改善肝癌预后关注背景治疗课件

关注背景治疗改善肝癌预后改善肝癌预后-关注背景治疗目录

肝炎/肝硬化是肝细胞癌的重要危险因素

合并肝炎/肝硬化对肝细胞癌预后的影响

肝细胞癌合并肝炎/肝硬化的治疗TherelationshipofHepatitis/Cirrhosis/HCCTheinfluenceofcoexistingHepatitis/CirrhosisonHCCOutcomeTheprincipleofHCCpatientswithHepatitis/Cirrhosismanagement改善肝癌预后-关注背景治疗肝炎/肝硬化是肝细胞癌的重要危险因素Part1改善肝癌预后-关注背景治疗原发性肝细胞癌(HCC)是

全球第七大常见癌症

全球每年报道600000例HCC患者，其中亚洲约占78%Hepatocellularcarcinoma(HCC)istheseventhmostcommoncancerandthirdleadingcauseofcancer-relateddeathintheworldaccordingtotheNat.Rev.Gastroenterol.Hepatol.7,448–458(2010);publishedonline13July2010亚洲欧洲大洋洲非洲拉丁美洲和地中海区域南美GloboCan2008report.Hepatocellularcarcinoma(HCC)is

the7thmostcommoncancerAsiancountriesaccountfornearly78%oftheroughly600000casesofhepatocellularcarcinoma(HCC)reportedgloballyeachyear.改善肝癌预后-关注背景治疗肝病三部曲肝细胞癌肝炎(主要为病毒性)肝硬化15-20%

在5年内发展至肝硬化患者的HCC年发病率约为3-6%MedClinNAm89(2005)371–389NEnglJMed.1997Dec11;337(24):1733-45HCCmaydevelopatanannualincidenceof3-6%incirrhosis改善肝癌预后-关注背景治疗肝炎类型概述肝炎类型抗原相应的抗体病毒类型AHAVAnti-HAVRNABHBsAgHBcAgHbeAgAnti-HBsAnti-HBcAnti-HBeDNACHCAgAnti-HCVRNADHDAgAnti-HDV缺陷RNAEHEAgAnti-HEVRNAGHGAgNARNA其他SystemicRegional自身免疫性肝炎病毒性肝炎HAVHBVHCVHDVHEVHGV酒精性肝炎药物性肝炎肝炎改善肝癌预后-关注背景治疗9.74%in19927.18%in20062008年，病毒性肝炎仍然是中国第一位的传染病，年发病数140.7万全国每年死于与乙肝相关肝病近30万例中国乙肝病毒感染现状改善肝癌预后-关注背景治疗HBeAg+(wild)HBeAg-/抗-HBe+ALTHBV-DNA正常或轻CHB中重度CHB中重度CHB正常或轻度CHB肝硬化非活动性携带状态HBeAg–

