醫(yī)院培訓(xùn)課件：《原發(fā)性肝癌的治療及進(jìn)展》

原發(fā)性肝癌的治療及進(jìn)展主要內(nèi)容肝癌的流行病學(xué)肝癌的危險(xiǎn)因素及早期診斷影響治療預(yù)后及治療選擇的因素多學(xué)科聯(lián)合治療及個(gè)體化治療肝癌的分子靶向治療2013美國(guó)癌癥死亡順位2013年美國(guó)肝癌的死亡:男性肝癌由2005的第7位上升到2013年的第5位女性肝癌由2005的第10位上升到第9位Men306,920 Lung&bronchus 28% Prostate 10% Colon&rectum 9% Pancreas 6% Liver&intrahepticbileduct 5% Leukemia 4% Esophagus 4% Urinarybladder 4% Non-Hodgkin’slymphoma 3% Kidney&renalpelvis 3% Allothersites 24%

Women273,430 26% Lung&bronchus 14% Breast 9% Colon&rectum 7% Pancreas 5% Ovary 4% Leukemia 3% Non-Hodgkin’slymphoma 3% Uterinecorpus 2% Liver&intrahepaticbileduct 2% Brain/othernervoussystem 25% AllothersitesSiegelR,etal.CACancerJClin.2013;63:11-30.ChineseCancerRegistryAnnualReports2012我國(guó)城市登記地區(qū)前10位惡性腫瘤發(fā)病率及死亡率全國(guó)肝癌登記地區(qū)年齡、性別與發(fā)病率及死亡率ChineseCancerRegistryAnnualReports2012JemalA,etal.CACancerJClin.2009;59:225-249.肝癌的死亡情況與其他惡性腫瘤的比較所有惡性腫瘤的死亡狀況在改善原發(fā)性肝癌的死亡沒有明顯的改善Hodgkin’slymphomaStomachProstateColorectalOropharynxLarynxLungGallbladderNon-Hodgkin’slymphomaSmallintestineBrainLeukemiaMyelomaSarcomasBladderKidneyPancreasMelanomaEsophagusLiverAllmalignantcancers-60-40-200204060PercentChangeUSCancerMortalityTrendsinMen,1990-2005BetterWorse全球HBV攜帶者的流行率HBsAg攜帶者的流行率 <2%

2–7%

>8%

資料不詳原發(fā)性HCC的年發(fā)病率病例/100,000人口 1–3

3–10

10–150

資料不詳WHO.2003乙型肝炎在全球范圍內(nèi)的流行以及

肝細(xì)胞肝癌的發(fā)病率Others:38%HBV:10%NAFLD:7%Alcoholalone:45%1976-1990Others:46%HBV:4%Alcoholalone:25%AlcoholandHCV:7%HCValone:18%1991-2000Others:21%HBV:4%NAFLD:11%Alcoholalone:19%AlcoholandHCV:17%HCValone:28%2001-20081991-2008年間HCV相關(guān)性肝癌增加50%YangJD,etal.MayoClinProc.2012;87:9-16.HCV相關(guān)性肝癌顯著增長(zhǎng)NationalCancerInstitute.SEERfaststats.1975-2009美國(guó)原發(fā)性肝癌的調(diào)整發(fā)病率及其趨勢(shì)01.02.03.04.05.06.07.08.09.0YrofDiagnosisRateper100,00019751980198519901995200020052009原發(fā)性肝癌的危險(xiǎn)因素任何原因所致的肝硬化慢性B型或C肝炎危險(xiǎn)因素:男性老年糖尿病原發(fā)性肝癌的診斷與分期HCC的早期診斷:高危人群的篩查對(duì)象:肝硬化患者或慢性HBV/HCV肝炎NCCN:每6-12月檢查AFP和超聲AASLDandEASL：每6個(gè)月檢查超聲NCIandUSPHSTaskForce不推薦理由:肝硬化患者并沒受益費(fèi)用和風(fēng)險(xiǎn)增加需要隨機(jī)對(duì)照研究進(jìn)一步研究AASLDDiagnosticCriteriaforHCCAdaptedfromBruixJ,etal.Hepatology.2011;53:1020-1022.Stable

