肺神经内分泌肿瘤.ppt

肺神经内分泌肿瘤Pulmonaryneuroendocrinetumors,复旦大学附属肿瘤医院内科王惠杰,IncidenceofNeuroendocrineTumors,Yao,JC,etal.JClinOncol2008;26:3063-3072.,WHO/IASLC/ATS/ERS,PreinvasivelesionsDiffuseidiopathicpulmonaryneuroendocrinecellhyperplasia(DIPNECH)CarcinoidtumorTypicalcarcinoid(TC)Atypicalcarcinoid(AC)SmallcellcarcinomaCombinedsmallcellcarcinomaLargecellneuroendocrinecarcinoma(LCNEC)-CombinedLCNEC,DIPNECH,女性，50-70岁可无症状慢性干咳、呼吸困难影像表现：磨玻璃影，双肺多发结节，细/支气管增厚，闭塞性细支气管炎可发展为TC/AC皮质激素、a-IFN、生长抑素，化疗,DIPNECH,100casesreviewedFemale89%诊断平均年龄57.8诊断前症状持续3-30年63%存在通气性障碍55例随访，66%病情稳定，27%缓慢进展，11%非疾病相关死亡SSA6例，SD,SmallCellLungCell-aforgottendiseaseintargetedera？！,病理分类,WHO/IASLC肺上皮性肿瘤组织学分类1.3.2.小细胞癌(Smallcellcarcinoma)变异(Variant).混合性小细胞癌(Combinedsmallcellcarcinoma)SCLC混合任何一种NSCLC成分，常见包括腺癌、鳞癌和大细胞癌（LCNEC），较少见的梭形、巨细胞癌等,临床特点,男性约占80%典型表现：肺门部原发肿瘤纵隔LN形成的大肿块、远处转移中央型占80%空洞少见胸腔积液发生率与其他类型相近伴瘤综合征,受累器官组织,SCLC-Staging,HistoryandphysicalexaminationRoutinehematologicandserumchemistrytests,LDHChest+(upper)abdomenCTscanBonescanCTwithcontrastorMRIofthebrainPET:invasiveprocedures/betterdefinitionofirradiationfield,possiblefutureroleforbetterptstaging,VALG：SCLC-Staging,-limited-stagedisease:tumorconfinedtoonehemithoraxwithorwithouthomolateralnodes/pleuraleffusionthatcanbeencompassedwithinasingletolerableradiationtherapyport-areasofcontroversy:contralateralhilarorsupraclavicularnodesormalignantpleuralorpericardialeffusions-extensivedisease:presenceofmetastaticdisease,2007：SCLCSurvivalbyTNMStage,ShepherdFAJThoracOncol2007;2:1067-1077,Historyoftreatment,1969RT优于SCTX优于BSC70年代放疗更广泛应用联合化疗优于单药CAO成为标准方案1979EP方案出现80年代EP成为标准方案90年代化放联合治疗（LD）新药研究（CPT-11/ARM等）靶向治疗？,治疗原则,ChemotherapyisthemainstayformoftreatmentRadiotherapyalsoplayarole，servingas“consolidation”therapyforindividualwithLDForpatientswithED，chemotherapyaloneisthestandardofcareAmericanCancerSocietyAtlasofClinicalOncology：LungCancer2002,LDSCLC的治疗,外科化疗放疗,外科在SCLC治疗中的理论优势,1）增加对原发肿瘤的控制率2）切除混合的非小细胞癌成分3）化放疗后长期存活者发生第二原发肿瘤的危险性增高，切除后可降低第二原发肿瘤的机会,外科治疗,缺乏比较术后辅助治疗和直接化放联合治疗可切除SCLC的RCT多项术后化疗的II期研究，入选病例I-IIA期5年生存率23-52%,N%INCIDENTAL%SURVIVALANYLOCALSTUDYRESECTEDTREATMENTSCLCpCRR0MST%2y%5yRECURRENCE(mo)%,Merkleetal170Various-18-Reaetal104Various-28-3224Prasadetal97Various27-123717-Massenetal94Various-86-15-Hageetal74Various43-173525-Davisetal118S-183920-Sorensenetal71S-12-Shoreetal40S57-2720Shahetal28S36-93345543-Shieldsetal132S-ChemoRT-113323-Karreretal112S-Chemo58-37605111Lucchietal92S-Chemo31-9924503216Shepherdetal63S-ChemoRT64-9019453111-Ladetal70Chemo-SRT+PCI-1977152010-Shepherdetal38Chemo-S-RT-88721473618Eherhartetal32Chemo-RT-S-347236-46-Holoyeetal22Chemo-S-19-25543314Wiliamsetal21Chemo-S-1684-28-Shepherdetal28Salvage*-82244823-Average8122442819,*ResectionofresidualdiseaseafterCT+/-RT,SurgeryinSCLC,化疗或化疗联合胸部放疗,Ameta-analysisNEngJMed1992；327：1618,13项随机临床试验共2140病例化疗化放疗P3YS8.9%14.3%P=