胰腺神经内分泌肿瘤

胰腺神经内分泌肿瘤中山大学附属第三医院肿瘤内科陈展洪2011年10月19日ASCO2011信息传达会近年来随着各种诊疗技术的进步,癌症的治愈率和生存率较以往有了较大的改善,可是,有一种肿瘤仍被冠以“早期诊断率低、预后极差、远期生存率最低、在所有肿瘤中治愈率最低……”,它就是——胰腺癌。胰腺神经内分泌肿瘤的治疗进展2003年10月超声内镜确诊胰岛细胞瘤试图饮食控制2004年7月31日，斯坦福大学医疗中心，whipple手术2006年8月起日益消瘦肿瘤复发？药物治疗？2009年4月田肝脏移植手术并长期服用免疫抑制剂抗排斥2011年肿瘤进展接受放疗化疗、靶向？（脱发明显）2011年10月6日死于呼吸衰竭OS：96个月2003年10月超声内镜确诊胰岛细胞瘤试图饮食控制2004年7月31日，斯坦福大学医疗中心，whipple手术2006年8月起日益消瘦肿瘤复发？2009年4月田纳西州孟菲斯市卫理公会大学医院移植研究所接受肝脏移植手术并长期服用免疫抑制剂抗排斥2011年肿瘤进展接受放疗化疗？（脱发明显）2011年10月6日一代巨星陨落死于呼吸衰竭PancreaticEndocrineTumors Accountfor3-5%ofallpancreaticneoplasms Mostaresporadic FamilialSyndromes 多发性内分泌瘤病1型MEN-1 结节性硬化症 神经纤维瘤病 林-希氏病(视网膜血管瘤病) Hormonalsecretion:insulin,gastrin,glucagon,VIP,serotonin,ACTH UsuallymetastasizetoliverIncidenceisfromSEER2005andprobablydoesnotincludesmallerbenignisletcells.VonHippel-Lindau-isletcelltumorsoccurin12%.ThevHLgeneislocatedonchromosome3p26–p25;inactivationofthevHLgeneisthoughttostimulateangiogenesisbypromotingincreasedHIF-1aactivity.*IncreasingIncidenceBasedonSEERdata1973-2004,35825casesinUS.*BetterprognosisthanpancreaticcancerLoalized、regional、distantmOS：124m,70m,and23mYao,JC,etal.,AnnalsofSurgOncol2007;14:3492-3500.PancreaticEndocrineTumors-SurvivalbySEER2005Stageandsurvivalof1157patientsfromthetimeofdiagnosis.Age,locationandstagecorrelatedwithsurvival.Adjustedforstage,pancreatictaillesionsdobetterthanhead.Maybeduetolocationofdifferenttumors,ieVIPomasandinsulinomasmorelikelyintail?Mediandurationofsurvivalofpatientswithlocalized(n=167),regional(n=289),anddistantdisease(n=558)was124,70,and23months,respectively(P<.001).Ofthe1310cases,125(10%)werenotstaged(Table2).Fortheremaining1185cases,179(14%)werelocalized;295(23%)wereclassifiedasregional;and711(54%)wereclassifiedasdistant.*局限期肿瘤手术原则 尽可能切除肿瘤病灶 伴有多发性内分泌瘤病1型、卓艾综合症的肿瘤应行whipple手术治疗 其余情况多采用局部切除或摘除 暂无辅助治疗临床试验数据卓艾综合症又称佐林格一埃利森综合征(Zollinger-Ellisonsyndrome),来源于G细胞，是一种以消化道溃疡为主要表现的综合病症卓艾综合症又称佐林格一埃利森综合征(Zollinger-Ellisonsyndrome),来源于G细胞，是一种以消化道溃疡为主要表现的综合病症.在胰腺内分泌瘤中发病率仅次于胰岛素瘤。60%~70%为恶性，常伴有淋巴结或肝转移。25%-30%的病人同时存在其他内分泌肿瘤〔多发性内分泌瘤病I型(MENI)]。部分肿瘤位于胰腺外，十二指肠为其好发部位。病因为胰岛D细胞的胃泌素瘤.由于肿瘤能分泌大量胃泌素,刺激胃酸分泌极度增加,导致顽故难治的不典型溃疡,容易出血和穿孔.常伴有甲状旁腺或垂体腺瘤及其相应症状.ManagementofMetastaticDisease Systemictherapy Somatostatinanalogues Interferon Chemotherapy “Targeted”Agents Peptidereceptortherapy Livermetastasis：SurgicalIntervention、TACE*Octreotide Symptomsofflushinganddiarrhearelievedin75-80% 50%becomerefractory