關注背景治療改善肝癌預后目錄

肝炎/肝硬化是肝細胞癌的重要危險因素

合并肝炎/肝硬化對肝細胞癌預后的影響

肝細胞癌合并肝炎/肝硬化的治療TherelationshipofHepatitis/Cirrhosis/HCCTheinfluenceofcoexistingHepatitis/CirrhosisonHCCOutcomeTheprincipleofHCCpatientswithHepatitis/Cirrhosismanagement原發(fā)性肝細胞癌(HCC)是

全球第七大常見癌癥全球每年報道600000例HCC患者，其中亞洲約占78%Hepatocellularcarcinoma(HCC)istheseventhmostcommoncancerandthirdleadingcauseofcancer-relateddeathintheworldaccordingtotheNat.Rev.Gastroenterol.Hepatol.7,448–458(2010);publishedonline13July2010亞洲歐洲大洋洲非洲拉丁美洲和地中海區(qū)域南美GloboCan2008report.Hepatocellularcarcinoma(HCC)is

the7thmostcommoncancerAsiancountriesaccountfornearly78%oftheroughly600000casesofhepatocellularcarcinoma(HCC)reportedgloballyeachyear.肝炎類型概述肝炎類型抗原相應的抗體病毒類型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酒精性肝炎藥物性肝炎肝炎9.74%in19927.18%in20062008年，病毒性肝炎仍然是中國第一位的傳染病，年發(fā)病數(shù)140.7萬全國每年死于與乙肝相關肝病近30萬例中國乙肝病毒感染現(xiàn)狀HBeAg+(wild)HBeAg-/抗-HBe+ALTHBV-DNA正常或輕CHB中重度CHB中重度CHB正?；蜉p度CHB肝硬化非活動性攜帶狀態(tài)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動期肝硬化109-1010cp/ml104-108cp/ml<103cp/ml>103cp/ml非活動肝硬化慢性HBV感染自然史慢性HBV攜帶者慢性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異常發(fā)展至肝硬化非活動性攜帶者HBeAg-DNA↓↓ALT正常HBeAg-慢性肝炎HBeAg-DNA↑ALT異常分別有23%和4.4%的HBeAg-肝炎患者進展為肝硬化和HCCHCCBothchronichepatitisB–andC–associatedHCCusuallyoccurwithcirrhosis.ForhepatitisC,cirrhosisispresentinover90%ofcases,whereasforhepatitisBitrangesfrom50%to70%ofcases.50~70%HBV是亞洲國家HCC的主要致病因素慢性HBV感染→東北及東南亞國家的主要致病因素﹙中國，香港，印度尼西亞，朝鮮及臺灣﹚。全世界共3.6億HBV攜帶者，其中亞洲HBV攜帶者占絕大多數(shù)亞洲HBV感染的患病率差異較大，日本、新加坡及泰國為1-5%，印度尼西亞和中國北部為6-10%，臺灣、中國南部、朝鮮及菲律賓超過10%。日本和臺灣→慢性HCV感染是HCC發(fā)生的重要因素。預計丙肝病毒將成為亞洲肝細胞癌增長的主要推動因素，不同肝炎病毒之間的協(xié)同作用以及環(huán)境等因素將共同影響HCC的發(fā)病率。LancetOncol2009;10:1111–18亞洲腫瘤峰會2010《亞洲肝細胞癌治療共識》指出：慢性HBV感染是東北及東南亞國家的主要致病因素，包括中國，香港，印度尼西亞，朝鮮及臺灣。全世界3.6億攜帶者中亞洲HBV攜帶者占絕大多數(shù)ThehighprevalenceofchronicHBVcarriersinAsiaconstitutesthemajorityofthe360millioncarriersworldwide.亞洲，HBV感染的患病率有很大差異，日本、新加坡及泰國為1-5%，印度尼西亞和中國北部為6-10%，而臺灣、中國南部、朝鮮及菲律賓則超過10%。在日本和臺灣，慢性HCV感染是HCC發(fā)生的重要因素.HCVinfectionisexpectedtoincreaseasanaetiologicalfactorassociatedwithHCCinAsia.Thesynergisticinteractionsofinterviral,viral,andenvironmentalriskfactorscomplicatematters.亞洲國家HCC的治療:

