關(guān)注背景治療改善肝癌預(yù)后目錄

肝炎/肝硬化是肝細(xì)胞癌的重要危險(xiǎn)因素

合并肝炎/肝硬化對(duì)肝細(xì)胞癌預(yù)后的影響

肝細(xì)胞癌合并肝炎/肝硬化的治療TherelationshipofHepatitis/Cirrhosis/HCCTheinfluenceofcoexistingHepatitis/CirrhosisonHCCOutcomeTheprincipleofHCCpatientswithHepatitis/Cirrhosismanagement肝炎/肝硬化是肝細(xì)胞癌的重要危險(xiǎn)因素Part1原發(fā)性肝細(xì)胞癌(HCC)是

全球第七大常見癌癥全球每年報(bào)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.肝病三部曲肝細(xì)胞癌肝炎(主要為病毒性)肝硬化15-20%

在5年內(nèi)發(fā)展至肝硬化患者的HCC年發(fā)病率約為3-6%MedClinNAm89(2005)371–389NEnglJMed.1997Dec11;337(24):1733-45HCCmaydevelopatanannualincidenceof3-6%incirrhosis肝炎類型概述肝炎類型抗原相應(yīng)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(guó)第一位的傳染病，年發(fā)病數(shù)140.7萬(wàn)全國(guó)每年死于與乙肝相關(guān)肝病近30萬(wàn)例中國(guó)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(dòng)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(dòng)期肝硬化109-1010cp/ml104-108cp/ml<103cp/ml>103cp/ml非活動(dòng)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(dòng)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(jìn)展為肝硬化和HCCHCCBothchronichepatitisB–andC–associatedHCCusuallyoccurwithcirrhosis.ForhepatitisC,cirrhosisispresentinover90%ofcases,whereasforhepatitisBitrangesfrom50%to70%ofcases.50~70%MapsweregeneratedusingincidenceratesoflivercancerfromGLOBOCAN2002全球78%的HCC歸因于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/丙肝病毒對(duì)原發(fā)性肝細(xì)胞癌及肝硬化的影響比例ThecontributionsofhepatitisBvirusandhepatitisCvirusinfectionstocirrhosisandprimarylivercancerworldwideHBV是亞洲國(guó)家HCC的主要致病因素慢性HBV感染→東北及東南亞國(guó)家的主要致病因素﹙中國(guó)，香港，印度尼西亞，朝鮮及臺(tái)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(guó)為1-5%，印度尼西亞和中國(guó)北部為6-10%，臺(tái)灣、中國(guó)南部、朝鮮及菲律賓超過10%。日本和臺(tái)灣→慢性HCV感染是HCC發(fā)生的重要因素。預(yù)計(jì)丙肝病毒將成為亞洲肝細(xì)胞癌增長(zhǎng)的主要推動(dòng)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(huì)2010《亞洲肝細(xì)胞癌治療共識(shí)》指出：慢性HBV感染是東北及東南亞國(guó)家的主要致病因素，包括中國(guó)，香港，印度尼西亞，朝鮮及臺(tái)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(guó)為1-5%，印度尼西亞和中國(guó)北部為6-10%，而臺(tái)灣、中國(guó)南部、朝鮮及菲律賓則超過10%。在日本和臺(tái)灣，慢性HCV感染是HCC發(fā)生的重要因素.HCVinfectionisexpectedtoincreaseasanaetiologicalfactorassociatedwithHCCinAsia.Thesynergisticinteractionsofinterviral,viral,andenvironmentalriskfactorscomplicatematters.亞洲國(guó)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(guān)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(jì)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(tái)灣/中國(guó)大陸4188698年0.70.51-0.70日本15137.30.20.08-0.39非活動(dòng)期攜帶者歐洲3410160.020-0.04臺(tái)灣118980.20-0.42慢性乙肝歐洲64715.90.10-0.27臺(tái)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(tái)灣/新加坡32784.33.21.94-4.55日本23065.84.33.40-5.25HBV負(fù)荷越高，HCC/肝硬化風(fēng)險(xiǎn)越高ClinLiverDis11(2007)797–816050010001500200025003000發(fā)病率（1/10萬(wàn)人*年）<300300-999910000-99999100000-999999≥1000000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(shí)HBVDNA水平的關(guān)系HBV感染的轉(zhuǎn)歸“持續(xù)病毒復(fù)制”