Stabilizediseasein50% Tumorregressionin4%ArnoldRetal.Digestion.1993;54(suppl1):72-75.SomatostatinanalogHighaffinityforsst2andsst5Moderateaffinityforsst3Cangiveupto500ugtid.Bindstoreceptorandgetsinternalized.Alsomentionsimilarsomatostatinanalog,lanreotide.ThesstarecoupledtocAMPanddecreasedcalciuminfluxandgenerallyinhibithormonalsecretionandintestinalmotility.InhibitproliferationofnormalandtumorcellsduetohypophosphorylationofRbgeneproductandcauseG1cellcyclearrest.Alsocancauseapoptosismediatedthroughsst3andalsothroughsst2.Somatostatindirectlyinhibitscellproliferationthroughsstreceptorsontargetcells1Effectsofsomatostatinareregulatedthrough5receptorsubtypes(sst-1–sst-5)1,2sst-1,sst-4,andsst-5inducecellcyclearrestsst-2andsst-3promoteapoptosisSomatostatinanaloguessuchasoctreotidecanexertantigrowtheffectsbybindingprimarilytosst-2,andtoalesserextent,sst-3andsst-53InhibitsangiogenesisdirectlythroughsomatostatinreceptorsonendothelialcellsIndirectlyinhibitsangiogenesisbyinhibitinggrowthfactorsecretion:Insulin-likegrowthfactor(IGF-I)Vascularendothelialgrowthfactor(VEGF)Onlyabout50%ofinsulinomasexpressthereceptorssolowrateofresponse.Gastrinomasalsooftendonotrespond.*Interferon Interferonalpha Biochemicalresponsein40% Stabilizestumorin15-40% Tumorregressionin12% Toxicity: Fatigue、Myelosuppression、Fever、Flu-likeillness DepressionÖbergK.AnnOncol.2001;12(suppl2):S111-S114.Shnirer,II,etal.ActaOncol2003;42:672-692.Useislimitedbytoxicity-fatigue,flu-likeillnessanddepression.Maybeaddedtooctreotidewhenoctreotidefails.Itmayimprovebiochemicalresponseratesincombinationwithchemotherapybutnotsurvival.Dosesof3-9mutiw.Inarandomizedtrialoflanreotide,IFNalphaorbothin80untreatedneuroendocrinetumors,1lanreotide,1IFNand2whoreceivedbothhadpartialresponse.AntiproliferativeeffectmaybethroughStat1andStat2Zhou,Y,etal.Oncology2001;60:330.*Chemotherapy Generallyineffective Lowmitoticrate Highbcl-2expression MDRgeneexpression Agents Streptozocin+Doxorubicin+FluoropyrimidinesRR30% DTIC：FirstlineRR33%Secondline8% Temozolamide±xelodaRR35-40% Poor-differentiaedCIS/L-OHP+VP-16RR40-60%withshortPFSMoreeffectiveinpancreaticendocrinethancarcinoids.*TargetedAgents VEGF Bevacizumab Pazopanib Sorafenib Sunitinib mTOR EverolimusTemozolamide+Bevacizumab 34patientswithneuroendocrinecarcinomasreceivedtemozolamide150mg/M2BIDx7dq14days+bevacizumab5mg/kgIVq14daysKulke,MH,etal.ProcASCO2006,abstract4044. Carcinoid PET PR(%) 0 24 SD(%) 92 70 PD(%) 8 6BactrimandAcyclovirprophylaxis*XELOX+Bevacizumab 40patientswithNETsreceivedcapecitabine850mg/M2BIDx14d,oxaliplatin130mg/M2+bevacizumab7.5mg/kgq21dKuntz,PL,etal.ProcASCO2010,abstract4104. PET(N=19) SB(N=5) Unknown(N=11) Other(N=5) Total(N=40) DOR PR 6 - 1 - 7(18%) 3-27m SD 11 4 7 3 25(63%) 3-27 PD - - 1 1 2(5%) - NE 2 1 2 1 6(15%) -PrimaryendpointPFS.~35%RRforPET.PR+SD81%.