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1、NCCN临床实践指南解读肝细胞癌(2023.V1方胆道肿瘤(2023.V1)既往的NCCN指南，肝细胞癌和胆道肿瘤是合在一起的,2023年V1版的肝胆指南是拆分了的，分别为肝细胞癌(2023.V1)和胆道肿瘤(2023.V1)。随着胆道肿瘤免疫治疗及靶向治疗药物的不断推陈出新，有必要对胆道肿瘤的系统治疗药物进行汇总整体。同时，随着DT双免疫组合获批aHCC一线治疗适应症，也宣告高度异质性的肝细胞癌，在免疫治疗时代，迎来了多款免疫为基础的系统治疗方案的获批。肝细胞癌(HCC)ECOGPS评分标准美国东部肿瘤协作组(EaSternCooperativeOncologyGroup,ECOG)制定了一
2、个较简化的活动状态(performancestatus,PS)评分表。将患者的活动状态分为05共6级。级别体力状态0活动能力完全正常，与起病前活动能力无任何差异1 能自由走动及从事轻体力活动，包括一般家务或办公室工作，但不能从事较重的体力活动2 能自由走动及生活自理，但已丧失工作能力，日间不少于一半时间可以起床活动3 生活仅能部分自理，日间一半以上时间卧床或坐轮椅4 卧床不起，生活不能自理5 死亡在肿瘤治疗前，ECOG评分是很重要的。因为有很多患者一经发现就是中晚期，对于这类患者来说，如果身体体质虚弱，就不能采取各种创伤性疗法，例如手术或者放化疗，都是有风险的。CHILD-PUGHSCOREC
3、hemicalandBiochemicalParametersScores(Points)forIncreasingAbnormality123Encephalopathy(grade)1None1-23-4AscitesAbsentSlightModerateAlbumin(gdL)3.52.8-3.52.8Prothrombintime2Secondsovercontrol6INR2.3Bilirubin(mgdL)3Forprimarybiliarycirrhosis10ClassA=5-6points;ClassB=7-9points;ClassC=10-15points.ClassA
4、:GoodoperativeriskClassB:ModerateoperativeriskClassC:Pooroperativerisk肝功能Child-PUgh分级ChiIdPugh分级标准是一种临床上常用的用以对肝硬化患者的肝脏储备功能进行量化评估的分级标准，该标准最早由Child于1964年提出，后经改良，目前临床上将患者5个指标（包括肝性脑病、腹水、血清胆红素、血清白蛋白浓度及凝血酶原时间）的不同状态分为三个层次，分别记以1分，2分和3分，并将5个指标计分进行相加，总和最低分为5分，最高分为15分，从而根据该总和的多少将肝脏储备功能分为A、B.C三级，预示着三种不同严重程度的肝脏损
5、害（分数越高，肝脏储备功能越差）。Child-Pugh分级A级：5Y分；B级：79分；C级：NIO分A级：56分手术危险度小，预后最好，12年存活率100%85%;B级：79分手术危险度中等，12年存活率80%60%;C级：10分手术危险度较大，预后最差，12年存活率45%35%.肝细胞癌的分期肝癌的分期对于肿瘤的预后评价、治疗方案选择至关重要，肝癌的分期方法很多，但与其他肿瘤不同，肝癌很少使用TNM分期(tumornodemetastasisclassification),更多使用巴塞罗那肝癌分期(BCLC,BarcelonaClinicLiverCancer)和中国肝癌临床分期(CNLC,
6、Chinalivercancerstaging)o在NCCN指南中,更加常用的自然是BCLC分期。国外分期国内分期BCLCCNLCTNMJSHAPASL备注：JSH分期：日本肝病学会分期；APASL分期：亚太肝脏研究协会分期AmericanJoint Committee on Cancer (AJCC)TNM Staging for Hepatocellular Cancec (8th d. 2017)Tt 1. Definitions for T, N, MTPrimary TbmorTXPrimary tumor cannot be assessedTONo evxtence o( Pnm
7、afy tumorT1 Solitary tumor 2 cm. or 2 cm without vascular invasionTIa Solitafy tumor 2 cmTlb Solitary tumor 2 cm without vascular invasionT2 Solitary tumor 2 cm Wrth vascular mvask). or multiple tumors, none 5 cmT3 Multiple tumors, at least one of which is 5 cmT4 Single tumor or multte tumors of any
8、 size VWOtving a major branch of the portal vem or hepatic ve or tumcM(s) Wrth direct VWaSlon of adjacent organs other than the gaNbladder 6 (severe fibrosis or OrrhOe幅)Usedwtpem0onoftheAmericanCoflege“Surgeons.Chicago.Mois.TheorigrtfSoUr8Ior5检informationis9eAJCCCancerSlagvigManual.EighthEdition(201