慢乙肝HBeAg+慢乙肝免疫耐受期免疫清除期免疫控制期再活动期肝硬化109-1010cp/ml104-108cp/ml<103cp/ml>103cp/ml非活动肝硬化慢性HBV感染自然史慢性HBV携带者改善肝癌预后-关注背景治疗慢性HBV自然史MayoClinProc.2007;82(8):967-975LiverInternational2005:25:472–489MedClinNAm89(2005)371–389免疫耐受HBeAg+DNA↑↑↑ALT正常HBeAg+慢性肝炎HBeAg+DNA↑↑ALT异常发展至肝硬化非活动性携带者HBeAg-DNA↓↓ALT正常HBeAg-慢性肝炎HBeAg-DNA↑ALT异常分别有23%和4.4%的HBeAg-肝炎患者进展为肝硬化和HCCHCCBothchronichepatitisB–andC–associatedHCCusuallyoccurwithcirrhosis.ForhepatitisC,cirrhosisispresentinover90%ofcases,whereasforhepatitisBitrangesfrom50%to70%ofcases.50~70%改善肝癌预后-关注背景治疗MapsweregeneratedusingincidenceratesoflivercancerfromGLOBOCAN2002全球78%的HCC归因于HBV/HCV感染PerzJF,ArmstrongGL,FarringtonLA,etal.ThecontributionsofhepatitisBvirusandhepatitisCvirusinfectionstocirrhosisandprimarylivercancerworldwide.JHepatol2006;45:529-538.57%ofcirrhosiswasattributabletoeitherHBV(30%)orHCV(27%)and78%ofHCCwasattributabletoHBV(53%)orHCV(25%).TheestimatedfractionsofcirrhosisattributabletoHBVinfectionrangedfrom5%(AMR-A)to57%(WPR-B)(Table4,Fig.1).ThefractionsofcirrhosisattributabletoHCVinfectionrangedfrom16%(AFRD/E)to62%(WPR-A).TheattributablefractionsofHCCduetoHBVorHCVrangedfrom16%(AMRA)to65%(WPR-B)andfrom13%(EMR-B)to66%(WPR-A),respectively.Thetwovirusestogetheraccountedfor>50%ofHCCinalloftheregions;thiswasalsotrueforcirrhosisin8of11regions.Globally,weestimatedthatapproximately57%ofcirrhosiswasduetoeitherHBV(30%)orHCV(27%)(Table4).ForHCC,approximatelythree-quarters(78%)wasattributabletoHBV(53%)orHCV(25%).Hepatol2006;45:529-538.乙肝/丙肝病毒对原发性肝细胞癌及肝硬化的影响比例ThecontributionsofhepatitisBvirusandhepatitisCvirusinfectionstocirrhosisandprimarylivercancerworldwide改善肝癌预后-关注背景治疗HBV是亚洲国家HCC的主要致病因素慢性HBV感染→东北及东南亚国家的主要致病因素﹙中国，香港，印度尼西亚，朝鲜及台湾﹚。全世界共3.6亿HBV携带者，其中亚洲HBV携带者占绝大多数亚洲HBV感染的患病率差异较大，日本、新加坡及泰国为1-5%，印度尼西亚和中国北部为6-10%，台湾、中国南部、朝鲜及菲律宾超过10%。日本和台湾→慢性HCV感染是HCC发生的重要因素。预计丙肝病毒将成为亚洲肝细胞癌增长的主要推动因素，不同肝炎病毒之间的协同作用以及环境等因素将共同影响HCC的发病率。LancetOncol2009;10:1111–18亚洲肿瘤峰会2010《亚洲肝细胞癌治疗共识》指出：慢性HBV感染是东北及东南亚国家的主要致病因素，包括中国，香港，印度尼西亚，朝鲜及台湾。全世界3.6亿携带者中亚洲HBV携带者占绝大多数ThehighprevalenceofchronicHBVcarriersinAsiaconstitutesthemajorityofthe360millioncarriersworldwide.亚洲，HBV感染的患病率有很大差异，日本、新加坡及泰国为1-5%，印度尼西亚和中国北部为6-10%，而台湾、中国南部、朝鲜及菲律宾则超过10%。在日本和台湾，慢性HCV感染是HCC发生的重要因素.HCVinfectionisexpectedtoincreaseasanaetiologicalfactorassociatedwithHCCinAsia.Thesynergisticinteractionsofinterviral,viral,andenvironmentalriskfactorscomplicatematters.亚洲国家HCC的治疗:

consensusstatementfromtheAsianOncologySummit2009InAsia,themainetiologicalfactorofHCCishepatitisBvirusThemainaetiologicalfactorischronichepatitisBvirus(HBV)infectioninnortheastandsoutheastAsia,includingChina,HongKong,Indonesia,Korea,andTaiwan.ThehighprevalenceofchronicHBVcarriersinAsiaconstitutesthemajorityofthe360millioncarriersworldwide.InAsia,thereiswidevariationintheprevalenceofHBVinfection;prevalenceis1–5%inJapan,Singapore,andThailand,6–10%inIndonesiaandnorthernChina,andhigherthan10%inTaiwan,southernChina,Korea,andthePhilippines.ChronichepatitisCvirus(HCV)infectionalsohasasubstantialroleinthedevelopmentofHCCinJapanandTaiwan.HCVinfectionisexpectedtoincreaseasanaetiologicalfactorassociatedwithHCCinAsia.Thesynergisticinteractionsofinterviral,viral,andenvironmentalriskfactorscomplicatematters.改善肝癌预后-关注背景治疗HBV及其相关性肝硬化患者HCC发病率根据不同地区及临床表现分层统计的乙肝患者HCC发病率横断面研究汇总GASTROENTEROLOGY2004;127:S35–S50HCCincidenceinHepatitisB