*Sorafenib 93patientsreceivedsorafenib400mgBID Ki-67correlateswithresponse(<2%RR0,>2%RR22%) 2/3ofpatientsdiscontinuedforreasonsotherthanprogression(toxicity)Hobday,TJ,etal.ProcASCO2007,abstract4504. PET(N=35) Carcinoid(N=42) PR(%) 11 7 MR(%) 14 7 PFS-6months(%) 72 58 PFS(months) 11.9 7.8VEGFR-2,3,RAF,PDGFR,FLT-3,c-KIT.Toxicitywasgreaterthanexpectedfromotherdisease.*Pazopanib+SandostatinLAR Pazopanib800mgorallyQD+octreotideLAR CarcinoidenrollmentstoppedearlyPhan,AT.ProcASCO2010,abstract4001. Overall(N=51) Carcinoid(N=20) PNET(N=31) PR(%) 12 0 19 MR(%) 18 20 16 SD(%) 69 70 68 PD(%) 12 15 10 Unknown(%) 8 15 3 PFS(months) 14.2 12 14.2 OS(months) 25.6 19.6 25.6 1y(%) 73 75 71Pazopanib(GW786034).OralTKIadministereddaily.BindstocytoplasmicdomainofVEGFR-1,VEGFR-2andVEGFR-3,aswellasPDGFR-αandPDGFR-β,andc-Kit.FDAapprovedformetastaticrenalcellcarcinoma.ParallellphaseIItrial,carcinoidorPNET.EnrolledatMDACCorDFCI.0or1cytotoxicchemotherapy.Minorresponse:≥15%but<30%regression.RRisprimaryendpoint.Didperfusional/functionalCTatbaselineand12weeks.Noresponsesincarcinoidarmsostoppedearly.Mostarelowgrade.61%ofPNETarmreceived1priortherapy.*SunitinibRAD001：依维莫斯RADIANT-1:EverolimusinPET PETpatientswhoprogressedonorafterchemotherapy,stratifiedbyprioroctreotideYao,JC,etal.JClinOncol2010;28:69-76. Everolimus(N=115) Everolimus+OctreotideLAR(N=45) PR(%) 9.6 4.4 SD(%) 67.8 80 PR+SD(%) 77.4 84.4 PD(%) 13.9 0 PFS(months) 9.7 16.7Everolimus10mgdaily.*RADIANT-3Phase3Double-Blind,Placebo-ControlledTrial:StudyDesignTreatmentuntildiseaseprogressionPatientswithadvancedpNETN=410Stratifiedby: WHOPS Priorchemotherapy1:1Multi-phasicCTorMRIperformedevery12weeksCrossoverPrimaryendpoint:PFS(RECIST)Secondaryendpoints:Response,OS,biomarkers,safety,andPKRANDOMIZEYaoJetal.12thWorldCongressonGastrointestinalCancer;June30-July3,2010;Barcelona,Spain.Poster#O-0028.RandomizationAugust2007–May2009****mTOR:centralregulatorofgrowth,proliferation,cellularmetabolism,andangiogenesis[a-c]mTORpathwayactivationobservedwithgeneticcancersyndromesassociatedwithpNET[d]TSC2,NF1,VHLDysregulationofmTORpathway,PTEN,andTSC2,insporadicpNETisassociatedwithpoorprognosis[e]EverolimusdemonstratedantitumouractivityinpNETintwophase-2studies[f,g]PFS&OSToxicity：AwareofpneumonitisAcceptablesafetyprofile:stomatitis,rash,infection,infrequentpneumonitis结论 依维莫斯显著延长PFS（延长6.4m） 可用做进展的低或中分级的胰腺神经内分泌肿瘤的 标准 excel标准偏差excel标准偏差函数exl标准差函数国标检验抽样标准表免费下载红头文件格式标准下载 治疗 注意肺毒性Bevacizumab+Everolimus 39patientswithloworintermediategradeNET PR/PRconfirmed 26%/21% SD 69% PD 3% PFS 14.6months 6/12month 92%/74% OS NR 1y/2y 92%/80%Yao,JC,etal.ProcASCO2010,abstract4002.RandomizedruninstudyinLGNETsusingperfusionCTasfunctionalmarker.ASCO2010ClinicalScienceSymposium,JamesYao.Patientsstartedwithbevaoreverolimusandthentheotherdrugadded.UsedperfusionCT/functionalimagingtodeterminebloodflow,meantransittimeandpermeability.Bevacizumabresultedindecreaseinbloodflowandvolume,whichwasassociatedwithresponse.MayuseperfusionCTtodeterminewhowillbenefitfromthistherapy.Everolimusincreasedmeantransittime,whichalsowasassociatedwithresponse.PhaseIIItrial–CALGB80701everolimus+/-bevtobeopened.