肝癌规范化治疗.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,肝癌,内科,依荷芭丽,.,迟,HCC,数据,HCC,占肝脏原发肿瘤首位,:,90%,1,男性肿瘤第五位,女性肿瘤第九位,2,。,恶性肿瘤死亡率第三位,3,是肝硬化患者死亡的主要原因,4,年新发病例,(560,000),年死亡病例,(550,000),5,1.Perz JF,et al.J Hepatol.2006;45:529-38.2.Jelic S.Ann Oncol.2009;Suppl 4:iv41,-5,.,3.Garcia M,et al.American Cancer Society.2007.www.cancer.org.Accessed Jan 2010.,4.Llovet J,J Hepatol.2000;33:423-,9.,5.Marrero CR,Marrero JA.Arch Med Res.2007;38:612-20.,Subject to PATH Program Disclaimer,HCC,流行病学,HCC,发病率,不同的地域性,时间相关性,(,不同地域有不同的时间相关性,),种族差异性,性别和社会地位差异性,高危因素,(,已知,),与肝硬化相关性,(6095%,的病例,),致癌机理,:,-,无正常肝脏,-,继发于慢性肝炎,炎症性癌症,El-Serag HB.Clin Liver Dis.2001;5:87-107.,Subject to PATH Program Disclaimer,El-Serag HB,Rudolph KL.Gastro.2007;132:2557-76.,HCC,地域死亡率,(,每,100,000,人,),50%of HCC,Annual mortality per region:,Europe:54,000,USA:19,000,ChinaKoreaJapan:390,000,Subject to PATH Program Disclaimer,HCC,高危因素和发病率,80%HCC,与,HBV,或,HCV,相关,Llovet JM,et al.Lancet.,2003;362:1907-7.,Pisani et al.,Cancer Epidemiol Biomarkers Prev.1997;6:387-400.,Subject to PATH Program Disclaimer,肝癌风险合并超重肥胖与正常体重人群对比荟萃分析,回顾性研究,:,173,463,糖尿病病例对比,650,620,非,糖尿病病例,.,患者无因急性或慢性肝脏疾病近一年内住院治疗,El-Serag HB,et al.Gastroenterology.2004;26:460-8.,824,263,住院治疗 美国退伍军人,(19851990):,肝细胞肝癌,:317 diabetes(2.39 x 10,5,person-years),515 controls (0.87 x 10,5,person-years),肝细胞高位因素,:,糖尿病,Subject to PATH Program Disclaimer,肝细胞肝癌,:,男性多于女性,24,倍,400,000,例,/,年,160,000,例,/,年,Database ITA.LI.CA,2008.,Subject to PATH Program Disclaimer,肝细胞肝癌,:,人种差别,(USA),2,倍,2,倍,遗传多态性,:,免疫应答,(i.e.HCV),炎症反应,酒精代谢,环境致癌,胰岛素抗药性,治疗反应,(IFN),高危因素,经济文化因素,:,传播,暴露,Thorgeirsson SS,et al.Hepatology.2006;43(2 Suppl 1):S145-50.,Avila MA,et al.Oncogene.2006;25:3866-84.,Subject to PATH Program Disclaimer,2+ve for arterial hypervascularization among:,Angiography,CT,MRI,Doppler US,or 1+ve plus AFP 400 ng/mL,Bruix J,et al.J Hepatol.2001;35:421-30.,Subject to PATH Program,Disclaimer,非转移早期肝癌的诊断标准,肝功能分期,Child-Pugh,分级,肿瘤大小分期,TNM,Vauthey(,改良的,TNM),Izumi(,改良的,TNM),JS(,日本分期,),联合分期,(,肝功能和肿瘤,),Okuda,Cancer of the Liver Italian Program(CLIP),Chinese University Prognostic Index(CUPI),Japanese integrated staging score(JIS),Barcelona Clinic Liver Cancer(BCLC),Subject to PATH Program Disclaimer,HCC,分期,Kudo M,et al.J Gastroenterol.2003;38:207-15;Wildi S,et al.Br J Surg.2004;91:400-8;,Dohmen K,et al.J Gastroenterol Hepatol.2004;19:1227-32;Marrero JA,et al.Hepatology.2005;41:707-16.,HCC,不同分期包含变量指标,(1),肿瘤大小,病变数量,血管侵犯,病变累及程度,远处转移,肝硬化,Child-Pugh,分级,实验室检查,其他,(,门静脉血栓,AFP,腹水等,.),Subject to PATH Program