,Liver transplant,PEI/RF,TACE,HCC,Single,Inc

4、reased,Associateddiseases,Normal,No,Yes,No,Yes,Terminalstage,PST 0-2,Child-Pugh A-B,Multinodular,PST 0,Portal invasion,N1,M1,Sorafenib,Portal pressure/bilirubin,3 nodules 3 cm,Intermediate stage,PST 2,Child-Pugh C,Very early stage,Single 2 cm,Early stage,Single or 3 nodules 3 cm,PST 0,Advanced stage

5、,Portal invasion,N1,M1,PST 1-2,PST 0,Child-Pugh A,Resection,Symptomatic(unless LT)20%,Nonsurgical treatments:applicable overall to 50%of HCC at first diagnosis and 50%to 70%of recurrent HCC,治疗的目的,肿瘤缩小改善生命质量延长生存QALY,HCC 治疗选择,早期HCC外科切除（肝部分切除）肝移植经皮毁损（PEI，RFA，HIFU，冷冻，微波）进展期HCCTACE系统治疗（化疗）新治疗（分子靶向，放疗）,早期

6、肝癌,早期HCC的手术切除,根治？根治术后5年生存率：50-70术后5年复发率：60-80问题：如何达到根治？如何降低复发？,Pre-operative TACE+Resection,Downstaging resection：术后5年生存率 小肝癌肝动脉插管结扎/TACE/Chemotherapy？减小瘤体：手术简单，且控制微小病灶减少血供：手术安全减少术中播散,Zhou 2009 Ann Surg 2009;249:195202,Pre-operative TACE,Risk：可切除 不可切除对肝功能差的病人：进一步损害肝功能Japan：RCT 结果类似（Sasaki A.Eur J Su

7、rg Oncol.2006;32:7739.）,肝移植,术后复发（周俭教授）肝源等待：Bridge Treatments of Hepatocellular Carcinoma in Cirrhotic Patients Submitted to Liver Transplantation.Dig Dis Sci(2008)53:28302831,TACE:Bridge to OLT,Does not improve long-term survival(grade C).No convincing evidence that TACE allows to expand the current

8、 selection criteria for OLT,nor that TACE decreases dropout rates on the waiting list(grade C).TACE does not increase the risk for postoperative complications(grade C).There is insufficient evidence that TACE offers any benefit when used prior to OLT,neither for early nor for advanced HCC.,American

9、journal of transplantation 2006;6(11):2644-50.,局部毁损,小肝癌：媲美于手术切除复发率值得担心,小肝癌2.8cm,PEI or RFA?,PEI3y5yChild A(survival 3 vs.5y.)79%47%Child B(survival 3 vs.5y.)63%29%Child C(survival 3 vs.5y.)12%0%,AASLD 2004:Leoncini et al.(n=104):PEIRFATumor destruction82%98%2-y Survival96%98%2-y Recurrence32%10%,RF

10、vs PEI,Local ablative therapies in HCC:percutaneous ethanol injection and radiofrequency ablation RFA is superior to PEI for treating small HCCsurvival after PEI or RFA in comparison with surgeryTACE+PEI/RFA survival was improved further.,Dig Dis.2009;27(2):148-56.,RF+PEI,操作性的,RF vs Resection,Ann Su

11、rg 2006;243:321328),Chen MS.Ann Surg 2006;243:321328,Puzzle,Pre-TACE+Resection no usePre-TACE+RF improvedRF=Resection,Radical resection IFN-a,resection+IFN resectionOS:63.8 months 38.8 months P=0.0003DFS:31.2 months 17.7 months P=0.142,Sun HC.J Cancer Res Clin Oncol 2006;132:458-65,Evidence of Benef

12、it in Treatment of HCC,Llovet JM,et al.J Natl Cancer Inst.2008;100:698-711.,Post adjuvant TACE,Post adjuvant TACE,进展期肝癌,Staging Strategy and Treatment for Patients With HCC,Liver transplant,PEI/RF,Curative treatments,TACE,HCC,Single,Increased,Associateddiseases,Normal,No,Yes,No,Yes,Terminalstage,PST

13、 0-2,Child-Pugh A-B,Multinodular,PST 0,Portal invasion,N1,M1,Sorafenib,Portal pressure/bilirubin,3 nodules 3 cm,Intermediate stage,PST 2,Child-Pugh C,Very early stage,Single 2 cm,Early stage,Single or 3 nodules 3 cm,PST 0,Advanced stage,Portal invasion,N1,M1,PST 1-2,PST 0,Child-Pugh A,Resection,Symp