0.001HR0.8670岁HR1.07（95%CI:0.70-1.64）,结论,放疗剂量和开始时间存在多种选择主要包括烷化剂和以ADM为基础的方案局限期SCLC标准治疗的地位,序贯或同期化放疗,JCOG9104,JCOG9104,19.7月27.2月,SeqorCon：meta-analysis,烷化剂和以ADM为基础的联合化疗者，同期或序贯放疗结果相近选择EP方案时同期化放疗优于序贯化放疗,ProcAmSocClinOncol1995;14abs,早期或后期同期化放疗,Systematicreview:earlyorlaterradiation,评价ERT和LRT对生存的影响7项随机研究共1524病例meta分析包括了同期化放疗和序贯化放疗,JClinOncol2004;22(23):4837,结果,LRTERT2YSRR1.17P=0.033YSRR1.13P=0.2HFRT者2YSRR1.44P=0.0013YSRR1.39P=0.04DDP-based2YSRR1.30P=0.0023YSRR1.35P=0.01,结论,与LRT相比，ERT能提高2年生存率ERT的获益相当于在化疗基础增加胸部放疗或预防性脑放疗的获益程度获益仅限于使用超分割放疗者、选择含DDP化疗方案者,EDSCLC的治疗,化疗放疗靶向治疗？,EPregimen:since1980s,Firstintroducedin1979Later1980s,extensivelyusedthemostacceptedandwidelyusedstandardtreatmentforSCLCforthepast20years,EPinRCT,EPorCEinSCLC,JCOG9702,CE方案CBPAUC5d1，VP-1680mg/m2d1-3q21dEP方案DDP25mg/m2d1-3VP-1680mg/m2d1-3q21d,JCOG9702,中位年龄74岁（92%70）男性88%PS0-1/2-3者分别为74%/26%CE组63%、EP组67%接受4周期化疗,疗效,CEEP方案有效率73%73%中位PFS5.3月4.7月（p=0.20）MST10.6月9.8月1年生存率41%35%（p=0.54）,结论,第一项比较CE和EP方案治疗老年或PS差的III期随机研究CE和EP方案在总生存和毒性反应方面相似EP方案仍是EDSCLC的标准方案CE可作为替代选择,IrinotecanandAmrubicin,mythsfromJapane,ED-SCLC1stLineTherapy-cisplatinbasedEtoposideorIrinotecan?,Carboplatinbased:EtoposideorIrinotecan?,ED-SCLCAmrubicin,Synthetic9-aminoantrhacyclineAntitumoreffectscorrelatedwithintratumoralconcentrationofamrubicinolApprovedinJapanforthetreatmentofbothNSCLCandSCLCin2002,JCOG0509:AmrubicinPlusCisplatinvsIrinotecanPlusCisplatininED-SCLC,Protocolamendedafterenrolling191patientstoreduceamrubicindoseto35mg/m2duetofebrileneutropeniaincidence,KotaniY,etal.ASCO2012.Abstract7003.,Patientswithuntreatedextended-stageSCLC,age20-70,PS0-1(N=284),Irinotecan60mg/m2onDays1,8,15+Cisplatin60mg/m2onDay1every28daysfor4cycles(n=142),Amrubicin40mg/m2onDays1-3+Cisplatin60mg/m2onDay1every21daysfor4cycles(n=142),StratifiedbyPS0vs1,institution,sex,PCIgivenifCR,JCOG0509:Outcomes,KotaniY,etal.ASCO2012.Abstract7003.,HR:1.33,*3ptswithnomeasurablelesionexcludedfromresponseanalysis(irinotecan+cisplatin;n=1;amrubicin+cisplatin:n=2).,JCOG0509,2013ASCO：AP341(7):476-84.,7项随机临床试验、987病例结果：PCI减少16%的死亡危险,RR0.84(P=0.01)PCI治疗组绝对提高3年生存率5.4%(20.7%P0.001）降低累计脑转移发生率(RR0.46;,P0.001)放射剂量的增加可降低脑转移发生率（P0.05）但对总生存期无明显意义；诱导治疗结束早期给予PCI比延迟治疗更能降低脑转移危险（P=0.01）,3年生存率PCI20.7%NoPCI15.3%RR0.84(P=0.01),EDSCLCPCI：StudyDesign,PCI20-30Gyin5-12fractions,NoPCI,Random,Anyresponse,5weeks,4-6weeks,Noresponse,Chemotherapy(4-6cycles),Slotmanetal.NEJM2007,(months),0,4,8,12,16,20,24,28,32,36,0,10,20,30,40,50,60,70,80,90,100,PCI,Control,1year:14.6%vs.40.4%HR:0.27(0.16-0.44)p6M：originalregimenRelapse3-6MTPT，PTX，DOC，GEM，IRI，NVB，oraVP-16，TEMOZ，CAORelapse3MTPT，PTX，DOC，GEM，IRI，IFO，TEMOZ，,小结,内科治疗30余年无进展生存的改善得益于RTLDRT同期、分割以及PCIEDPCI靶向治疗?.问题：对治疗高度敏感、快速耐药,Newtargets？