TherapyofMalignantPheochromocytoma

惡性嗜鉻細胞瘤的治療LiteratureReport.10/27/20221

TherapyofMalignantPheochroIntroduction

ruleof10sforpheochromocytoma(PCC)

10%bilateral10%extra-adrenal10%extra-abdomen10%malignant10%familial10%children10%normalbloodpressure.10/27/20222Introductionruleof10sforpIntroductionThemostfrequentsiteofmetastasesistheskeletonAdditionalsitesareliver,retroperitoneumwithlymphnodes,CNS,pleura,andkidney.10/27/20223IntroductionThemostfrequentMalignantvs.BenignCurrently,thereisnoeffectivecureformalignantpheochromocytoma.Therearealsonoreliablehistopathologicalmethodsfordistinguishingbenignfrommalignanttumors.Malignancyrequiresevidenceofmetastasesatnon-chromaffinsitesdistantfromthatoftheprimarytumor..10/27/20224Malignantvs.BenignCurrently,Metastaticdiseaseinpheochromocytomamaybepresentatthetimeofinitialdiagnosisormayonlybecameevidentaftersurgicalremovaloftheprimarytumor,usuallywithin5years,butsometimes16ormoreyearslater..10/27/20225MetastaticdiseaseinpheochroDuetotherarityofthetumor,clinicalstudiesaboutpheochromocytomasufferfromafragmentednatureandusuallyinvolvetoosmallanumberofcasestoreachconclusiveresults..10/27/20226DuetotherarityofthetumorBecausethereiscurrentlynoeffectivecureformalignantpheochromocytoma,mosttreatmentarepalliative,butinsomecasesmayreducetumorburdenandprolongsurvival.Withouttreatment,the5-yearsurvivalisgenerallylessthan50%.Thecourse,however,canbehighlyvariablewithoccasionalpatientslivingmorethan20yearsafterdiagnosis..10/27/20227BecausethereiscurrentlynoOncemalignancyisdiagnosed,therapyisgenerallydirectedatcontrollingbloodpressure,butmayalsoincludetumordebulking..10/27/20228Oncemalignancyisdiagnosed,AlternativeofCurrentTherapySurgeryRadiopharmaceuticalsCombinedChemotherapyArterialEmbolization.10/27/20229AlternativeofCurrentTherapyAlternativeofCurrentTherapySurgeryRadiopharmaceuticalsCombinedChemotherapyArterialEmbolization.10/27/202210AlternativeofCurrentTherapyPrimarysurgicalresectionisthetreatmentofchoicewheneverpossibleLimiteddisease:curativeintentionExtendeddisease:stilltobeconsideredinthefirstplacefordebulkingandaspalliativetreatment(Mundschenketal.1998).10/27/202211PrimarysurgicalresectionisProblemWhensignsofregionalinvolvementordistantdiseaseareabsent,thereiscurrentlynoreliablepreoperativediagnostictestthatcandifferentiatebetweenmalignantandbenignpheochromocytomasShouldpheochromocytomasizeinfluencesurgicalapproach?.10/27/202212ProblemWhensignsofregionalAcomparisonof90malignantand60benignpheochromocytomas

(WenT.Shenetal.2004)ComparisonoftumorsizeforbenignpheochromocytomasandmalignantpheochromocytomaswithlocaldiseaseonlySizedoesnotreliablypredictmalignancyinpheochromocytomaswithlocaldiseaseonly.10/27/202213Acomparisonof90malignantaMalignant(n

=

29)Benign(n

=

55)Tumorsize(mean±SD)6.1±3.1cm5.3±2.3cm<2cm012.0-3.9cm9104.0-5.9cm6256.0-7.9cm5138.0-9.9cm53≥10cm43.10/27/202214Malignant(n

