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 1 3 2 1 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 S RT 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 Firstintroducedin1979Later1980 s 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 SCLC Amrubicin 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 AP EPfromChina SunY etal ASCO2013 Abstract7507 Patientswithuntreatedextended stageSCLC N 299 VP 16100mg m2onDays1 3DDP80mg m2onDay1every21daysfor4 6cycles n 150 Amrubicin40mg m2onDays1 3Cisplatin60mg m2onDay1every21daysfor4 6cycles n 149 2013ASCO AP EP 一线治疗持续时间 6项随机临床研究4项选择序贯化放疗2项未选择放疗选择CAV CEV CAE EP等方案延长治疗时间并不能获益免疫 靶向治疗不能获益 预防性脑放疗ProphylacticCranialIrradiationPCI PCI 初治达CR者 2年内约有45 发生脑转移 其中20 30 为单发转移器官 脑转移者中位生存期4 5个月 1999年的meta分析NEnglJMed1999 341 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 15 3 1999年的meta分析 提高PFS RR0 75 P 0 001 降低累计脑转移发生率 RR0 46 P 0 001 放射剂量的增加可降低脑转移发生率 P 0 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 p 0 001 Symptomaticbrainmetastases 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 27 1 vs 13 3 HR 0 68 0 52 0 88 p 0 003 Overallsurvival 二线治疗 TPT PhaseIIIin2nd TPT和CAV疗效相近 MST25W 24 7WTPTvsBSCMST26vs14W口服与静脉TPT疗效相近MST35vs33WPhaseII TPTweeklyequalto5daysschedule PhaseIII AMRvsTPTin2ndline StrategiesinES SCLC Paradigm IncreaseDurationofTherapy InitialDoseEscalation MaintenanceTherapy HighDose TherapywithGF s ModifiedSchedule Weekly IncorporationofNewAgents Incorporationof Targeted Agents Effect Negative Negative Negative Negative Negative Negative TargetedTherapies DasatinibAT 101ABT263Vorinostat HDAC AMG102 HGF BEC 2 BCGImatinibMarimastatTanomastatTipafarnibGefitinibVandetanibCediranibTemsirolimusEverolimusBiricodarOblimersenBortezomibThalidomideTamoxifenBevacizumabSorafenibSunitinibVismodegibCixutumumabpravastatinNTX 010 SCLC 2014NCCN SCLC Max4 6cyclesLimiteddiseaseDDP CBP VP 16ConcurrentRT EPExtensivediseaseDDP CBP VP 16DDP CBP IRI SalvageClinicaltrialRelapse 6M originalregimenRelapse3 6MTPT PTX DOC GEM IRI NVB oraVP 16 TEMOZ CAORelapse 3MTPT 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 medianage65 45 73 yearsmale85 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 1 2 0 oflungcancerAC10 16 carcoids75 asintraluminalcentrallylocatedtypicalcarcinoidsregionalLNmetastasesin10 15 anddistantmetastasesin3 5 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 4897 904 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 117 268 75 CAPTEM 21 70 patientsachievedanobjectiveradiographicresponse 27 SDMedianPFSwas18months Mediandurationresponse20monthsTherateofsurvivalattwoyearswas92 Only4patients 12 experiencedgrade3 4AE Treatmentwith Interferons IFN s Typesof IFN SRecommendeddosesforclassicalmidgutcarcinoids HumanleukocyteIFNLymphoblastoidIFN Welferon RecombinantIFN 2a Roferon RecombinantIFN 2b 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 100 600 g days c givenas2 3dosesExperimental 1 500 3 000 g days c Preoperatively 100 gs c 30 priortooperationandthereafter50 g hri v infusionduringop continuepostop eitherwiths c ori v therapyOctreotidei v 50 100 g 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 80 60 40 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 80 60 40 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 EnrollmentJanuary2007 March2008 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 59 1 00 P 026 PavelM etal ESMO2010 AbstractLBA8 Independentadjudicatedcentralreviewcommittee Pvalueobtainedfromone sidedlog ranktest HRobtainedfromunadjustedCoxmodel E O everolimus octreotideLAR HR hazardratio P O placebo octreotideLAR RADIANT 3Phase3Double Blind Placebo ControlledTrial StudyDesign Everolimus10mg d BSC n 207 Placebo BSC n 203 Treatmentuntildiseaseprogression PatientswithadvancedpNETN 410Stratifiedby WHOPSPriorchemotherapy 1 1 Multi phasicCTorMRIperformedevery12weeks Crossover Primaryendpoint PFS RECIST Secondaryendpoints Response OS biomarkers safety andPK RANDOMIZE BSC bestsupportivecare PS performancestatus WHO WorldHealthOrganization YaoJetal 12thWorldCongressonGastrointestinalCancer June30 July3 2010 Barcelona Spain Poster O 0028 RandomizationAugust2007 May2009 RADIANT 3 OverallSurvival 148placebopatientscrossedovertoreceiveeverolimus HazardratioisobtainedfromtheunadjustedstratifiedCoxmodelP valueisobtainedfromthestratifiedone sidedlogranktest YaoJetal 12thWorldCongressonGastrointestinalCancer June30 July3 2010 Barcelona Spain Poster O 0028 RADIANT 3SummaryandConclusions RADIANT 3 largestrandomizedcontrolledtrialevercompletedinadvancedpNETEverolimusreducedriskofprogressionby65 vsplacebo HR 0 35 P 0001 MedianPFS 11 0mowitheverolimusvs4 6mowithplaceboAcceptablesafetyprofile stomatitis rash infection infrequentpneumonitisEverolimusshouldbeconsideredastandardofcareinadvancedpNET Thanksforyourattention