14、tomatic(unless LT),Llovet JM,et al.J Natl Cancer Inst.2008;100:698-711.Bruix J,et al.Hepatology.2005;42:1208-1236.,RCTs(50%)Median survival:11-20 mos,Approved&Investigational Noncurative Agents for Unresectable HCC,AASLD 2005 recommendationsChemoembolization(TACE)(with doxorubicin,cisplatin,or mitom

15、ycin)is recommended as first-line,noncurative therapy for nonsurgical patients with large/multifocal HCC who do not have vascular invasion or extrahepatic spread(and are not eligible for percutaneous ablation)(level I)Tamoxifen,octreotide,antiandrogens,and hepatic artery ligation/embolization are no

16、t recommended(level I);other options such as drug-eluting beads,radiolabelled yttrium glass beads,radiolabelled lipiodol,or immunotherapy cannot be recommended as standard therapy for advanced HCC outside clinical trials,Bruix J,et al.Hepatology.2005;42:1208-1236.,TACE,Intra-arterial Locoregional Th

17、erapy,EstablishedTACERadioembolization:yttrium-90 radioactive microspheresUndergoing clinical trialsDrug-eluting beads,Primary Treatment Modality Used in Korea,TACE 48.2%,RFA1.5%,Surgery 11.2%,Chemotherapy7.5%,Radiotherapy2.1%,Conservative treatment 29.5%,N=1078,Joong-Won Park,MD,National Cancer Cen

18、ter.Adapted with permission.,Chemoembolization:Randomized Trials(Nearly Identical Techniques),Llovet et al2:N=112 with unresectable HCC,80%to 90%HCV positive,5-cm tumors(70%multifocal),Lo et al1:N=80 with newly diagnosed unresectable HCC,80%HBV positive,7-cm tumors(60%multifocal),1.Lo CM,et al.Hepat

19、ology.2002;35:1164-1171.2.Llovet JM,et al.Lancet.2002;359:1734-1739.,Chemoembolization:Predictors of Survival,Lo et al1Absence of presenting symptoms(ECOG PS 5 cm)Okuda stage(I vs II)Llovet et al2Absence of constitutional syndrome(ECOG PS 6 months),1.Lo CM,et al.Hepatology.2002;35:1164-1171.2.Llovet

20、 JM,et al.Lancet.2002;359:1734-1739.,Largest Prospective Study of TACE for Unresectable HCC to Date,N=8510 patientsPrimary endpoint:OSMultivariate analysis conducted of factors affecting survivalOSYear 1:82%;Year 3:47%;Year 5:26%;Year 7:16%OS better with lesser degree of liver damageFactors affectin

21、g survivalChild-Pugh stageTNM stage(OS better with stage I,increasingly worse progressing toward stage IV)Alpha-fetoprotein level,Takayasu K,et al.Gastroenterology.2006;131:461-469.,TACE vs Surgical Resection:A Case-Control Prospective Study,N=182,70%HBV positive,99%Okuda stage I,76%with tumors 3 cm

22、,Surgery superior to TACE for tumors smaller than 2 cm and/or CLIP stage 0BUT for tumors 3 cm and/or CLIP stage 1-2,5-year survival identical for both groups(27%)Median OS(P=.1529)Resection:65.1 monthsTACE:50.4 months,Lee HS,et al.J Clin Oncol.2002;20:4459-4465.,Chemoembolization:Efficacy Before Tra

23、nsplantation,Major issue:dropout rate(20%)Lower in US since adoption of MELD criteriaRole of TACEControl tumor and prevent progressionShould be considered if waiting time 6 monthsComplications from TACE:rare(no increased rate of hepatic artery complications),Richard HM 3rd,et al.Radiology.2000;214:7

24、75-779.Graziadei IW,et al.Liver Transpl.2003;9:557-563.Alba E,et al.Am J Roentgenol.2008;190:1341-1348.,Can TACE Be Used as a Determinant of Tumor Biology?,96 consecutive patients treated with TACE62 exceeded Milan criteria34 meeting Milan criteria listed immediately50 patients transplanted27 exceed

25、ed Milan criteria,Otto G,et al.Liver Transpl.2006;12:1260-1267.,FunctionalDecompensation(n=1),Patients with HCC;age 65 years without contraindication against LT(n=96),Milan criteria fulfilled(n=34),Listing,TACE,Milan criteria exceeded(n=62),6 weeks,6 weeks,6 weeks,TACE,Listing(n=34),WL(n=4),WL(n=1),