9、7)publishedbySpongerIntemMionaiPubinhingContinueBarcelonaClinicLiverCancer(BCLC)StagingSystem(2022)1Table1.DefinitionsforPrognosticGroupsStageDefinitionVeryearlystage(O) Single2cm Preservedliverfunction,3PSOEarlystage(A) Single,or3noduleseach3cm Preservedliverfunction.aPSOIntermediatestage(B) Multin
10、odular Preservedliverfunction,3PSOAdvancedstage(C)Portalinvasionand/orextrahepaticspreadPreservedliverfunction.PS1-2Terminalstage(D) Anytumorburden Endstageliverfunction,PS3-4aExceptforthosewithtumorburdenacceptablefortransplant.BCLe临床分期系统由LI。Vet在1999年提出后经美国研究协会在2005年进行修改，而近年又进行了更新。在更新版的BCLC分期中，根据肿瘤
11、负荷.肝功能和身体状况进行分期，主要评判参考的指标包括：AFP.ALBI（白蛋白胆红素）分级、ChildPugh分级、MELD（终末期肝病模型）评分。2022年的BCLC分期和治疗策略2022NCCNV1肝胆管癌指南中对于BCLC分期有具体的划分描述。0期（极早期）：单个病灶2cm,肝功能保留，PS0A期（早期）：单个病灶2cm或3个病灶，每个3cm,肝功能保留，PS0B期（中期）：多发性病灶，肝功能保留，PS0（:期（晚期）：门脉侵入和/或肝外扩散，肝功能保留zPS1-2D期（终末期）：任何肿瘤负担，终末期肝功能，PS3-42022年，在更新版的BCLC分期中，根据肿瘤负荷、肝功能和身体状况
12、，主要评判参考的指标包括：AFP.ALBI（白蛋白胆红素）分级、ChildPugh分级、MELD（终末期肝病模型）评分。2022年的BCLC分期和治疗策略肝癌的五期分期（极早期，早期，中期，进展期和终末期）没有变化,最大的变化在于BcLCB期病人治疗方案的推荐上。更新前，BCLCB期推荐方案仅为TACE治疗，也是饱受争议的一点。2022版指南将B期细化为三个亚组。B1,边界清楚的肝细胞癌患者，考虑肝移植；B2,无法进行肝移植患者若其门静脉血流良好.肿瘤界限清晰.选择性进入肿瘤供血动脉有可行性，对这部分患者建议进行TACE;B3,弥漫.浸润性、肝脏广泛受累肝癌患者，施行TACE不能获益，应该要考
13、虑系统治疗。CNLC的分期主要是根据肝脏肿瘤的数目、大小.血管侵犯、肝外转移.Child-Pugh分级以及体力状况（PS牌分6个因素,综合判定肿瘤分期。在讲解具体的分期之前，有必要对Child-Pugh分级以及体力状况（PS）评分进行明确。ABBREVIATIONSAASLDAmericanAssociationfortheMELDModelforEnd-StageLiverStudyofLiverDiseasesDiseaseAFPalphafetoproteinMMRmismatchrepairMSImicrosatelliteInstabilityCCACholanglocarclnom
14、aMSI-HmlcrosatelllteInstability-highCEUScontrast-enhancedultrasoundCHBchronichepatitisBNAFLDnon-alcoholicfattyliverdiseasecHCC-combinedhepatocellularCCAcarcinoma-CholanglocarclnomaOPTNOrganProcurementandTransplantationNetworkdMMRmismatchrepairdeficientREradioembolizationRTradiationtherapyHBcAbhepati
15、tisBreantibodyHBsAghepatitisBsurfaceantigenSBRTstereotacticbodyradiationHBVhepatitisBvirustherapyHCChepatocellularcarcinomaHCVhepatitisCvirusTACEtransarterialChemoembolizatlonICCAIntrahepaticTMBtumormutationalburdenCholanglocarclnomaTMB-Htumormutationalburden-highIMRTIntensity-modulatedradiationther
16、apyUNOSUnitedNetworkforOrganINRInternationalnormalizedratioUSSharingultrasoundLbLiverImagingReportingandRADSDataSystem延伸阅读：中国肝癌临床分期更新与治疗策略原发性肝癌诊疗指南（2022年版）也有一定程度的更新。增加了采用“推荐分级的评估、制定和评价（gradeofrecommendationsassessment,development,andevaluation,GRADE）系统，GRADE系统包括两部分：第一部分为证据评价，分为高.中.低和极低4个水平；第二部分为推荐意见