=

29)Benign(n

=

MalignantPCCspresentingwithonlylocaldiseasecannotbediscriminatedfrombenignPCCsbysizealone.WhenPCCsdonothaveevidenceofinvasionordistantmetastasesandthesurgeonacquiresanappropriatelevelofexperience,themajorityofthesetumorscanbesafelyresectedlaparoscopically..10/27/202215MalignantPCCspresentingwithLaparoscopicadrenalectomyforpheochromocytomashouldbeconvertedtoopenadrenalectomyfordifficultdissection,invasion,adhesions,orsurgeoninexperience.10/27/202216LaparoscopicadrenalectomyforSurgicalapproachTransabdominalapproachisnecessaryminimallyinvasiveproceduresretroperitonealapproachesshouldbeabandonedtodefinitelypreservethetumorcapsuleandperformtotallymphadecectomy(Orchardetal.1993).10/27/202217SurgicalapproachTransabdominaSecondaryTumorsNoexperiencewithadjuvantpreandpostoperativeradiationexistsGenerallyaremultipleRadicalsurgicalresectionisoftenimpossibleOthertreatmentmodalitieshavetobeconsidered.10/27/202218SecondaryTumorsNoexperienceAlternativeofCurrentTherapySurgeryRadiopharmaceuticalsCombinedChemotherapyArterialEmbolization.10/27/202219AlternativeofCurrentTherapy.10/27/202220.10/22/202220131I-MIBGisthetreatmentofchoiceforallunresectable,MIBGpositivetumors58casesofmalignantPCCtreatedby131I-MIBG—therapeuticresultsandadverseevents(ZHURuisenetal.1999).10/27/202221131I-MIBGisthetreatmentofPatientswereclassifiedinto3groupsaccordingtotheirtumorsize<8cm3(11cases),8～20cm3(21cases),>20cm3(26cases)Ingroup1,themeanabsorptiondosepergramoftumorwasabove1000cGy.Aftertreatment,tumorsdisappearedorshrinkedinallpatients.10/27/202222PatientswereclassifiedintoIngroup2,theabsorptiondosewassimilartothatofgroup1,butthemeanabsorptiondosepergramwas717.6cGy,andtumormassregressionwas36%;76%reducedurinarycatecholamineIngroup3,theabsorptiondosepergramtumortissuewas277cGy,and30%tumorenlargement,20%died;theremaining50%symptomaticimprovementwithoutanychangeintumorsize.10/27/202223Ingroup2,theabsorptiondo131I-MIBGisofcertaintherapeuticeffectivenessofsymptomaticimprovementCompletetumormassdisappearancehasonlybeenfoundinsmalltumorsTreatmentwith131I-MIBGshouldbeinstitutedimmediatelyaftersurgicalresectiontoeradicatetheresidualtumorcellsandtopreventrecurrencesBonemarrowsuppressionistemporaryandnotdosagerelated.10/27/202224131I-MIBGisofcertaintheraIn1997,Lohetal.publishedareviewoftheworldwideexperienceinvolving116patientstreatedwith131I-MIBGformalignantpheochromocytoma.Overall,therewasasymptomaticresponsein76%,ahormonalresponsein45%,andtumorregressionin30%.Theactivityof131I-MIBGpersingledosewas96–300mCi,andthemeancumulativeactivitywas490±350mCi.OnlyfiveCRsto131I-MIBGwerereported..10/27/202225In1997,Lohetal.publishedLimitationsNotallpatientswithmultiplemetastasesofmalignantpheochromocytomashavesufficientuptakeofMIBGtoallowMIBGtherapyMIBGnegativelesionscoexistwithMIBGpostivelesions,requiringcombinedtreatment.10/27/202226LimitationsNotallpatientswiAsasingleagent,131I-MIBGhaslimitedefficacyintreatingmalignantpheochromocytoma.Itsuseincombinationwithothercytotoxicagents,asiscurrentlybeingstudiedinpatientswithneuroblastoma,mayresultinadditionalbenefit(Sissonetal.1999).10/27/202227Asasingleagent,131I-MIBGhaAlternativeofCurrentTherapySurgeryRadiopharmaceuticalsCombinedChemotherapyArterialEmbolization.10/27/202228AlternativeofCurrentTherapyOnlysparsedataonchemotherapeuticregimensareavailable,mostoftheminreportsoffewcasesThemostwell-establishedregimenisCVD(Averbuchetal.1988)CTX750mg/m2d1,VCR1.4mg/m2d1,Dacarbazine600mg/m2d1,2Cycle21days.10/27/202229OnlysparsedataonchemotheraTheCVDregimenwasbasedonthetreatmentforadvancedneuroblastoma.Thisregimenhasbeenreportedtoproducegoodresponsesinmalignantpheochromocytoma,butthemediandurationofremissionis21monthsCompletelong-termdiseaseremissionswithchemotherapyhavenotbeenreported..10/27/202230TheCVDregimenwasbasedontAlternativeofCurrentTherapySurgeryRadiopharmaceuticalsCombinedChemotherapyTranscatheterArterialEmbolization.10/27/202231AlternativeofCurrentTherapyTAEhasbeensuccessfullyperformedinthetreatmentofmalignantPCCwithlivermetastasesThetherapeuticeffectsofTAEhavebeendemonstratedtobeenhancedbythecombinationtherapywithanticancerchemotherapy.10/27/202232TAEhasbeensuccessfullyperfMitomycinChasbeensuccessfullyusedinTAEforlivermetastasisinseveralcasesofmalignantPCC..10/27/202233MitomycinChasbeensuccessfu.10/27/202234.10/22/202234Malignantpheochromocytoma:past,presentandfuturePastPresentFutureAdrenergicblockers,α-methyl-paratyrosine&useofotherdrugsforsymptomaticreliefSurgicaldebulking;131I-MIBGradiotherapy;Chemotherapy;ChemoembolizationMoleculartargeting,cancervaccines,genetherapy.10/27/202235Malignantpheochromocytoma:pa