26、Progress(n=6),Functionaldecompensation(n=5),Functionaldecompensation(n=1),Extrahepaticdisease(n=5),Stable18 Progress*9,27 LT,Stable21 Progress 2,23 LT,TACE,Regress,Stable or progress(n=23),Restaging,Otto G,et al.Liver Transpl.2006;12:1260-1267.,Transplanted,All patients,TACE nonresponders,Overall 5-

27、year survival:51.9%Highly significant difference in 5-year survival between downstaged(transplanted)patients and patients not responding to TACE(P.0001)Survival calculated from the beginning of TACE treatment,Survival,0,0.2,0.4,0.6,0.8,1.0,0,365,730,1095,1460,1825,Days,80.9%,51.9%,0%,Response to TAC

28、E as a Biological Selection Criterion for LT in HCC,TACE nonresponders,TACE responders,Otto G,et al.Liver Transpl.2006;12:1260-1267.,Response to TACE as a Biological Selection Criterion for LT in HCC,0,Freedom From Recurrence,0,0.2,0.4,0.6,0.8,1.0,365,730,1095,1460,1825,Days,35.4%,94.5%,P=.0017,Abso

29、lute contraindicationsChild-Pugh class C diseasePoor performance status(ECOG PS 2)Relative contraindicationExtrahepatic disease(benefit unclear)Former contraindicationPVT Minimize embolization and be more selective,Chemoembolization:Ineligibility Criteria,32 patients with HCC and PVTMedian OS:10 mon

30、thsChild-Pugh score:best prognostic factor(ie,most strongly related to survival)30-day mortality:0%No evidence of TACE-related hepatic infarction or acute liver failure,Safety&Efficacy of TACE in Patients With Unresectable HCC&PVT,Georgiades CS,et al.J Vasc Interv Radiol.2005;16:1653-1659.,Radioembo

31、lization:Use of intra-arterially delivered yttrium-90 microspheres emitting high-dose radiation for the treatment of liver tumorsYttrium-90 microspheresAverage diameter:20-30 m 100%pure beta emitter(0.9367 MeV)Physical half-life:64.2 hoursIrradiates tissue with average path length of 2.5 mm(maximum:

32、11 mm),Intra-arterial Radioembolization With Yttrium-90:Rationale and History,Murthy R,et al.Biomed Imaging Interv J.2006;3:e43.,Clinical Response to Yttrium-90 Microspheres,1.Dancey JE,et al.J Nucl Med.2000;41:1673-1681.2.Carr BI.Liver Transpl.2004;10(2 suppl 1):S107-S110.3.Geschwind JF,et al.Gastr

33、oenterology.2004;127(5 suppl 1):S194-S205.4.Salem R,et al.J Vasc Interv Radiol.2005;16:1627-1639.,Phase II study:N=108(37 with PVT,71 without PVT)Stratified by toxicity:Child-Pugh score(in cirrhotics),dose,location of PVTMedian dose:134 GyPartial response rate:42%(WHO),70%(EASL)Adverse event rate hi

34、ghest in patients with main PVT and cirrhosisMedian survival,main PVT:260 daysBranch PVT:370 daysNo PVT:460 days,Yttrium-90 Radiotherapy for HCC Patients With and Without PVT,Kulik LM,et al.Hepatology.2008;47:5-7.,Lessons Learned,Patient selectionGood performance status(ECOG PS 2)Total bilirubin 2.0

35、 mg/dL(possibly 1.4 mg/dL)Tumor burden 50%90Y or TACE:Which is best for first-line treatment of HCC?,27 patients with Child-Pugh A stage disease Response rate(assessed by CT)at 6months:75%1-and 2-year survival rates:92%and 89%Median follow-up:28months,Varela M,et al.J Hepatol.2007;46:474-481.,Doxoru

36、bicin at Serum(ng/mL),Doxorubicin at Serum(ng/mL),DEB-TACE,Conventional TACE,Time Postprocedure,Time Postprocedure,0,200,400,600,800,1000,0,200,400,600,800,1000,BL,5 mins,20 mins,40 mins,60 mins,2 hrs,6 hrs,24 hrs,48 hrs,7 days,BL,5 mins,20 mins,40 mins,60 mins,2 hrs,6 hrs,24 hrs,48 hrs,7 days,TACE

37、With Doxorubicin-Eluting Beads:Efficacy and Pharmacokinetics,Courtesy Jean-Francois Geschwind,MD.,65-Year-Old Woman,Child-Pugh B Disease,and Large HCC:First Treatment,Posttreatment 1:Residual Viable Tumor,Pretreatment,Pretreatment and Posttreatment 1,Courtesy Jean-Francois Geschwind,MD.,Second Treat