是慢性乙肝病情進(jìn)展的主要病因肝細(xì)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(nèi)12%-20%5年內(nèi)6%-15%5年內(nèi)20%-23%10％-30%失代償肝硬化慢性HCV的并發(fā)癥及預(yù)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HBV/HCV相關(guān)性肝硬化患者

HCC發(fā)病率約為3%/年NEnglJMed1991;325:675-680.無腫瘤生存率（%）0612182430364248100806040200HCC:3%3%2%意大利肝硬化患者調(diào)查，n=447，肝硬化代償期，每3-12個(gè)月進(jìn)行血清AFP及腹部超聲檢查≈3%compensatedcirrhosiswithHBV/HCVdevelopHCCperyearPART1小結(jié)HBVHCV肝硬化肝癌肝癌的發(fā)生是一個(gè)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(guān)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(rèn)再生結(jié)節(jié)是惡性克隆形成和增殖位點(diǎn)MedClinNAm89(2005)371–389合并肝炎/肝硬化對(duì)HCC預(yù)后的影響Part2概述HCC合并HBeAg+肝炎HBV高負(fù)荷肝硬化肝功能儲(chǔ)備低影響HCC預(yù)后減少生存期增加復(fù)發(fā)風(fēng)險(xiǎn)HBeAg+的HBV相關(guān)性HCC患者根治術(shù)后早期復(fù)發(fā)風(fēng)險(xiǎn)增加，生存率降低JournalofHepatology47(2007)684–690n=203，小肝癌，手術(shù)切除術(shù)后，分為HBeAg陽(yáng)性及陰性兩組，中位數(shù)隨訪32.9個(gè)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(guān)性HCC患者根治術(shù)后早期復(fù)發(fā)風(fēng)險(xiǎn)增高，生存率降低HBeAg+

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

HCC術(shù)后復(fù)發(fā)的獨(dú)立危險(xiǎn)因素持續(xù)高病毒血癥HBVDNA波動(dòng)持續(xù)低病毒血癥P<0.001HCC復(fù)發(fā)(%)隨訪時(shí)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(guān)性HCC,已接受手術(shù)切除治療，平均隨訪48.5個(gè)月0100806040203倍OR:3.13SustainedhighviremiaFluctuatingHBVDNASustainedlowviremiaHCCrecurrence(%)持續(xù)高HBV負(fù)荷——

HCC術(shù)后OS的獨(dú)立危險(xiǎn)因素P=0.018OS(%)01224364860728496108JournalofGastroenterologyandHepatology.Jun2010.Publishedonlinefirst.n=188,HBV相關(guān)性HCC,已接受手術(shù)切除治療，平均隨訪48.5個(gè)月010080604020Figure3.Overallsurvivalinthe115patientssurvivingmorethan1yearwithoutrecurrenceafterresection.Thereisasignificantlylongersurvivalinthesustainedlowviremiagroupthantheothergroups(log-ranktest,P=0.018).Sustainedhighviremiagroup(solidline),patientswithsustainedHBVDNAlevels>105copies/mlduringthefollow-up;sustainedlowviremiagroup(dottedline),patientswithsustainedHBVDNAlevels<104copies/ml;fluctuatingHBVDNAgroup(dashedline),theremainingpatients.持續(xù)低病毒血癥HBVDNA波動(dòng)持續(xù)高病毒血癥隨訪時(shí)間（月）HCV亦是HCC術(shù)后肝內(nèi)復(fù)發(fā)

的重要危險(xiǎn)因素EurJSurgOncol.2003Apr;29(3):266-71.肝內(nèi)復(fù)發(fā)累積概率（%）肝切除術(shù)后時(shí)間020406080100012345678910NBNC(N=24)B-viral(N=32)C-viral(N=55)P=0.0306n=111，HCC術(shù)后，分為HCV/HBV/無HV3組HCVissignificantriskfactorforintrahepaticrecurrenceafterHCCresection肝功能低下的HCV相關(guān)性HCC患者

RFA治療后遠(yuǎn)處復(fù)發(fā)率高M(jìn)onthsafterRFAAlimentPhar