,MutationfrequenciesTP5376.6%RB142.6%MYCfamily12.8%PTEN4.3%,CREBBP4.3%,EP3004.3%,SLIT24.3%,MLL4.3%,CCNE18.5%andSOX22.1%ERBB2amplifications5.3%mutationsinPIK3CA6.5%,HRAS3.4%,AKT12.2%,BRAF2%andKRAS2%.,UmemuraS，etal2013ASCOabs7512GiacconeG,，etal2013ASCOabs7513,大细胞神经内分泌癌,AttheCrossRoadsofSmallandNon-smallCellLungCancer,LCNECs,3-5%ofalllungcaner84%外周型吸烟相关老年男性多见外周大肿块，早期区域LN及远处受累CT：不均质强化，10%钙化,LCNECs,化放疗敏感性低于SCLC早期:外科仍占有重要角色回顾性研究辅助治疗获益化疗方案？,StageILCNEC,Overallsurvivalofnon-smallcelllungcarcinoma(NSCLC)n=774(84.5%)largecellneuroendocrinecarcinoma(LCNEC)n=27(65.4%),IPasadjuvanttherapyforHGNECs,completelyresectedstageI-IIIAHGNECfourcyclesofirinotecan(60mg/m2,day1,8,15)pluscisplatin(60mg/m2,day1).40pts,medianage6545-73yearsmale85%;ECOG-PS160%LCNEC57%andSCLC43%stageIA/IB/IIB/IIIA32/35/8/5%;95%receivedlobectomy.,LungCancer.2014,results,ChemotherapyforadvanceLCNEC,ChemotherapyforadvanceLCNEC,LCNECs,IRI/DDPirinotecan(60mg/m,days1,8,and15)andcisplatin(60mg/m,day1)every4weeks4cycles30ptsRR46.7%MST12.6months,JThoracOncol.2013,Typicalandatypicalcarcoids,indolentbutnotbenign,Carcoids,12.0%oflungcancerAC10-16%carcoids75%asintraluminalcentrallylocatedtypicalcarcinoidsregionalLNmetastasesin1015%anddistantmetastasesin35%类癌综合征少见0.7%,Chestradiographs,acentrallylocated(hilarorperihilar),well-definedsolitarynoduleormassAssociatedpostobstructivepneumoniaandatelectasismaybepresentMostcarcinoids(60%)occurintherightlung.Tumorsrangeinsizefrom2to5cm,withanaverageofabout3cm,可切除者，外科切除辅助治疗作用不明确The5-and10-yearsurvivalratesforpatientswithtypicalcarcinoidare87%100%and82%94%,respectively,comparedwith44%88%and18%64%forpatientswithatypicalcarcinoid,Advancecarcoids,SimilartoLowgradeneuroendocrinetumorsADM,5-FU,dacarbazine,DDP,etoposide,streptozotocin,andCBPa-IFNSomatostatinanalogues（SSA）Targetedtherapy,ECOG1281trial,249casesadvancedcarcinoidtumorsTheORRwas15.9%forADM/5-FUarmwithanOSof15.7months16%forthestreptozotocin/5-FUgroup,withanOSof24.3monthsAtprogressionallpatientsreceiveddacarbazinewithanORRof8.2%,JClinOncol2005;23:4897904.,Temozolamide,10advancedTCsand3advancedACsORRof31%andSDof31%withamediantimetoprogression(TTP)of7months,Temozolamide+Thalidomide,29patientswithneuroendocrinecarcinomasreceivedtemozolamide150mg/M2x7daysq14days+thalidomide50-40mgQD,Kulke,MH,etal.JClinOncol2006;24:401-406.,CAPTEMforMetastaticPancreaticEndocrineCarcinomas,30casesThemediantimefromdiagnosisuntilonsetoftreatment12(1-101)monthsCapecitabine(750mg/m2twicedaily,days1-14)andtemozolomide(200mg/m2oncedaily,days10-14)every28daysThemediandurationoftreatmentwas8cycles(range3-23),Cancer2011;117:26875.,CAPTEM,21(70%)patientsachievedanobjectiveradiographicresponse.27%SDMedianPFSwas18months.Mediandurationresponse20monthsTherateofsurvivalattwoyearswas92%.Only4patients(12%)experiencedgrade3/4AE,Treatmentwith-Interferons(-IFN:s),Typesof-IFN:SRecommendeddosesforclassicalmidgutcarcinoids,HumanleukocyteIFNLymphoblastoidIFN(Welferon)RecombinantIFN2a(Roferon)RecombinantIFN2b(Intron-A)IFNa2b3-5MUxIII-V/weeks.c.,NB!Individualdosingaccordingtotoleranceandleukocytecount(3.0 