anditsrelatedcirrhosisOverallHepatocellularCarcinomaIncidenceRatesinLongitudinalStudiesofPatientsWithChronicHepatitisBInfectionAccordingtoClinicalSettingandGeographicArea临床表现地区研究数量患者人数平均

随访期HCC发病率95%CI无症状乙肝携带者北美2180416年0.10.07-0.14台湾/中国大陆4188698年0.70.51-0.70日本15137.30.20.08-0.39非活动期携带者欧洲3410160.020-0.04台湾118980.20-0.42慢性乙肝欧洲64715.90.10-0.27台湾24614.01.00.36-1.56日本27375.10.80.46-1.06肝硬化代偿期欧洲64015.82.21.94-4.55台湾/新加坡32784.33.21.94-4.55日本23065.84.33.40-5.25改善肝癌预后-关注背景治疗HBV负荷越高，HCC/肝硬化风险越高ClinLiverDis11(2007)797–816050010001500200025003000发病率（1/10万人*年）<300300-999910000-99999100000-999999≥肝硬化肝癌HBVDNA水平（copies/mL）图示为肝硬化，肝癌与不同HCC研究入组时HBVDNA水平的关系改善肝癌预后-关注背景治疗HBV感染的转归“持续病毒复制”

是慢性乙肝病情进展的主要病因肝细胞癌急性HBV感染慢性HBV感染5%-10%成年期感染95%围产期/婴幼儿期感染肝硬化慢性肝炎5年內12%-20%5年內6%-15%5年內20%-23%10％-30%失代偿肝硬化改善肝癌预后-关注背景治疗慢性HCV的并发症及预后HEPATOLOGY1997;26(Suppl1):1520SMedClinNAm89(2005)371–389S-ForhepatitisC,cirrhosisispresentinover90%ofcasesBothchronichepatitisB–andC–associatedHCCusuallyoccurwithcirrhosis.ForhepatitisC,cirrhosisispresentinover90%ofcases,whereasforhepatitisBitrangesfrom50%to70%ofcases.Complications&outcomeof

chronicHepatitisC90%的HCV患者出现肝硬化急性HCV感染慢性HCV感染痊愈轻度重度肝硬化慢性肝炎肝病晚期HCC85%15%中度>90%慢性HCV感染患者出现肝硬化改善肝癌预后-关注背景治疗HBV/HCV相关性肝硬化患者

HCC发病率约为3%/年NEnglJMed1991;325:675-680.无肿瘤生存率（%）0612182430364248100806040200HCC:3%3%2%意大利肝硬化患者调查，n=447，肝硬化代偿期，每3-12个月进行血清AFP及腹部超声检查≈3%compensatedcirrhosiswithHBV/HCVdevelopHCCperyear改善肝癌预后-关注背景治疗PART1小结HBVHCV肝硬化肝癌肝癌的发生是一个多因素、多阶段的发展过程，其中HBV、HCV慢性感染与肝癌的发生关系最为密切。大多数肝癌患者多由肝炎肝硬化发展而来肝硬化是大多数肝癌的共同特征，目前公认再生结节是恶性克隆形成和增殖位点MedClinNAm89(2005)371–389改善肝癌预后-关注背景治疗合并肝炎/肝硬化对HCC预后的影响Part2改善肝癌预后-关注背景治疗概述HCC合并HBeAg+肝炎HBV高负荷肝硬化肝功能储备低影响HCC预后减少生存期增加复发风险改善肝癌预后-关注背景治疗HBeAg+的HBV相关性HCC患者根治术后早期复发风险增加，生存率降低JournalofHepatology47(2007)684–690n=203，小肝癌，手术切除术后，分为HBeAg阳性及阴性两组，中位数随访32.9个月HBeAg(-)HBeAg(+)P=0.0020.00.20.40.60.81.0012243648607284无瘤生存率(%)总体生存率(%)HBeAg(-)HBeAg(+)P=0.0460.00.20.40.60.81.0012243648607284HBeAg+的HBV相关性HCC患者根治术后早期复发风险增高，生存率降低HBeAg+