17、分级，其结合了美国临床肿瘤学会指南的分级方案，分为强、中等和弱推荐3个等级。GRADE分级是目前使用最广泛的证据评价和推荐意见分级系统。原发性肝癌诊疗指南（2022年版）肝癌的手术切除，在CNLC分期治疗中占据很重要的地位。近年来，肝胆外科在肝癌治疗中的影响也逐步显现，有必要对肝脏的外科手术切除的基本概念进行整理，也是我设计试验方案时的知识盲区。晚期肝细胞癌系统治疗推荐其他推荐方案中，度伐利尤单抗的证据等级由2A类更新为1类；某些情况下有用的方案中，纳武利尤单抗（若不适用于酪氨酸激酶抑制剂或其他抗血管生成药物）（仅限Child-PughA级或B级患者）更新为纳武利尤单抗（仅限Child-Pug
18、hB级患者），证据等级由2B类更新为2A类；某些情况下有用的方案中，新增阿替利珠单抗+贝伐珠单抗（仅限ChiId-PUghB级患者）;某些情况下有用的方案中，对于TMB-H型肿瘤，新增纳武利尤单抗+伊匹木单抗，证据等级为2B类。PRINCIPLESOFSYSTEMICTHERAPYFirst-LineSystemicTherapyPrMrrWRmimen*QttMtfRgcomnwMKIfflimm Atezolizumabbevacizumab(Chiki-PugbClassASorafenib(ChildPghClassAonly)(category1)lbc1(category1orB7
19、)de34 Tremelimumabctldurvalumab(category1)b2Lenvatinib(Child-PughClassAOnty)(category1) Durvalumab(category1产 Pemtxolizumib(category2B)b7Uefulin Certain Circumvtances Nivolumab (ChikPugh Class B only)bt Atezolizumab bevacizumab(ChiIdFWh Class B only)9 For TMB-H tumors: Nivolumab ipilimumab (category
20、 2B)10Subsequent4JneSystemicTherapyifDiseaseProgressionfflhOption，OtherRecommendedRemem Regorafenib(ChldPughClassAonly)(category1)Ntvolumibipilwnumb Cabozantimb(Chdd-PughClassAonly)(categoryI)12(Chtld-PughClassAonly)bl13 Lenvatintb(Child-PughClassAonly)Pembrolixumab(ChikIFughUseful而 Certatn Circumst
21、ance Ramucirufnab (AFP 400 nmL and Child-Pugh Class A Only)(CategoCy 1-7 Nivolumab (CzldFugh Class B OnIy尸JglFor MShHZdMMR tumors Dostarlmab-gxly (category 2B)bi2223 For RET gene fusion-positive tumors: Selpefcitinib (category 2B)24For TMB-H tumors: Ntvolumab 甲 IIImUmab (category 28)bu1iAn FDAfProgd
22、 btosimOar is an appcopnate substitute for bevaczumab )See CCN Guidehnes for Ktanaoement of Imfnqnotherapv-Related Toxjctt:Pabente on alezmonthsprior to treatment or according to institubonal practice and 3sssst of blcjQ sk-3 See Chi!d-PugA Sro HCC-Cf and assess portal hypertension (eg. varices.,Cau
23、don Tnefe anClassBocC Irver function and pabens with elevated bilirtxn I 1805). The impact of sorafenib unknownavailablefor patents wrt Chid-Pugh is uncertain Use with extreme caution inlevels.(Miller AA.e(al. JCinOncd2009:27:1800- on patients potentially eligible 1(x transplant isLafOtrecbmband ntr
24、ectinib are treatment options for patients wrth hepatoceular carcinoma that is NTRK oene fusion positive. (Drilon A, ecuar Tp (HCCH).For patients WhO have not been previously treated with a checkpoint inhibitor because there ts a lack of data for subsequent use of immunotherapy in patents who have p