x109/l)isrecommended,-IFN:Treatment,SubjectiveResponsesBiochemicalResponsesTumourResponses,50-70%30-70%10-15%,TreatmentwithSomatostatinAnalogues(Octreotide),OctreotideCarcinoidSyndromeCarcinoidCrisesOctreotideLAR,Recommendeddosing:100-600g/days.c.givenas2-3dosesExperimental:1,500-3,000g/days.c.Preoperatively:100gs-c-30priortooperationandthereafter50g/hri.v.infusionduringop.,continuepostop.eitherwiths.c.ori.v.therapyOctreotidei.v.50-100g/hr(Foregutcarcinoidwithhistamineproduction,continuewithH1andH2receptorblockers)Long-actingformulation,dosing20-30mgi.m./4w.,OctreotideTreatment,SubjectiveResponseBiochemicalResponseTumourResponse,30-75%(Dosedependent)30-60%(Dosedependent)0-15%(Notdosedependent),SomatostatinAnaloguesPROMID:PlaceboControlled,DoubleBlind,ProspectiveRandomizedStudyoftheEffectofOctreotideLARinthecontroloftumorgrowthinpatientswithMetastaticNeuroendocrineMidgutTumors,PrimaryEndpointTimetoProgressionSecondaryEndpointsOverallSurvivalResponseRates,Arnold,GIASCO2009,abstract#121.,85patientswithwell-differentiatedmetastaticmidgutNETs,OctreotideLAR30mgIMq4wksN=42,PlaceboIMq4wksN=43,p=0.000072,HR0.34(95%CI0.20-0.59),TimetoProgression,OverallSurvival,Octreotide,Placebo,MedianOSnotyetreached,SunitinibPhaseIIITrial-PET,171patientsrandomizedtosunitinib37.5mgorplaceboCrossoverallowedStudyclosedearlyduetobenefitoftreatment,Niccoli,P,etal.ProcASCO2010,abstract4000.,Progression-FreeSurvival,1.00.20,Proportionofpatients,0510152025,86391940085287210,NumberatriskSunitinibPlacebo,Time(months),MedianPFSSunitinib11.4months(95%CI7.4,19.8)Placebo5.5months(95%CI3.6,7.4),HR=0.418(95%CI0.263,0.662)P=0.0001,OverallSurvival,1.00.20,Proportionofpatients,0510152025,86603816308561331230,NumberatriskSunitinibPlacebo,Time(months),RADIANT-2Phase3Double-Blind,Placebo-ControlledTrial:StudyDesign,Everolimus10mg/d+octreotideLAR30mg/28daysn=216,Placebo+octreotideLAR30mg/28daysn=213,Treatmentuntildiseaseprogression,PatientswithadvancedNETandhistoryofsymptomsattributedtocarcinoidsyndrome,N=429,1:1,MultiphasicCTorMRIperformedevery12weeks,Crossover,Primaryendpoint:PFS(RECIST)Secondaryendpoints:Tumorresponse,OS,biomarkers,safety,PK,EnrollmentJanuary2007March2008,CT:computedtomography;MRI:magneticresonanceimaging;OS:overallsurvival;PFS:progression-freesurvival;PK:pharmacokinetics;RECIST:ResponseEvaluationCriteriaInSolidTumors,PavelM,etal.ESMO2010;AbstractLBA8.,RANDOMIZE,RADIANT-2:PFSbyCentralReview,No.ofpatientsstillatriskE+OP+O,Kaplan-MeiermedianPFSEverolimus+octreotideLAR:16.4monthsPlacebo+octreotideLAR:11.3monthsHR=0.77;95%CI(0.591.00)P=.026,PavelM,etal.ESMO2010;AbstractLBA8.,*Independentadjudicatedcentralreviewcommittee;Pvalueobtainedfromone-sidedlog-ranktest;HRobtainedfromunadjustedCoxmodel.E+O:everolimus+octreotideL