医院培训课件：《原发性肝癌的治疗及进展》

原发性肝癌的治疗及进展主要内容肝癌的流行病学肝癌的危险因素及早期诊断影响治疗预后及治疗选择的因素多学科联合治疗及个体化治疗肝癌的分子靶向治疗2013美国癌症死亡顺位2013年美国肝癌的死亡: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我国城市登记地区前10位恶性肿瘤发病率及死亡率全国肝癌登记地区年龄、性别与发病率及死亡率ChineseCancerRegistryAnnualReports2012JemalA,etal.CACancerJClin.2009;59:225-249.肝癌的死亡情况与其他恶性肿瘤的比较所有恶性肿瘤的死亡状况在改善原发性肝癌的死亡没有明显的改善Hodgkin’slymphomaStomachProstateColorectalOropharynxLarynxLungGallbladderNon-Hodgkin’slymphomaSmallintestineBrainLeukemiaMyelomaSarcomasBladderKidneyPancreasMelanomaEsophagusLiverAllmalignantcancers-60-40-200204060PercentChangeUSCancerMortalityTrendsinMen,1990-2005BetterWorse全球HBV携带者的流行率HBsAg携带者的流行率 <2%

2–7%

>8%

资料不详原发性HCC的年发病率病例/100,000人口 1–3

3–10

10–150

资料不详WHO.2003乙型肝炎在全球范围内的流行以及

肝细胞肝癌的发病率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年间HCV相关性肝癌增加50%YangJD,etal.MayoClinProc.2012;87:9-16.HCV相关性肝癌显著增长NationalCancerInstitute.SEERfaststats.1975-2009美国原发性肝癌的调整发病率及其趋势01.02.03.04.05.06.07.08.09.0YrofDiagnosisRateper100,00019751980198519901995200020052009原发性肝癌的危险因素任何原因所致的肝硬化慢性B型或C肝炎危险因素:男性老年糖尿病原发性肝癌的诊断与分期HCC的早期诊断:高危人群的筛查对象:肝硬化患者或慢性HBV/HCV肝炎NCCN:每6-12月检查AFP和超声AASLDandEASL：每6个月检查超声NCIandUSPHSTaskForce不推荐理由:肝硬化患者并没受益费用和风险增加需要随机对照研究进一步研究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原发性肝癌分期与预后的ABCs原发性肝癌的预后与治疗决定于：Anatomicalextentoftumor(stage)Biologicalaggressiveness(grade)Cirrhosisseverityandfunctionalstatus分期检查应当包括：腹部多相CT/MRI，胸部CT和骨扫描肝癌的解剖学分期:TNMGoodmanJ,etal.ArchSurg.2005;140:459-464.StageTNMISingletumor<2cmII1tumor2-5cmor2or3tumors,largest<3cmIII1tumor>5cmor2or3tumors,largest>3cmIV4ormoreintrahepatictumorsorvascularinvasionor

extrahepaticmetastasis肝癌的分期与生存率:1997-2005肝癌的生存与诊断时的分期明显相关早期诊断能明显提高生存率StravitzRT,etal.AmJMed.2008;121:119-126.IIIIIIVI00.20.60.40.81.0012345YrsSurvival肝脏疾病的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、肝功能状态与肝癌的生存率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.原发性肝癌的治疗原发性肝癌治疗选侧策略早期肝癌(I-II期) ：目标争取治愈 消融技术：热消融、冷冻消融、化学消融手术切除：部分肝叶切除肝移植中晚期肝癌(III-IV期)介入治疗：TACE、TAI姑息化疗：FOFOX分子靶向治疗：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直径<5cm、孤立病灶的原发性肝癌通过手术或是消融术可以达到治愈Normalbilirubinconcentration,andtheabsenceofclinicallysignificantportalhypertensionmeasuredbyhepaticveincatheterization(hepaticveinpressuregradient<10mmHg)arepredictorsofexcellentoutcomesaftersurgeryBruixJ,SermanM.Hepatology.2005;42:1208-1236.RFA消融术BRFA的指针不能手术切除的肝实质内病灶最佳是:病灶<3；直径<3cm病灶位置:非包膜下的,非隔下的,不靠近大血管在超声或非增强CT下可见凝血功能正常RFA早期HCC的消融术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手术切除随机临床试验N=168病灶直径<4cm，不超过2个病灶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关于肝移植原发病灶的彻底切除消除肝硬化理论上达到治愈严格的移植标准HCC肝移植:Milan(Stage1and2)5-yrsurvivalwithtransplantation:~70%5-yrrecurrentrates:<15%+没有大血管受侵和肝外转移Singletumor,not>5cmUpto3tumors,none>3cmMazzaferroV,etal.NEnglJMed.1996;334:693-699.LlovetJM.JGastroenterolHepatol.2002;17(suppl3):S428-S433.原发性肝癌的姑息治疗TACE选择性和靶向性化疗药物的直接杀伤化疗药物的缓慢释放肿瘤血管终末栓塞TAC选择性和靶向性化疗药物的直接杀伤有A-V也能进行门静脉癌栓无禁忌系统治疗全身化疗激素治疗分子靶向治疗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随机临床研究发现TACE能延长晚期

原发性肝癌生存期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.传统TACEvsDEBTACE010203040506070DCbeadcTACEDCbeadcTACEDCbeadcTACEDCbeadcTACE原发性肝癌的靶向治疗NucleusAngiogenesisMitogenesisInhibitionofapoptosisCytoskeletonchangesDNATranscriptionFactorsCOOHATPActivatedRTKCellmembraneDifferentiationPI3-KPO-AKT-OPSHCGrb2SOSRASRAFMEKMAPKPO-PLCγPKCTKIAntibody分子靶向治疗的机理之EGFR通道SHARPIII临床研究:总生存期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)