38、ment,Courtesy Jean-Francois Geschwind,MD.,Underwent successful resection Tumor free 16 months after initial treatment,MRI Posttreatment 2,Courtesy Jean-Francois Geschwind,MD.,TACE accepted as treatment of choice for unresectable(nonablatable?)HCC Prolonged survival established through randomized tri

39、als and prospective studiesBest vs good performance status,Child-Pugh class A-BRole for yttrium-90 microspheresGrowing role for doxorubicin-loaded beads,pending outcome of clinical trials,Conclusions,Chemotherapy,Chemo-immunotherapy,Radiotherapy,Conclusion,There is lack of effective treatment for pa

40、tients with advanced HCCNew treatment options are needed,分子靶向,Treatment of Advanced HCC(BCLC Stage C),AASLD 2005 recommendation:no standard therapy;patients should enroll in a randomized clinical trial12008 recommendation:sorafenib has become the standard of care for advanced HCC2Prolongs OS by 3 mo

41、nths31-year survival:44%4,1.Bruix J,et al.Hepatology.2005;42:1208-1236.2.Llovet JM,et al.J Hepatol.2008;48:S20-S37.3.Llovet J,et al.ASCO 2007.Abstract LBA 1.4.Llovet J,et al.N Engl J Med.2008;359:378-390.,Intermediate/Advanced HCC:Future Directions,499 trials registered at clinicaltrials.gov for HCC

42、 as of August 21,2008,includingImproving efficacy of RF and TACE(drug-eluting beads)Exploring alternative treatments for intermediate HCC(yttrium-90)Molecularly targeted agents in combination regimens(advanced HCC)Molecularly targeted agents in combination with current modalities(early/intermediate

43、HCC)Improving tumor targeting of chemotherapeutic agentsNew molecular targets and new molecularly targeted agents,Sorafenib:Ongoing Studies in HCC,Europe10 studies approved4 TACE+sorafenib(1 phase I,1 phase II,2 phase III)Sorafenib+tegafur Sorafenib+erlotinib Sorafenib+temsirolimus Sorafenib dose es

44、calation Sorafenib+gemcitabine/oxaliplatin Biomarkers,Asia-Pacific4 studies approvedSorafenib+tegafurSorafenib+capecitabine/oxaliplatinSorafenib+bevacizumabSorafenib+gemcitabineUnited States4 studies(nonactivated)2 TACE+sorafenibSorafenib+erlotinibSorafenib+lapatinib,Evidence of Benefit in Treatment

45、 of HCC,Llovet JM,et al.J Natl Cancer Inst.2008;100:698-711.,Evidence of Benefit in Treatment of HCC(contd),Llovet JM,et al.J Natl Cancer Inst.2008;100:698-711.,Key Pathways in Hepatocarcinogenesis:Possible Targets for Novel Therapies,Growth factor-stimulated receptor tyrosine kinase signalingWnt/be

46、ta-catenin pathwayp13Kinase/AKT/mTORJAK/STAT signalingAngiogenic signaling pathwaysp53 and cell cycle regulatory pathwaysUbiquitin-proteasome pathwayEpigenetic promoter methylation and histone acetylation pathwaysRas-Raf-MEK-MAPK pathway,Roberts LR,et al.Semin Liver Dis.2005;25:212-225.,Sorafenib in

47、 Advanced HCC:The SHARP Trial,Entry criteriaAdvanced HCC Not eligible for or failed surgical or locoregional therapiesChild-Pugh class A diseaseAt least 1 untreated target lesionExclusionsPrevious chemotherapy Previous molecularly targeted therapy,Llovet JM,et al.N Engl J Med.2008;359:378-390.,226 d

48、iscontinued sorafenib86 had an adverse event61 had radiologic and systematic progression28 withdrew consent 1 had ECOG score of 4 3 died47 had other reason,297 received sorafenib(safety population),71 included in the ongoing study,1 had an adverse event1 had a protocol violation,299 were assigned to

49、 receive sorafenib(intent-to-treat population),602 underwent randomization,902 patients were screened,300 were excluded244 had protocol exclusion criteria 24 withdrew consent 15 had an adverse event 11 died 6 were lost to follow-up,303 were assigned to receive placebo(intent-to-treat population),1 h

50、ad a protocol violation,302 received placebo(safety population),242 discontinued placebo90 had an adverse event62 had radiologic and systematic progression25 withdrew consent 7 had ECOG score of 4 6 died52 had other reason,60 included in the ongoing study,Llovet JM,et al.Sorafenib in advanced hepato