Disclaimer,Kudo M,et al.J Gastroenterol.2003;38:207-15;Wildi S,et al.Br J Surg.2004;91:400-8;,Dohmen K,et al.J Gastroenterol Hepatol.2004;19:1227-32;Marrero JA,et al.Hepatology.2005;41:707-16.,Subject to PATH Program Disclaimer,HCC,不同分期包含变量指标,(2),Wildi S,et al.Br J Surg.2004;91:400-8.,日本分期,(JS),UICC 2002 TNM,分期,Subject to PATH Program Disclaimer,Wildi S,et al.Br J Surg.2004;91:400-8.,T1,期评定中的问题,(1),定义太宽：,符合肿瘤大小,1 cm,肝功能分级,Child-Pugh A (5,年无治疗预期生存期,50%),，而一个大小,11 cm,肿瘤,肝功能分级,Child-Pugh B(,5,年无治疗预期生存期,5%),两者均属同期肿瘤。,Subject to PATH Program Disclaimer,TNM stage according to UICC 2002,Wildi S,et al.Br J Surg.2004;91:400-8.,Tumor,single,2 cm,without vascular invasion,Evidence ofStage Score,3 factorsT1 I0,2 factorsT2II1,1 factorT3III2,0 factorsT4 or T1,T3+N1/M1IV3,Liver function:Child-Pugh class,A0,B1,C,2,TOTAL range scores:05,Japanese Integrated Staging(JIS)system,TNM stage of Cancer Study Group Japan,Kudo M,et al.J Gastroenterol.2003;38:207-15.,Subject to PATH Program Disclaimer,Child-Pugh,评分,评分,1,2,3,总胆红素,3 mg/dl,国际标准化比值,INR 2.2,白蛋白,3.5 gr/dl,3.52.8 gr/dl,50%,的肝脏,2,甲胎蛋白,400 ng/ml,0,400 ng/ml,1,门静脉血栓形成,No,0,Yes,1,早期,HCC,在多种分期中的判定,早期肝癌诊断在不同分期标准中均不够准确,TNM,分期,(,独立病灶,5 cm,未限定肝功能状态,),Child-Pugh,评分,(,未限定肿瘤大小,),OKUDA,和,CLIP(,涉及瘤负荷占肝脏体积,50%),JIS,分期较好,;,定义了较早期肝癌,(JIS,评分,=0),较准确判定早期肝细胞肝癌,(JIS,评分,=1,）包括了门静脉血栓,或,Child-Pugh B,或,10 cm,的大肝癌,),最好的确定早期肝癌分期为,BCLC,分期标准,Subject to PATH Program Disclaimer,Kudo M,et al.J Gastroenterol.2003;38:207-15;,Llovet JM,et al.Semin Liver Dis.1999;19:329-38.,BCLC,分期,预后和治疗分配体系,*Grieco A,et al.Gut.2005;54:411-18;Llovet JM,et al.Semin Liver Dis.1999;19:329-38.,Subject to PATH Program Disclaimer,肿瘤,伴随特征,肝脏特征,中位生存,(,月,)*,A,期,(,早期,HCC),A1 PST 0,单一,无门静脉高血压,胆红素无异常,43,A2 PST 0,单一,门静脉高血压,胆红素无异常,29,A3 PST 0,单一,门静脉高血压,胆红素异常,25,A4 PST 0,3,个肿瘤均,3 cm,Child Pugh AB,22,Stage B(,中期,HCC),PST 0,多个大结节,Child-Pugh AB,18,Stage C(,晚期,HCC),PST 12,血管侵犯或肝外转移,Child-Pugh AB,7,Stage D(,终末期,HCC),PST 34,任何情况,Child-Pugh C,无法肝移植,-,PEI/RFA,Sorafenib,Stage 0,PST 0,Child-Pugh A,Very early stage(0),1 HCC 2 cmcarcinoma in situ,Early stage(A),1 HCC or 3 nodules 2,Child-Pugh C,HCC,Intermediate stage(B),multinodular,PST 0,Stage AC,PST 02,Child-Pugh AB,BCLC staging system and treatment strategy,Subject to PATH Program Disclaimer,不能切除的,HCC,“,不能切除的,”,患者并不代表晚期,HCC,Terminalstage,PST 0-2,ChildPugh AB,Multinodular,PST 0,N1,M1,PST 12,Intermediate stage,PST 2,ChildPugh C,Very early stage,Single 2 cm,Early stage,Single or 3 nodules,Advanced stage,Portal invasion,PST 0,ChildPugh A,BCLC stage 