isassociatedwithhigherriskofearlyrecurrenceandpoorersurvivalinpatientsaftercurativeresectionofhepatitisB-relatedHCC改善肝癌预后-关注背景治疗乙肝相关性HCC及肝硬化死亡率升高与病毒负荷（ViralLoad）相关AmJGastroenterol2006;101:1797–18030.800.840.880.920.961.00生存率（%）0123456789101112DNA-DNA+低负荷RR=1.7DNA+高负荷RR=11.2阳性低负荷指乙肝病毒DNA：<105生存时间（年）n=2763,HBsAg+,主要终点为HCC或CLD所致死亡.研究入组时不同HBVDNA检测量与HCC生存率曲线ViralloadisassociatedwithincreasedmortalityfromHCCandCLDinHBV-infectedsubjectsHCCmortalitycurvesbyviralloadcategoryatstudyentryn=2763,HBsAg+,MajorendpointsweredeathfromHCCorCLD.改善肝癌预后-关注背景治疗持续高HBV负荷——

HCC术后复发的独立危险因素持续高病毒血症HBVDNA波动持续低病毒血症P<0.001HCC复发(%)随访时间（月）01224364860728496108Figure2.Recurrenceofhepatocellularcarcinoma(HCC)inthe115patientssurvivingmorethan1yearwithoutrecurrenceafterresection.ThereisasignificantlylowrecurrenceofHCCinthesustainedlowviremiagroupthantheothergroups(log-ranktest,P<0.001).Sustainedhighviremiagroup(solidline),patientswithsustainedHBVDNAlevels>105copies/mlduringthefollow-up;sustainedlowviremiagroup(dottedline),patientswithsustainedHBVDNAlevels<104copies/ml;fluctuatingHBVDNAgroup(dashedline),theremainingpatients.JournalofGastroenterologyandHepatology.Jun2010.Publishedonlinefirst.n=188,HBV相关性HCC,已接受手术切除治疗，平均随访48.5个月0100806040203倍OR:3.13SustainedhighviremiaFluctuatingHBVDNASustainedlowviremiaHCCrecurrence(%)改善肝癌预后-关注背景治疗持续高HBV负荷——

HCC术后OS的独立危险因素P=0.018OS(%)01224364860728496108JournalofGastroenterologyandHepatology.Jun2010.Publishedonlinefirst.n=188,HBV相关性HCC,已接受手术切除治疗，平均随访48.5个月010080604020Figure3.Overallsurvivalinthe115patientssurvivingmorethan1yearwithoutrecurrenceafterresection.Thereisasignificantlylongersurvivalinthesustainedlowviremiagroupthantheothergroups(log-ranktest,P=0.018).Sustainedhighviremiagroup(solidline),patientswithsustainedHBVDNAlevels>105copies/mlduringthefollow-up;sustainedlowviremiagroup(dottedline),patientswithsustainedHBVDNAlevels<104copies/ml;fluctuatingHBVDNAgroup(dashedline),theremainingpatients.持续低病毒血症HBVDNA波动持续高病毒血症随访时间（月）改善肝癌预后-关注背景治疗HCV亦是HCC术后肝内复发

的重要危险因素

EurJSurgOncol.2003Apr;29(3):266-71.肝内复发累积概率（%）肝切除术后时间020406080100012345678910NBNC(N=24)B-viral(N=32)C-viral(N=55)P=0.0306n=111，HCC术后，分为HCV/HBV/无HV3组HCVissignificantriskfactorforintrahepaticrecurrenceafterHCCresection改善肝癌预后-关注背景治疗肝功能低下的HCV相关性HCC患者