25、reviously been treated with a checkpoint inhibitor.J Pembrokzumab is a recommended treatment option for PabentS wth or WithOUt maosaterte instabiltygh (MSI-H) HCC PembfOtaufnab s FDA-approved for MSI-H tumorsX DostarlimabxJy is a recommended treatment option for pabents with MSI-H/ mismatch repair d
26、eficient (dMMR) recurrent or advanced tumors that have progressed on or following prior treatment and who have no satistadory alternative treatment options,Foc patients with disease refractory to standard therapies or who have no standard treatment OPbonS available Sorafenib(ChiIdFughClassAorB7)dCla
27、ssAonty)b,j-uu晚期肝细胞癌后线治疗推荐其他推荐方案中，帕博利珠单抗的证据等级由2B类更新为2A类;雷莫西尤单抗（AFP400ng/ml且仅限Child-PughA级患者）由治疗选择转移至某些情况下有用的方案；某些情况下有用的方案中，纳武利尤单抗（仅限Child-PughB级患者）的证据等级由2B类更新为2A类；某些情况下有用的方案中，对于TMB-H型肿瘤，新增纳武利尤单抗+伊匹木单抗，证据等级为2B类，附带脚注I:用于对标准治疗耐药或无标准治疗方案的患者。ABBREVIATIONSAASLDAmerican Association for the Study of Liver D
28、iseasesAFPalpha fetoproteinCCACholangiocarcinomaCEUS contrast-enhanced ultrasoundCHBchronic hepatitis BcHCC- combined hepatocellularCCAcarcinoma-CholangiocarcinomadMMR mismatch repair deficientHBcAb hepatitis B core antibody HBsAg hepatitis B surface antigen HBV hepatitis B virusHCC hepatocellular c
29、arcinomaHCV hepatitis C virusiCCA intrahepaticCholanglocarcinomaIMRTintensity-modulated radiationtherapyINRinternational normalizedratioLl-Liver Imaging ReportingandRADSData SystemMELDModel for End-Stage Liver DiseaseMMR mismatch repairMSImicrosatellite instabilityMSI-Hmicrosatellite instability-hig
30、hNAFLD non-alcoholic fatty liver diseaseOPTN Organ Procurement and Transplantation NetworkREradioembolizationRTradiation therapySBRTstereotactic body radiationtherapyTACEtransarterialchemoembolizationTMB tumor mutational burdenTMB-H tumor mutational burden-highUNOS United Network for Organ SharingUS
31、 ultrasound胆道恶性肿瘤（BTC）BTC是仅次于肝细胞癌的第二常见原发性肝癌，占癌症相关死亡人数的2%oBTC根据其解剖起源分为肝内（iCCA）、肝门周围或远端胆管癌以及胆囊癌。虽然总体而言，BTC是相对罕见肿瘤，约占整个消化道肿瘤的3%,但相较于肝细胞癌，胆道恶性肿瘤，在免疫和精准靶向药物领域进展同样迅速，且基因突变型的靶向治疗进展(IDH1/2.FGFR2)要快于肝细胞癌(HCC),值得仔细梳理下。胆道溺性肿瘤I流行病学与治疗现状胆道恶性肿痛(BTC)分子特征胆道恶性肿痛(BTC)流行病学对于BTC,近年来主要的药物研究突破是靶向药物。靶向药物进展BTC亚型的基因突变，在很大程度
32、上是重叠的，但iCCA的IDH1/2突变频率很高(10-22%)z在IO-I5%的患者中几乎只发生FGFR2融合。靶向治疗在ICC进展缓慢，2020年4月，FDA加速批准Pemigatinib(FGFR1-3抑制剂，佩米替尼,InCyte公司研发)上市，开启了ICC靶向治疗的新时代。2022年3月，佩米替尼又获NMPA批准。但目前价格较贵，患者负担压力较重。但无疑也是ICC领域靶向治疗的突破。GenomicHeterogeneitywithinBiliaryTractCancerIntrahepaticCholangiocarcinomaFGFRKRASTP53MCUIDHV2SMAD4ARt
33、OIAMLL3CDKN2ABAPIBTC的基因组异质性Tible2.Targetedtherapyinbiliarytractcancer.TatgHedThtftAyinBiHaryTXCancerAuthorThEPyPh4ePatientPopulationNT13ORR(%)PFS(MMIlChrmotherafnarefrclorPMHSwithkR2fusion/rcdrrAngcmcnteiniCCAIWFGFRM3556.921.1)avlcctLLMYrGMnI2021InligrdtifiibChpmotherop)refrWorvptntwithFGFRhMUng*MgI