0A,Survival,36 months,BCLC stage B,Survival,16 months,BCLC stage C,Survival,6(48)months,BCLC stage D,Survival,3 months,Subject to PATH Program Disclaimer,中期或晚期肝癌患者的预后不佳,1,7080%,肝癌患者在确诊时已为中晚期,失去根治机会,1,102,肝癌患者生存分析,2,患者中不包括接受过根治性治疗*或,终末期患者,OS(%),Disease stage,1 year,2 years,3 years,Intermediate,80,65,50,Advanced,29,16,8,*,Surgical resection,liver transplantation or ethanol injection,Okuda stage 3 or performance status 3,1.Llovet JM.Gastroenterology.2005;40:225-35.,2.Llovet JM.Hepatology.1999;29:62-7.,HCC=,hepatocellular carcinoma;,OS=overall survival,Subject to PATH Program,Disclaimer,化学治疗或内分泌治疗,:,晚期肝癌几乎无效,研究,期别,N,客观有效率,化学治疗,Doxorubicin,单药,1,2,II/III,203,10%,Doxorubicin,联合,(PIAF),1,3,II/III,144,24%,Cisplatin,4,II,28,15%,Epirubicin,5,6,II,62,11%,Mitoxantrone,7,II,22,27%,Irinotecan,8,paclitaxel,9,gemcitabine,10,5-FU,11,II/III,10%,Anti-androgen(flutamide+leuproline),12,III,376,No benefit vs control,Interferon,13,III,30,10%,Octreotide,14,III,35,5%,Seocalcitol,15,III,746,2,Child-Pugh C,Very early stage(0),Single 2 cmcarcinoma in situ,Early stage(A),13 nodules 3 cm,PS 0,Intermediate stage(B),Multinodular,PS 0,Advanced stage(C),Portal invasion,N1,M1,PS 12,End stage(D),Single,3 nodules 3 cm,Portal pressure/bilirubin,Increased,Associated diseases,Normal,No,Yes,Resection,Liver transplantation(CLT/LDLT),PEI/RFA,Chemoembolization,Sorafenib,Curative treatments,Randomized controlled trials,Symptomatictreatment,RFA=radiofrequency ablation;PEI=percutaneous ethanol injection.,Llovet JM,et al.J Natl Cancer Inst.2008;100:698-711.,Subject to PATH Program,Disclaimer,NCCN Guidelines(2009),NCCN Clinical Practice Guidelines in Oncology.Hepatobiliary Cancer.V2.2009;,Available at:www.nccn.org.Accessed February 2010.,Subject to PATH Program,Disclaimer,Japan Society of Hepatology:consensus-based treatment algorithm for HCC,Kudo M.Oncology.2009;75 Suppl 1:1-12.,Subject to PATH Program,Disclaimer,Extrahepatic metastasis,Main portal vein tumor thrombus,Resectable,Sorafenib or systemic therapy trial,Resection/RFA(for,3 cm HCC),Solitary tumor,5 cm,3 tumors,3 cm,No venous invasion,Child-Pugh A Child-Pugh B Child-Pugh C Child-Pugh A/B Child-Pugh C,Transplantation,TACE,Supportive care,Local ablation,HCC,Confined to the liver,Main portal vein patent,APASL working committee meeting consensus on treatment guidelines for HCC,Tumor,5 cm,3 tumors,Invasion of hepatic/portal vein branches,Yes,No,Child Pugh A/B Child-Pugh C,Omata M et al.,APASL working committee meeting consensus on HCC,APASL February 