*Peptidereceptortherapy:PPRT多肽受体放射性核素治疗生长抑素受体显像技术呈高摄取的患者可以选择多肽受体靶向放射治疗仍需随机临床试验确定其疗效，通常用于二线治疗肝转移灶的处理 最常见的死亡原因：肝转移 治疗 方案 气瓶 现场处置方案 .pdf气瓶 现场处置方案 .doc见习基地管理方案.doc关于群访事件的化解方案建筑工地扬尘治理专项方案下载 ：肝叶切除、不规则的转移瘤切除术、术中射频消融或冷冻治疗、多种方法联合 介入栓塞Takehomemessage 胰腺神经内分泌肿瘤，散发，约占胰腺恶性肿瘤3-5%，发病率呈上升趋势。 多伴有激素异常释放。经常转移到肝脏。 预后较胰腺癌好，局限期、局部晚期、晚期mOS：124m,70m,and23m 尽可能切除肿瘤病灶；伴有多发性内分泌瘤病1型、卓艾综合症的肿瘤应行whipple手术治疗；其余情况多采用局部切除或摘除。 积极处理患者肝转移病灶可能改善生存 晚期患者多采用生长抑素、化疗或靶向治疗 生长抑素ORR低4%，以缓解症状、稳定肿瘤为主 化疗有效的药物：链脲霉素+5Fu+ADM、替莫唑胺（或DTIC）联合卡培他滨、CIS/L-OHP+VP-16 靶向治疗：舒尼替尼、依维莫斯，延长PFS为主注意依维莫斯肺毒性近年来随着各种诊疗技术的进步,癌症的治愈率和生存率较以往有了较大的改善,可是,有一种肿瘤仍被冠以“早期诊断率低、预后极差、远期生存率最低、在所有肿瘤中治愈率最低……”,它就是——胰腺癌。2003年10月超声内镜确诊胰岛细胞瘤试图饮食控制2004年7月31日，斯坦福大学医疗中心，whipple手术2006年8月起日益消瘦肿瘤复发？2009年4月田纳西州孟菲斯市卫理公会大学医院移植研究所接受肝脏移植手术并长期服用免疫抑制剂抗排斥2011年肿瘤进展接受放疗化疗？（脱发明显）2011年10月6日一代巨星陨落死于呼吸衰竭IncidenceisfromSEER2005andprobablydoesnotincludesmallerbenignisletcells.VonHippel-Lindau-isletcelltumorsoccurin12%.ThevHLgeneislocatedonchromosome3p26–p25;inactivationofthevHLgeneisthoughttostimulateangiogenesisbypromotingincreasedHIF-1aactivity.*BasedonSEERdata1973-2004,35825casesinUS.*Stageandsurvivalof1157patientsfromthetimeofdiagnosis.Age,locationandstagecorrelatedwithsurvival.Adjustedforstage,pancreatictaillesionsdobetterthanhead.Maybeduetolocationofdifferenttumors,ieVIPomasandinsulinomasmorelikelyintail?Mediandurationofsurvivalofpatientswithlocalized(n=167),regional(n=289),anddistantdisease(n=558)was124,70,and23months,respectively(P<.001).Ofthe1310cases,125(10%)werenotstaged(Table2).Fortheremaining1185cases,179(14%)werelocalized;295(23%)wereclassifiedasregional;and711(54%)wereclassifiedasdistant.*卓艾综合症又称佐林格一埃利森综合征(Zollinger-Ellisonsyndrome),来源于G细胞，是一种以消化道溃疡为主要表现的综合病症.在胰腺内分泌瘤中发病率仅次于胰岛素瘤。60%~70%为恶性，常伴有淋巴结或肝转移。25%-30%的病人同时存在其他内分泌肿瘤〔多发性内分泌瘤病I型(MENI)]。部分肿瘤位于胰腺外，十二指肠为其好发部位。病因为胰岛D细胞的胃泌素瘤.由于肿瘤能分泌大量胃泌素,刺激胃酸分泌极度增加,导致顽故难治的不典型溃疡,容易出血和穿孔.常伴有甲状旁腺或垂体腺瘤及其相应症状.