>18-24mosEnlargingReturntosurveillance

every6-12mosProceedaccordingtolesionsizeNondiagnostic

ofHCCRepeatimagingand/orbiopsy+-Other

diagnosisDiagnostic

ofHCCTypicalvascularpatternAtypicalvascularpatternwithbothtechniquesAtypical

vascular

patternTypicalvascularpatternondynamicimagingTreatasHCCBiopsy>2cm1dynamic

imagingtechnique<1cmRepeatUS

every3-4mos1-2cm1dynamic

imagingstudyRepeatbiopsyorimagingfollow-upChangeinsize/profileMassonsurveillanceUSorhighAFPinacirrhoticliver原發(fā)性肝癌分期與預(yù)后的ABCs原發(fā)性肝癌的預(yù)后與治療決定于：Anatomicalextentoftumor(stage)Biologicalaggressiveness(grade)Cirrhosisseverityandfunctionalstatus分期檢查應(yīng)當(dāng)包括：腹部多相CT/MRI，胸部CT和骨掃描肝癌的解剖學(xué)分期:TNMGoodmanJ,etal.ArchSurg.2005;140:459-464.StageTNMISingletumor<2cmII1tumor2-5cmor2or3tumors,largest<3cmIII1tumor>5cmor2or3tumors,largest>3cmIV4ormoreintrahepatictumorsorvascularinvasionor

extrahepaticmetastasis肝癌的分期與生存率:1997-2005肝癌的生存與診斷時(shí)的分期明顯相關(guān)早期診斷能明顯提高生存率StravitzRT,etal.AmJMed.2008;121:119-126.IIIIIIVI00.20.60.40.81.0012345YrsSurvival肝臟疾病的Child-Pugh分期PughRN,etal.BrJSurg.1973;60:646-649.LuceyMR,etal.LiverTransplSurg.1997;3:628-637.Measure1Point2Points3PointsBilirubin,mg/dL

<2.02.0-3.0>3.0Albumin,g/dL>3.52.8-3.5<2.8Prothrombintime,sec<4.04.0-6.0>6.0AscitesNoneSlightModerateEncephalopathy,gradeNoneI-IIIII-IVGradeTotalPointsSurgicalRisk2-YrSurvival,%A(well-compensateddisease)1-6Good85B(significantfunctionalcompromise)7-9Moderate60C(decompensateddisease)10-15Poor35肝硬化程度、肝功能狀態(tài)與肝癌的生存率BCLCstagingsystemcombinesanatomicextentofdiseasewithseverityofliverfailure(CTPclass)andfunctionalstatusPatientswithpoorfunctionalstatusordecompensatedcirrhosisarestageDregardlessofanatomicalstageBCLCstageDhaspoorestsurvivalandfewtreatmentoptionsPtsatRisk,nStageA 64 51 25 8StageB 60 22 11 4StageC 76 10 3 1StageD 39 7 1 0Log-RankPValueAvsB:<.0001BvsC:.04CvsD:.01BADC02060408010001020304050MosSurvivalProbability6070MarreroJA,etal.Hepatology.2005;41:707-716.原發(fā)性肝癌的治療原發(fā)性肝癌治療選側(cè)策略早期肝癌(I-II期) ：目標(biāo)爭(zhēng)取治愈 消融技術(shù)：熱消融、冷凍消融、化學(xué)消融手術(shù)切除：部分肝葉切除肝移植中晚期肝癌(III-IV期)介入治療：TACE、TAI姑息化療：FOFOX分子靶向治療：sorafenib、BrivanibLivertransplantationRFA/PEICurativetreatments(30%);5-yrsurvival:40%-70%TACESingleIncreasedAssociateddiseasesNormalNoYesSorafenibPortalpressure/bilirubin3nodules≤3cmResectionSymptomatic(20%);survival<3mosRCTs(50%);3-yrsurvival:10%-40%Terminal

stage(D)Okuda1-2,PS0-2,Child-PughA-BIntermediatestage(B)Multinodular,PS0Okuda3,PS>2,

Child-PughCVeryearlystage(0)Single<2cmCarcinomainsituEarlystage(A)Singleor3nodules<3cm,PS0Advancedstage(C)Portalinvasion,N1,M1,PS1-2PS0,Child-PughAHCCBCLCStagingandTreatmentStrategyLlovetJM,etal.JournaloftheNationalCancerInstitute.2008;100:698-711.UnresectableHCC直徑<5cm、孤立病灶的原發(fā)性肝癌通過手術(shù)或是消融術(shù)可以達(dá)到治愈Normalbilirubinconcentration,andtheabsenceofclinicallysignificantportalhypertensionmeasuredbyhepaticveincatheterization(hepaticveinpressuregradient<10mmHg)arepredictorsofexcellentoutcomesaftersurgeryBruixJ,SermanM.Hepatology.2005;42:1208-1236.RFA消融術(shù)BRFA的指針不能手術(shù)切除的肝實(shí)質(zhì)內(nèi)病灶最佳是:病灶<3；直徑<3cm病灶位置:非包膜下的,非隔下的,不靠近大血管在超聲或非增強(qiáng)CT下可見凝血功能正常RFA早期HCC的消融術(shù)AuthorChild-PughClassNSurvival1Yr3Yrs5YrsLencioni[1]AB144431008976465131Tateishi[2]AB/C22198969083656331Choi[3]AB359160NANA784964381.LencioniR,etal.Radiology.2005;234:961-967.2.TateishiR,etal.Cancer.2005;103:1201-1209.