1316,2009,Hong Kong,Subject to PATH Program,Disclaimer,HBV,HCV,酒精,黄曲霉毒素,B1,损伤,干细胞增殖停止,星形细胞活化,慢性肝病,Liver cirrhosis,Abnormal livernodules,Extensive scarring(collagen),染色体不稳定,染色体重度不稳定,和,P53,缺失,Hepatocellularcarcinoma,幼稚细胞结节,Hyperplasticnodule,分化好的,中等分化的,分化差的,增殖,坏死,Farazi PA,DePinho RA.Nat Rev Cancer.2006;6:674-87.,肝细胞肝癌的组织病理学和分子病理学特征,Subject to PATH Program Disclaimer,肝硬化,广泛瘢痕形成,肝脏结节形成,结节增生,肝细胞肝癌,肝细胞肝癌的发病机制与多个信号传导通路相关,细胞膜,c-MYC,c-JUN,Wnt,受体,BcL-XL,BAD,ERK1/2,MEK1/2,-catenin,GSK3,GBP,DSH,HBx,Akt,mTOR,Raf,PKC,NF-B,Ras,NF-B,PLC,SHC,GrB2,GEF,PI3K,PTEN,p53,生存,l,转录和翻译,-catenin,HBx,RTK:FGFR EGFRIGF-IRc-MET,受体,r,Adapted from Avila MA,et al.Oncogene.2006;25:3866-84.,Subject to PATH Program Disclaimer,肝细胞肝癌的分子学发病机制,肝细胞肝癌的发病机制与多个信号传导通路相关,肝细胞恶变是基于炎症、细胞再生、细胞增生、肝硬化、遗传、后天因素等,肝细胞肝癌多伴有细胞信号通路失调，主要包括：,1,2,血管生成信号,Ras/Raf/MEK/ERK,PI3K/Akt/mTOR,Wnt/-catenin,分子治疗的主要靶点,1.Thorgeirsson S,et al.Hepatology.2006;43:S145-50.2.Avila MA,et al.Oncogene.2006;25:3866-84,.,Subject to PATH Program Disclaimer,肝细胞肝癌靶向治疗,:,临床研究,肝细胞肝癌临床研究全面展开,Sorafenib,的有效性，引发靶向治疗临床研究,主要在早期和晚期患者临床研究，一线治疗、二线治疗及辅助治疗方面的研究,Llovet JM,Bruix J.J Clin Oncol.2009;27:833-35.,Subject to PATH Program Disclaimer,Adapted from Tanaka S,Arii S.Cancer Sci.2009;100:1-8.,临床开发,:,分子靶向药物和其主要靶点,Agent,抗血管生存,抗增殖,VEGF,VEGFR,PDGFR,EGFR,Raf,mTOR,Bevacizumab,Cediranib,Thalidomide,Erlotinib,Gefitinib,ABT-869,Sorafenib,Lapatinib,Sunitinib,Cetuximab,Brivanib,SU6668,Everolimus,Subject to PATH Program Disclaimer,Agent,抗生成血管,抗增殖,VEGF,VEGFR,PDGFR,EGFR,Raf,mTOR,Bevacizumab,Cediranib,Thalidomide,Erlotinib,Gefitinib,ABT-869,Sorafenib,Lapatinib,Sunitinib,Cetuximab,Brivanib,SU6668,Everolimus,III,期临床研究,:,分子靶向药物和其主要靶点,Sorafenib targets both tumor-cell proliferation and angiogenesis in vitro,KIT/Flt-3/RET,Angiogenesis,Raf,Endothelial cell or pericyte,Nucleus,VEGFR-2,PDGFR-,MEK,Apoptosis,Tumor cell,Proliferation,PDGF,VEGF,EGF,Survival,Wilhelm SM,et al.Cancer Res.2004;64:7099-109.,Ras,Nucleus,Ras,ERK,Raf,MEK,Apoptosis,ERK,PDGF-,VEGF,Paracrine stimulation,Sorafenib,X,X,X,X,X,X,X,X,Subject to PATH Program,Disclaimer,Primary endpoints:OS,TTSP,Secondary endpoints:TTP,DCR,safety,Phase III SHARP and AsiaPacific studies,Eligibility,Advanced HCC,ECOG PS 02,Child-Pugh A,no prior systemic therapy,Stratification,MVS and/or EHS,ECOG PS(0 vs 12),geographic region,RANDOMIZE1:1,SHARP,1,AsiaPacific,2,RANDOMIZE2:1,Sorafenib,400 mg bid,Placebo,Sorafenib,400 mg bid,Placebo,Endpoints:OS,TTSP,TTP,DCR,safety(no primary endpoint defined),n=299,n=303,n=150,n=76,1.Llovet JM,et