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.HBV及其相關性肝硬化患者HCC發(fā)病率根據(jù)不同地區(qū)及臨床表現(xiàn)分層統(tǒng)計的乙肝患者HCC發(fā)病率橫斷面研究匯總GASTROENTEROLOGY2004;127:S35–S50HCCincidenceinHepatitisB

anditsrelatedcirrhosisOverallHepatocellularCarcinomaIncidenceRatesinLongitudinalStudiesofPatientsWithChronicHepatitisBInfectionAccordingtoClinicalSettingandGeographicArea臨床表現(xiàn)地區(qū)研究數(shù)量患者人數(shù)平均

隨訪期HCC發(fā)病率95%CI無癥狀乙肝攜帶者北美2180416年0.10.07-0.14臺灣/中國大陸4188698年0.70.51-0.70日本15137.30.20.08-0.39非活動期攜帶者歐洲3410160.020-0.04臺灣118980.20-0.42慢性乙肝歐洲64715.90.10-0.27臺灣24614.01.00.36-1.56日本27375.10.80.46-1.06肝硬化代償期歐洲64015.82.21.94-4.55臺灣/新加坡32784.33.21.94-4.55日本23065.84.33.40-5.25HBV負荷越高，HCC/肝硬化風險越高ClinLiverDis11(2007)797–816050010001500200025003000發(fā)病率（1/10萬人*年）<300300-999910000-99999100000-999999≥肝硬化肝癌HBVDNA水平（copies/mL）圖示為肝硬化，肝癌與不同HCC研究入組時HBVDNA水平的關系HBV感染的轉歸“持續(xù)病毒復制”

是慢性乙肝病情進展的主要病因肝細胞癌急性HBV感染慢性HBV感染5%-10%成年期感染95%圍產(chǎn)期/嬰幼兒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%失代償肝硬化慢性HCV的并發(fā)癥及預后HEPATOLOGY1997;26(Suppl1):1520SMedClinNAm89(2005)371–389S-ForhepatitisC,cirrhosisispresentinover90%ofcasesBothchronichepatitisB–andC–associatedHCCusuallyoccurwithcirrhosis.ForhepatitisC,cirrhosisispresentinover90%ofcases,whereasforhepatitisBitrangesfrom50%to70%ofcases.Complications&outcomeof

chronicHepatitisC90%的HCV患者出現(xiàn)肝硬化急性HCV感染慢性HCV感染痊愈輕度重度肝硬化慢性肝炎肝病晚期HCC85%15%中度>90%慢性HCV感染患者出現(xiàn)肝硬化PART1小結HBVHCV肝硬化肝癌肝癌的發(fā)生是一個多因素、多階段的發(fā)展過程，其中HBV、HCV慢性感染與肝癌的發(fā)生關系最為密切。大多數(shù)肝癌患者多由肝炎肝硬化發(fā)展而來肝硬化是大多數(shù)肝癌的共同特征，目前公認再生結節(jié)是惡性克隆形成和增殖位點MedClinNAm89(2005)371–389合并肝炎/肝硬化對HCC預后的影響Part2概述HCC合并HBeAg+肝炎HBV高負荷肝硬化肝功能儲備低影響HCC預后減少生存期增加復發(fā)風險HBeAg+的HBV相關性HCC患者根治術后早期復發(fā)風險增加，生存率降低JournalofHepatology47(2007)684–690n=203，小肝癌，手術切除術后，分為HBeAg陽性及陰性兩組，中位數(shù)隨訪32.9個月HBeAg(-)HBeAg(+)P=0.0020.00.20.40.60.81.0012243648607284無瘤生存率(%)總體生存率(%)HBeAg(-)HBeAg(+)P=0.0460.00.20.40.60.81.0012243648607284HBeAg+的HBV相關性HCC患者根治術后早期復發(fā)風險增高，生存率降低HBeAg+

isassociatedwithhigherriskofearlyrecurrenceandpoorersurvivalinpatientsaftercurativeresectionofhepatitisB-relatedHCC乙肝相關性HCC及肝硬化死亡率升高與病毒負荷（ViralLoad）相關AmJGastroenterol2006;101:1797–18030.800.840.880.920.961.00生存率（%）0123456789101112DNA-DNA+低負荷RR=1.7DNA+高負荷RR=11.2陽性低負荷指乙肝病毒DNA：<105生存時間（年）n=2763,HBsAg+,主要終點為HCC或CLD所致死亡.研究入組時不同HBVDNA檢測量與HCC生存率曲線ViralloadisassociatedwithincreasedmortalityfromHCCandCLDinHBV-infectedsubjectsHCCmortalitycurvesbyviralloadcategoryatstudyentryn=2763,HBsAg+,MajorendpointsweredeathfromHCCorCLD.持續(xù)高HBV負荷——