*SomatostatinanalogHighaffinityforsst2andsst5Moderateaffinityforsst3Cangiveupto500ugtid.Bindstoreceptorandgetsinternalized.Alsomentionsimilarsomatostatinanalog,lanreotide.ThesstarecoupledtocAMPanddecreasedcalciuminfluxandgenerallyinhibithormonalsecretionandintestinalmotility.InhibitproliferationofnormalandtumorcellsduetohypophosphorylationofRbgeneproductandcauseG1cellcyclearrest.Alsocancauseapoptosismediatedthroughsst3andalsothroughsst2.Somatostatindirectlyinhibitscellproliferationthroughsstreceptorsontargetcells1Effectsofsomatostatinareregulatedthrough5receptorsubtypes(sst-1–sst-5)1,2sst-1,sst-4,andsst-5inducecellcyclearrestsst-2andsst-3promoteapoptosisSomatostatinanaloguessuchasoctreotidecanexertantigrowtheffectsbybindingprimarilytosst-2,andtoalesserextent,sst-3andsst-53InhibitsangiogenesisdirectlythroughsomatostatinreceptorsonendothelialcellsIndirectlyinhibitsangiogenesisbyinhibitinggrowthfactorsecretion:Insulin-likegrowthfactor(IGF-I)Vascularendothelialgrowthfactor(VEGF)Onlyabout50%ofinsulinomasexpressthereceptorssolowrateofresponse.Gastrinomasalsooftendonotrespond.*Useislimitedbytoxicity-fatigue,flu-likeillnessanddepression.Maybeaddedtooctreotidewhenoctreotidefails.Itmayimprovebiochemicalresponseratesincombinationwithchemotherapybutnotsurvival.Dosesof3-9mutiw.Inarandomizedtrialoflanreotide,IFNalphaorbothin80untreatedneuroendocrinetumors,1lanreotide,1IFNand2whoreceivedbothhadpartialresponse.AntiproliferativeeffectmaybethroughStat1andStat2Zhou,Y,etal.Oncology2001;60:330.*Moreeffectiveinpancreaticendocrinethancarcinoids.*BactrimandAcyclovirprophylaxis*PrimaryendpointPFS.~35%RRforPET.PR+SD81%.*VEGFR-2,3,RAF,PDGFR,FLT-3,c-KIT.Toxicitywasgreaterthanexpectedfromotherdisease.*Pazopanib(GW786034).OralTKIadministereddaily.BindstocytoplasmicdomainofVEGFR-1,VEGFR-2andVEGFR-3,aswellasPDGFR-αandPDGFR-β,andc-Kit.FDAapprovedformetastaticrenalcellcarcinoma.ParallellphaseIItrial,carcinoidorPNET.EnrolledatMDACCorDFCI.0or1cytotoxicchemotherapy.Minorresponse:≥15%but<30%regression.RRisprimaryendpoint.Didperfusional/functionalCTatbaselineand12weeks.Noresponsesincarcinoidarmsostoppedearly.Mostarelowgrade.61%ofPNETarmreceived1priortherapy.*Everolimus10mgdaily.*****mTOR:centralregulatorofgrowth,proliferation,cellularmetabolism,andangiogenesis[a-c]mTORpathwayactivationobservedwithgeneticcancersyndromesassociatedwithpNET[d]TSC2,NF1,VHLDysregulationofmTORpathway,PTEN,andTSC2,insporadicpNETisassociatedwithpoorprognosis[e]EverolimusdemonstratedantitumouractivityinpNETintwophase-2studies[f,g]RandomizedruninstudyinLGNETsusingperfusionCTasfunctionalmarker.ASCO2010ClinicalScienceSymposium,JamesYao.Patientsstartedwithbevaoreverolimusandthentheotherdrugadded.UsedperfusionCT/functionalimagingtodeterminebloodflow,meantransittimeandpermeability.Bevacizumabresultedindecreaseinbloodflowandvolume,whichwasassociatedwithresponse.MayuseperfusionCTtodeterminewhowillbenefitfromthistherapy.Everolimusincreasedmeantransittime,whichalsowasassociatedwithresponse.PhaseIIItrial–CALGB80701everolimus+/-bevtobeopened.*