RFA治疗后远处复发率高MonthsafterRFAAlimentPharmacolTher.2008Jun;27(12):1253-60n=117，HCV，非晚期肝癌，行导管射频消融（RFA）治疗P=0.003远处复发率率(%)0102030405060010080604020ChildAChildBDistantrecurrenceisathighratesinLOWLIVERFUNCTIONRESERVEHCVrelatedpatientsafterRFADistantrecurrence(%)改善肝癌预后-关注背景治疗合并肝硬化的HCC患者

死亡和复发风险显著增加024681020406080100复发率(%)024681020406080100OS(%)肝切除术后时间（年）肝切除术后时间（年）P<0.03P<0.0001P<0.0001Surgery2007;142:685-94.n=293，HCC，肝切除术后CirrhosisC-PB(n=37)CirrhosisC-PA(n=129)Noncirrhosis(n=127)改善肝癌预后-关注背景治疗肝硬化与HCC肝内复发显著相关EurJSurgOncol.2003Apr;29(3):266-71.n=111，HCC术后，分为HCV/HBV/无HV3组指标RR95%CIP值肝炎病毒状态0.0429HBV及非HBV非HCV1.00HCV1.691.02-2.79肝硬化0.0040无1.00有2.141.28-3.59肿瘤大小(mm)0.0098≤501.00≥502.031.19-3.47改善肝癌预后-关注背景治疗PART2小结HBVHCV肝硬化加速肝癌恶化肝炎、肝硬化影响肝癌预后除常规治疗外，还需注重背景治疗合并HBeAg+,持续HBV高负荷增加复发风险，降低OS，并对现有治疗反应不佳合并肝硬化增加HCC死亡率改善肝癌预后-关注背景治疗HCC合并肝炎/肝硬化者的治疗Part3改善肝癌预后-关注背景治疗HCC的背景治疗——不可忽视的问题我国肝癌治疗难点:大多数患者有乙肝和肝硬化背景常合并肝功能障碍发病年龄较低，进展迅速，容易发生肝内播散和远处转移仅部分患者可接受手术治疗手术后复发率高CSLC、CSCO原发性肝癌规范化诊疗专家共识指出关注HCC的背景治疗抗病毒(HBV)治疗肝硬化并发症提高肝功能储备ChineseHepatology，Jun．2009，Vo1．14，No．3.最大程度改善肝癌预后改善肝癌预后-关注背景治疗研究复发率RR(95%CI)干扰素组安慰剂组Ikeda1/107/100.14（0.02-0.96）Kubo9/1513/150.69（0.44-1.09）Lin8/209/100.44（0.25-0.79）Shiratori40/4923/250.89（0.74-1.06）Mazzaferro44/7647/740.91（0.70-1.18）Sun67/11871/1180.94（0.76-1.17）Lo21/4022/400.95（0.64-1.43）总体190/328192/2920.86（0.76-0.97）抗病毒治疗（IFN）使

乙肝相关性HCC复发风险降低14%BrJSurg.

2009Sep;96(9):975-81.Meta-analysisofinterferonaftercurativetreatmentofhepatocellularcarcinomainpatientswithviralhepatitisMeta分析，7项RCT，n=620，HCC术后，合并病毒性肝炎120.50.25改善肝癌预后-关注背景治疗HBV治疗指征JournalofHepatology50(2009)227–242治疗指征血清

HBVDNA>2000IU/ml血清转氨酶水平ALT>正常值的上限组织学分级与分期中至重度活动性坏死性炎症和/或纤维化AASLD乙肝治疗指南2009更新代偿的肝硬化及可检测到HBVDNA者应当治疗，即使ALT水平正常和/或HBVDNA水平低于2000IU/ml(例如：约10,000copies/ml)(B1).失代偿的肝硬化患者需立即抗病毒治疗。极需快速抑制病毒并有效预防耐药性。临床症状显著改善与病毒复制控制有关，但患极晚期肝脏疾病的患者未必从治疗获益，应当考虑肝移植