HCC術后復發(fā)的獨立危險因素持續(xù)高病毒血癥HBVDNA波動持續(xù)低病毒血癥P<0.001HCC復發(fā)(%)隨訪時間（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相關性HCC,已接受手術切除治療，平均隨訪48.5個月0100806040203倍OR:3.13SustainedhighviremiaFluctuatingHBVDNASustainedlowviremiaHCCrecurrence(%)HCV亦是HCC術后肝內復發(fā)

的重要危險因素EurJSurgOncol.2003Apr;29(3):266-71.肝內復發(fā)累積概率（%）肝切除術后時間020406080100012345678910NBNC(N=24)B-viral(N=32)C-viral(N=55)P=0.0306n=111，HCC術后，分為HCV/HBV/無HV3組HCVissignificantriskfactorforintrahepaticrecurrenceafterHCCresection肝功能低下的HCV相關性HCC患者

RFA治療后遠處復發(fā)率高MonthsafterRFAAlimentPharmacolTher.2008Jun;27(12):1253-60n=117，HCV，非晚期肝癌，行導管射頻消融（RFA）治療P=0.003遠處復發(fā)率率(%)0102030405060010080604020ChildAChildBDistantrecurrenceisathighratesinLOWLIVERFUNCTIONRESERVEHCVrelatedpatientsafterRFADistantrecurrence(%)肝硬化與HCC肝內復發(fā)顯著相關EurJSurgOncol.2003Apr;29(3):266-71.n=111，HCC術后，分為HCV/HBV/無HV3組指標RR95%CIP值肝炎病毒狀態(tài)0.0429HBV及非HBV非HCV1.00HCV1.691.02-2.79肝硬化0.0040無1.00有2.141.28-3.59腫瘤大小(mm)0.0098≤501.00≥502.031.19-3.47PART2小結HBVHCV肝硬化加速肝癌惡化肝炎、肝硬化影響肝癌預后除常規(guī)治療外，還需注重背景治療合并HBeAg+,持續(xù)HBV高負荷增加復發(fā)風險，降低OS，并對現(xiàn)有治療反應不佳合并肝硬化增加HCC死亡率HCC的背景治療——不可忽視的問題我國肝癌治療難點:大多數(shù)患者有乙肝和肝硬化背景常合并肝功能障礙發(fā)病年齡較低，進展迅速，容易發(fā)生肝內播散和遠處轉移僅部分患者可接受手術治療手術后復發(fā)率高CSLC、CSCO原發(fā)性肝癌規(guī)范化診療專家共識指出關注HCC的背景治療抗病毒(HBV)治療肝硬化并發(fā)癥提高肝功能儲備ChineseHepatology，Jun．2009，Vo1．14，No．3.最大程度改善肝癌預后HBV治療指征JournalofHepatology50(2009)227–242治療指征血清HBVDNA>2000IU/ml血清轉氨酶水平ALT>正常值的上限組織學分級與分期中至重度活動性壞死性炎癥和/或纖維化AASLD乙肝治療指南2009更新代償?shù)母斡不翱蓹z測到HBVDNA者應當治療，即使ALT水平正常和/或HBVDNA水平低于2000IU/ml(例如：約10,000copies/ml)(B1).失代償?shù)母斡不颊咝枇⒓纯共《局委?。極需快速抑制病毒并有效預防耐藥性。臨床癥狀顯著改善與病毒復制控制有關，但患極晚期肝臟疾病的患者未必從治療獲益，應當考慮肝移植(A1).PatientswithcompensatedcirrhosisanddetectableHBVDNAmaybeconsideredfortreatmentevenifALTlevelsarenormaland/orHBVDNAlevelsarebelow2000IU/ml(i.e.approximately10,000copies/ml)(B1).Patientswithdecompensatedcirrhosisrequireurgentantiviraltreatment.Rapidandprofoundviralsuppressionandefficaciouspreventionofresistanceareparticularlyneededinthisgroup.Significantclinicalimprovementcanbeassociatedwithcontrolofviralreplication,butpatientswithveryadvancedliverdiseasemaynotalwaysbenefitiftreatedatthislatestageandshouldbeconsideredforlivertransplantation(A1).HBV治療目標慢性乙肝治療的主要目標→持續(xù)抑制HBV.降低致病性和傳染性→阻止或減輕肝壞死性炎癥.Asian-PacificconsensusstatementonthemanagementofchronichepatitisB:a2005updateInclinicalterms,theshort-termgoaloftreatmentistoensureHBV-DNAsustainedsuppression,ALTnormalizationandpreventthedevelopmentofdecompensation(initialresponse),toreducehepaticnecroinflammationandfibrosisduringandaftertherapy(maintainedandsustainedresponse).Theultimatelong-termgoaloftherapyistopreventhepaticdecompensation,toreduceorpreventprogressiontocirrhosisand/orHCC,andtoprolongsurvival(durableresponse).短期目標長期目標確保HBV-DNA持續(xù)抑制，ALT正常及預防失代償?shù)陌l(fā)生以減輕肝壞死性炎癥和纖維化預防肝功失代償，以減輕或預防肝硬化和/或HCC的進展，從而延長生命GoalsofHBVtreatmentPrimarygoaloftreatmentforchronichepatitisBistoeliminateorpermanentlysuppressHBV.Thiswilldecreasepathogenicityandinfectivity,andtherebystoporreducehepaticnecroinflammation.Asian-PacificconsensusstatementonthemanagementofchronichepatitisB:a2005updateshort-termgoalshort-termgoalEnsureHBV-DNAsustainedsuppression,ALTnormalizationandpreventthedevelopmentofdecompensationtoreducehepaticnecroinflammationandfibrosisduringandaftertherapyPreventhepaticdecompensation,toreduceorpreventprogressiontocirrhosisand/orHCC,andtoprolongsurvival.LiverInternational,25:

472–489.肝硬化防治是綜合性的針對病因抗病毒戒酒免疫抑制其他早期晚期處理并發(fā)癥腹水食管靜脈曲張出血自發(fā)性腹膜炎肝腎綜合征其他研究名稱患者人數(shù)RR（95%CI）Pascal227Ideo306Strause342Lebrec449IMMP622Anderant674Conn721Vanburan811Pascal227Ideo306Strause342Lebrec449IMMP622Vanburan811非選擇性β受體阻滯劑降低靜脈曲張出血及死亡風險SEMINARSINLIVERDISEASE-VOL.19,NO.4,1999GastrointestinalbleedingduetogastroesophagealvaricesAtotalof12trialsassessingbeta-adrenergicblockersforthepreventionoffirstbleedinghavebeenreported.Meta-analysisofthesestudiesshowsthatcontinuedpropranololornadololtherapyreducesmarkedlythebleedingrisk,from25%withnon-activetreatmentto15%withbeta-adrenergicblockersoveramedianfollow-upof2years[3].Mortalitywasonlyslightlyreducedfrom27to23%;thiseffectbarelyapproachedthelevelofstatisticalsignificance.Thebenefitoftherapyhasbeenprovedinpatientswithmoderate/largevarices(.5mm),eitherwithorwithoutascitesorwithgoodorpoorliverfunction.胃食管靜脈曲張出血Meta分析，入選12項β受體阻滯劑預防性治療肝硬化胃底食管靜脈曲張研究，中位數(shù)隨訪2年出血死亡β受體阻滯劑更優(yōu)安慰劑更優(yōu)1.00.60.21.4IAC推薦的自發(fā)性細菌性腹膜炎治療措施InternationalAscitesClub(IAC)SBP共識推薦推薦等級腹水中性粒細胞計數(shù)>250/mm3需起始經(jīng)驗性抗生素治療A,II初始經(jīng)驗性抗生素治療的建議頭孢噻肟;最低劑量2g/1