3.ChoiD,etal.EurRadiol.2007;17:684-692.RFAvs手術(shù)切除隨機(jī)臨床試驗(yàn)N=168病灶直徑<4cm，不超過2個(gè)病灶85%病毒性肝炎(77%withHBV)FengK,etal.JHepatol.2012;57:794-802.00.20.60.40.81.00612182430MosProbabilityofSurvival36OSResectiongroupRadiofrequencyablationgroupCensoredPtsatRisk,nRESgroup 84 75 7066 63 55 52RFAgroup 84 73 6764 58 50 46關(guān)于肝移植原發(fā)病灶的徹底切除消除肝硬化理論上達(dá)到治愈嚴(yán)格的移植標(biāo)準(zhǔn)HCC肝移植:Milan(Stage1and2)5-yrsurvivalwithtransplantation:~70%5-yrrecurrentrates:<15%+沒有大血管受侵和肝外轉(zhuǎn)移Singletumor,not>5cmUpto3tumors,none>3cmMazzaferroV,etal.NEnglJMed.1996;334:693-699.LlovetJM.JGastroenterolHepatol.2002;17(suppl3):S428-S433.原發(fā)性肝癌的姑息治療TACE選擇性和靶向性化療藥物的直接殺傷化療藥物的緩慢釋放腫瘤血管終末栓塞TAC選擇性和靶向性化療藥物的直接殺傷有A-V也能進(jìn)行門靜脈癌栓無禁忌系統(tǒng)治療全身化療激素治療分子靶向治療SorafenibBrivanibLinifanibLlovetJM,etal.Hepatology.2003;37:429-442.ArterialEmbolizationforHCC

Meta-analysisof6RCTs(2-YrSurvival)RandomEffectsModel,OR(95%CI)Author,JournalYr Patients,nLin,Gastroenterology1988 63GETCH,NEJM1995 96Bruix,Hepatology1998 80Pelletier,JHepatol1998 73Lo,Hepatology2002 79Llovet,Lancet2002 112Overall 503Mediansurvival:~20mos0.010.10.51210100Z=-2.3P=.017FavorsTreatmentFavorsControl隨機(jī)臨床研究發(fā)現(xiàn)TACE能延長(zhǎng)晚期

原發(fā)性肝癌生存期LlovetJ,etal.Lancet.2002;359:1734-1739.LlovetJ,etal.Hepatology.2003;37:429-442.0206040801000122436MosSinceRandomizationProbabilityofSurvival(%)4860Chemoembolisation(n=40)Control(n=35)Log-rankP<.009Patients(%)Child-PughBECOG1BilobarRecurrentDiseaseCompleteresponseObjectiveresponseDiseasecontrol4(25%)7(44%)10(63%)3(16%)4(21%)6(32%)7(37%)12(63%)4(14%)8(29%)9(32%)7(17%)20(49%)24(59%)6(13%)18(40%)22(49%)3(27%)6(55%)8(73%)2(15%)4(31%)7(54%)LammerJ,etal.CardiovascInterventRadiol.2010;33:41-52.傳統(tǒng)TACEvsDEBTACE010203040506070DCbeadcTACEDCbeadcTACEDCbeadcTACEDCbeadcTACE原發(fā)性肝癌的靶向治療NucleusAngiogenesisMitogenesisInhibitionofapoptosisCytoskeletonchangesDNATranscriptionFactorsCOOHATPActivatedRTKCellmembraneDifferentiationPI3-KPO-AKT-OPSHCGrb2SOSRASRAFMEKMAPKPO-PLCγPKCTKIAntibody分子靶向治療的機(jī)理之EGFR通道SHARPIII臨床研究:總生存期LlovetJM,etal.NEnglJMed.2008;359:378-390.MosSinceRandomizationProbabilityofSurvival00.250.500.751.0001234567891011121314151617SorafenibMedian:10.7mos

(95%CI:9.4-13.3)PlaceboMedian:7.9mos(95%CI:6.8-9.1)HR(S/P):0.69

(95%CI:0.55-0.87;

P<.001)ClinicalT.StudyDrug

(TrialAcronym)