(A1).PatientswithcompensatedcirrhosisanddetectableHBVDNAmaybeconsideredfortreatmentevenifALTlevelsarenormaland/orHBVDNAlevelsarebelow2000IU/ml(i.e.approximately10,000copies/ml)(B1).Patientswithdecompensatedcirrhosisrequireurgentantiviraltreatment.Rapidandprofoundviralsuppressionandefficaciouspreventionofresistanceareparticularlyneededinthisgroup.Significantclinicalimprovementcanbeassociatedwithcontrolofviralreplication,butpatientswithveryadvancedliverdiseasemaynotalwaysbenefitiftreatedatthislatestageandshouldbeconsideredforlivertransplantation(A1).改善肝癌预后-关注背景治疗HBV治疗目标慢性乙肝治疗的主要目标→持续抑制HBV.降低致病性和传染性→阻止或减轻肝坏死性炎症.Asian-PacificconsensusstatementonthemanagementofchronichepatitisB:a2005updateInclinicalterms,theshort-termgoaloftreatmentistoensureHBV-DNAsustainedsuppression,ALTnormalizationandpreventthedevelopmentofdecompensation(initialresponse),toreducehepaticnecroinflammationandfibrosisduringandaftertherapy(maintainedandsustainedresponse).Theultimatelong-termgoaloftherapyistopreventhepaticdecompensation,toreduceorpreventprogressiontocirrhosisand/orHCC,andtoprolongsurvival(durableresponse).短期目标长期目标确保HBV-DNA持续抑制，ALT正常及预防失代偿的发生以减轻肝坏死性炎症和纤维化预防肝功失代偿，以减轻或预防肝硬化和/或HCC的进展，从而延长生命GoalsofHBVtreatmentPrimarygoaloftreatmentforchronichepatitisBistoeliminateorpermanentlysuppressHBV.Thiswilldecreasepathogenicityandinfectivity,andtherebystoporreducehepaticnecroinflammation.Asian-PacificconsensusstatementonthemanagementofchronichepatitisB:a2005updateshort-termgoalshort-termgoalEnsureHBV-DNAsustainedsuppression,ALTnormalizationandpreventthedevelopmentofdecompensationtoreducehepaticnecroinflammationandfibrosisduringandaftertherapyPreventhepaticdecompensation,toreduceorpreventprogressiontocirrhosisand/orHCC,andtoprolongsurvival.LiverInternational,25:

472–489.改善肝癌预后-关注背景治疗肝硬化防治是综合性的针对病因抗病毒戒酒免疫抑制其他早期晚期处理并发症腹水食管静脉曲张出血自发性腹膜炎肝肾综合征其他改善肝癌预后-关注背景治疗研究名称患者人数RR（95%CI）Pascal227Ideo306Strause342Lebrec449IMMP622Anderant674Conn721Vanburan811Pascal227Ideo306Strause342Lebrec449IMMP622Vanburan811非选择性β受体阻滞剂降低静脉曲张出血及死亡风险SEMINARSINLIVERDISEASE-VOL.19,NO.4,1999GastrointestinalbleedingduetogastroesophagealvaricesAtotalof12trialsassessingbeta-adrenergicblockersforthepreventionoffirstbleedinghavebeenreported.Meta-analysisofthesestudiesshowsthatcontinuedpropranololornadololtherapyreducesmarkedlythebleedingrisk,from25%withnon-activetreatmentto15%withbeta-adrenergicblockersoveramedianfollow-upof2years[3].Mortalitywasonlyslightlyreducedfrom27to23%;thiseffectbarelyapproachedthelevelofstatisticalsignificance.Thebenefitoftherapyhasbeenprovedinpatientswithmoderate/largevarices(.5mm),eitherwithorwithoutascitesorwithgoodorpoorliverfunction.胃食管静脉曲张出血Meta分析，入