al.N Engl J Med 2008;359:378-90.2.,Cheng A-L,et al.Lancet Oncol 2009;10:25-34.,Subject to PATH Program,Disclaimer,Sorafenib consistently increased overall survival in different global patient populations,HR=hazard ratio;OS=overall survival;,SHARP=,Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol.,Llovet JM et al.N Engl J Med.2008;359:378-90.,Cheng A-L,et al.Lancet Oncol.2009;10:25-34.,Survival probability,1.00,0.75,0.50,0.25,Months,0,4,6,8,10,12,14,16,2,0.00,Sorafenib(n=299),Median OS:10.7 months,Placebo(n=303),Median OS:7.9 months,18,HR=0.69,Survival probability,1.00,0.75,0.50,0.25,Months,0,4,8,12,22,0.00,Sorafenib(n=150),Median OS:6.5 months,Placebo(n=76),Median OS:4.2 months,2,6,10,14,16,18,20,HR=0.68,SHARP,1,AsiaPacific,2,Subject to PATH Program,Disclaimer,Asia-Pacific(N=226),SHARP(N=602),Median age(range),years,51(23-86),67(21-89),Sex(male),%,85,87,ECOG PS(0/1/2),%,26/69/5,54/38/8,MVI,%,35,38,EHS,%,69,51,BCLC stage(B/C),%,4/96,17/82,Hepatitis virus status(HBV/HCV),%,73/8,18/28,No.of tumor sites,%,1,11,44,2,35,31,3,20,12,4,35,13,Sites of disease,%,Lung,50,21,Lymph node,32,26,AsiaPacific trial,1,vs SHARP,2,:baseline patient characteristics,1.Cheng A,et al.J Clin Oncol.2008;26.Abstract 4509.Updated from oral presentation at ASCO;Chicago,IL;June 2008.,2.Llovet JM,et al.N Engl J Med.2008;359:378-90.,Subject to PATH Program,Disclaimer,SHARP:sorafenib prolongs OS by 44%and TTP by 74%in patients with advanced HCC,Llovet JM,et al.N Engl J Med.2008;359,:378-90.,1.00,Survival probability,0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17,Sorafenib(n=299)=10.7 months,Placebo(n=303)=7.9 months,Time from randomization(months),Probability of radiologic progression,0 1 2 3 4 5 6 7 8 9 10 11 12,Sorafenib(n=299)=5.5 months,Placebo(n=303)=2.8 months,Time from randomization(months),1.00,0.75,0.50,0.25,0,HR=0.69(95%CI:0.550.87),p0.001,0.75,0.50,0.25,0,HR=0.58,(95%CI,:0.450.74)p0.001,Overall survival,Time to progression,(independent central review),Subject to PATH Program Disclaimer,Sorafenib prolongs OS by 47%and TTP by 74%in AsiaPacific patients with advanced HCC,Cheng A-L,et al.Lancet Oncol.2009;10:25-34.,Overall survival,Time to progression,Sorafenib,Median:6.5 months,(95%CI:5.67.6),Placebo,Median:4.2 months,(95%CI:3.75.5,Sorafenib,Median:2.8 months,(95%CI:2.63.6),Placebo,Median:1.4 months,(95%CI:1.31.5,HR(S/P):0.57,(95%CI:0.420.79),p 0.001,Sorafenib,Sorafenib,Subject to PATH Program Disclaimer,AsiaPacific study,1,vs SHARP,2,:efficacy similar in both