34、emenbinaCCAIaBFGFRM23.173BridgruitrrcaLLSMO202Dlv57FutihaKinibnCbemother书，MrxtocyPati,np*rrfrcioryIMrwithPGFRfusion/rearrangementsiniCCA29Non-M-IectKemu!tkuuM*inhibitor207ParkctaLASCOGI2O9wiErdafitinibChrmothcrAfn*refractorypjtntawithFGFRfwUo/grMgpwnyiniCCA12FGFRM505.6NgmLHqttMuySwrs.2019(4O)DcbolM7
35、!ChpmothNfrrfrAclorypatwntiwithFGFRVision/rt*drrngefnenttnMlidtuf9FCFR1-322Abou*AlfaetaLLrnrrtOnB2020Mho4denibPUvboinCHptnothcfjp%,refrMloryPMftwithXA185IDHl2271.4pbUheALUncrtOwoi2020(61MxUenibaIramctinibIUfrMlaryQIdtumor*33BRAFQMEK5172113lmoKHLAnn.Oncol2O203RifgarAfcwbvs.PUccboUIUfractor)*BTC66VEGF
36、03IS”0004MSlIp-021Mk8al.UnatOwoi.2021163Trastuzumab.PcftuzumabURffrMaryM)Ildtumor*includingBTC39HFK2amt6c4bmormuUtan23%410.9BTC靶向治疗研究试验汇总NCCNNationalComprehensive Cancer NetworkNCCNGuidelines Version 1.2023 Biliary Tract CancersNCCNGUideIineS IndeX lble a ContQntS DiSCUSSiOnPRINCIPLESOFMOLECULARTEST
37、INGTable1:RecommendationsforMolecularTestinginUnresectableorMetastaticBiliaryTractCancersledRecommendedMolecularTestingAnatomicSubslteGallbladderIntrahepaticCCAExtrahepaticCCANTRKgenefusionXXXMSIWdMMRXXXTMB44XXXRAFV600EmutationXXXFGFR2fusionorrearrangement-XXIDH1mutation-XXHER2(ERBB2)overexpressiona
38、nd/oramplificationXXXRETgenefusionXXXMSbH:microsatelliteinstability-highdMMR:mismatchrepairdeficientTMB-H:tumormutationalburden4lghaConsiderrepeatbiopsyorpedormingcfDNAanalysisifinitialbiopsysampleyieldsinsufficienttumorcontent,dependingonclinicalcontext.bIfunsureabouttheprimaryanatomics(tewithinthe
39、bdarytree,comprehensivetestingtsrecommended,wludrconsiderationofFGFR2fusonorrearrangementtestingandIDH1mutationtestingingallbladdercancerorinlargetumorsofuncertainaatomcongnwithintheMiarytree.cTestingforFGFR2fusionsorrearrangementsandfDH1mutationsshouldbensideredinpatientswithUrvesectableOCmetastati
40、cgallbladdercancerRzerenCeSBIL-B2 OF 8dGenebccounselingreferralandgermlinetestingshouldbensideredinpabent5withanyo(thefollowingcharacteristics：youngageatdiagnosis;astrongpersonalorfamilyhistoryofcancer；noriskfactorsforliverdisease；(xpresenceofmutationskientdedduringtumortestingthataresuspectedtobepossiblegermlinealterations.NoU:Allrcommndtionrct90fy2Aun*sOtMrwMIndlcMdCUnioiITrtalrNCCNbvtbtthbtm0gnototryptlntwttcncritInClinietltrialParticipationinc*nicalthlpcillyncourgdPRINCIPLESOFMOLECULARTESTINGTable2:IncidenceofTherapeuticTargetsinAdvancedBiliaryTractCancersAberrationAp