patient populations,Endpoint,AsiaPacific,SHARP,Hazard ratio,(95%CI),P-value,Hazard ratio,(95%CI),P-value,OS,0.68,0.014,0.69,0.001,(0.50,0.93),(0.55,0.88),TTSP,0.90,0.498,1.08,0.77,(0.67,1.22),(0.88,1.31),TTP,0.57,0.001,0.58,0.001,(0.42,0.79),(0.45,0.74),1.Cheng A,et al.J Clin Oncol.2008;26.Abstract 4509.Updated from oral presentation at ASCO;Chicago,IL;June 2008.,2.Llovet JM,et al.N Engl J Med.2008;359:378-90.3.Llovet JM et al.Hepatology.2008;48:1312-27.,Subject to PATH Program,Disclaimer,Sorafenib,在晚期肝细胞肝癌为标准治疗,Sorafenib,是第一个也是迄今为止唯一延长肝细胞肝癌患者生存的药物,在西方和东方不同人种、不同病因中得到验证,疗效和安全性得到验证,早期肝细胞肝癌的研究在进行中,Sorafenib,在肝细胞肝癌患者的安全性是在可控范围内的,不良反应多为中度,可预料和可管理的,Llovet JM et al.N Engl J Med.2008;359:378-90.,Cheng A-L,et al.Lancet Oncol.2009;10:25-34.,Subject to PATH Program,Disclaimer,不同靶向药物治疗在实体瘤带来的获益,Tumor type or randomized trial(s),Endpoint,HR(95%CI),Hepatocellular carcinoma(advanced),Sorafenib(n=299)vs placebo(n=303),1,SurvivalTTP,0.69,(0.550.87),0.58,(0.450.74),Renal cell carcinoma(advanced),Sorafenib(n=384)vs placebo(n=385),8,9,PFS,Survival,0.44,(0.350.55),0.78,(0.620.97),Colorectal cancer(metastatic),IFL+bevacizumab(n=402)vs IFL(n=411),2,Cetuximab(n=287)vs best supportive care(n=285),3,Survival,Survival,0.66,(NA),0.77,(0.640.92),Lung cancer,Pac/carbo+bevacizumab(n=434)vs pac/carbo(n=444),4,Erlotinib(n=488)vs placebo(n=243),5,Survival,Survival,0.79,(0.690.93),0.79,(0.580.85),Breast cancer(advanced,HER2+ve),Chemo+trastuzumab(n=235)vs chemo(n=234),6,Paclitaxel+bevacizumab vs paclitaxel(n=326),7,TTP,PFS,0.51,(0.390.59),0.60,(0.510.70),1.Llovet et al,N Engl J Med.2008;359:378-90,.2.Hurwitz et al,N Engl J Med.2004;350:2335-42.,3.Jonkers et al N Eng J Med 2007.4.Sandler et al,N Engl J Med.2006;355:2542-50,.5.Shepherd et al,N Engl J Med.2005 Jul 14;353:123-32,.6.Slamon et al,N Engl J Med.2001;344:783-92.,7.Miller et al,N Engl J Med.2007;357:2666-76.,8.Escudier B,et al.N Engl J Med.2007;356:125-34.9.Escudier B,et al.J Clin Oncol.2009;27:3312-18.,Table adapted from Llovet and Bruix,Hepatology 2008.,Subject to PATH Program Disclaimer,抗血管生成药物耐药方式,适应性,(,逃逸,),耐药,原发无效,Bergers G,Hanahan D.Nat Rev Cancer.2008;8:592-603.,Subject to PATH Program Disclaimer,诱导预血管生成因子替代重建新生血管生成,Bergers G,Hanahan D.Nat Rev Cancer.2008;8:592-603.,Subject to PATH Program Disclaimer,Bergers G,Hanahan D.Nat Rev Cancer.2008;8:592-603.,募集骨髓衍生细胞促使新生血管生成,Subject to PATH Program Disclaimer,Bergers G,Hanahan D.Nat Rev Cancer.2008;8:592-603.,肿瘤血管外周防御细胞增加,Subject to PATH Program Disclaimer,Bergers G,Hanahan D.Nat Re