TherapyofMalignantPheochromocytoma

惡性嗜鉻細胞瘤的治療LiteratureReport.10/27/202236

TherapyofMalignantPheochroIntroduction

ruleof10sforpheochromocytoma(PCC)

10%bilateral10%extra-adrenal10%extra-abdomen10%malignant10%familial10%children10%normalbloodpressure.10/27/202237Introductionruleof10sforpIntroductionThemostfrequentsiteofmetastasesistheskeletonAdditionalsitesareliver,retroperitoneumwithlymphnodes,CNS,pleura,andkidney.10/27/202238IntroductionThemostfrequentMalignantvs.BenignCurrently,thereisnoeffectivecureformalignantpheochromocytoma.Therearealsonoreliablehistopathologicalmethodsfordistinguishingbenignfrommalignanttumors.Malignancyrequiresevidenceofmetastasesatnon-chromaffinsitesdistantfromthatoftheprimarytumor..10/27/202239Malignantvs.BenignCurrently,Metastaticdiseaseinpheochromocytomamaybepresentatthetimeofinitialdiagnosisormayonlybecameevidentaftersurgicalremovaloftheprimarytumor,usuallywithin5years,butsometimes16ormoreyearslater..10/27/202240MetastaticdiseaseinpheochroDuetotherarityofthetumor,clinicalstudiesaboutpheochromocytomasufferfromafragmentednatureandusuallyinvolvetoosmallanumberofcasestoreachconclusiveresults..10/27/202241DuetotherarityofthetumorBecausethereiscurrentlynoeffectivecureformalignantpheochromocytoma,mosttreatmentarepalliative,butinsomecasesmayreducetumorburdenandprolongsurvival.Withouttreatment,the5-yearsurvivalisgenerallylessthan50%.Thecourse,however,canbehighlyvariablewithoccasionalpatientslivingmorethan20yearsafterdiagnosis..10/27/202242BecausethereiscurrentlynoOncemalignancyisdiagnosed,therapyisgenerallydirectedatcontrollingbloodpressure,butmayalsoincludetumordebulking..10/27/202243Oncemalignancyisdiagnosed,AlternativeofCurrentTherapySurgeryRadiopharmaceuticalsCombinedChemotherapyArterialEmbolization.10/27/202244AlternativeofCurrentTherapyAlternativeofCurrentTherapySurgeryRadiopharmaceuticalsCombinedChemotherapyArterialEmbolization.10/27/202245AlternativeofCurrentTherapyPrimarysurgicalresectionisthetreatmentofchoicewheneverpossibleLimiteddisease:curativeintentionExtendeddisease:stilltobeconsideredinthefirstplacefordebulkingandaspalliativetreatment(Mundschenketal.1998).10/27/202246PrimarysurgicalresectionisProblemWhensignsofregionalinvolvementordistantdiseaseareabsent,thereiscurrentlynoreliablepreoperativediagnostictestthatcandifferentiatebetweenmalignantandbenignpheochromocytomasShouldpheochromocytomasizeinfluencesurgicalapproach?.10/27/202247ProblemWhensignsofregionalAcomparisonof90malignantand60benignpheochromocytomas

(WenT.Shenetal.2004)ComparisonoftumorsizeforbenignpheochromocytomasandmalignantpheochromocytomaswithlocaldiseaseonlySizedoesnotreliablypredictmalignancyinpheochromocytomaswithlocaldiseaseonly.10/27/202248Acomparisonof90malignantaMalignant(n

=

29)Benign(n

=

55)Tumorsize(mean±SD)6.1±3.1cm5.3±2.3cm<2cm012.0-3.9cm9104.0-5.9cm6256.0-7.9cm5138.0-9.9cm53≥10cm43.10/27/202249Malignant(n

=

29)Benign(n

=

MalignantPCCspresentingwithonlylocaldiseasecannotbediscriminatedfrombenignPCCsbysizealone.WhenPCCsdonothaveevidenceofinvasionordistantmetastasesandthesurgeonacquiresanappropriatelevelofexperience,themajorityofthesetumorscanbesafelyresectedlaparoscopically..10/27/202250MalignantPCCspresentingwithLaparoscopicadrenalectomyforpheochromocytomashouldbeconvertedtoopenadrenalectomyfordifficultdissection,invasion,adhesions,orsurgeoninexperience.10/27/202251LaparoscopicadrenalectomyforSurgicalapproachTransabdominalapproachisnecessaryminimallyinvasiveproceduresretroperitonealapproachesshouldbeabandonedtodefinitelypreservethetumorcapsuleandperformtotallymphadecectomy(Orchardetal.1993).10/27/202252SurgicalapproachTransabdominaSecondaryTumorsNoexperiencewithadjuvantpreandpostoperativeradiationexistsGenerallyaremultipleRadicalsurgicalresectionisoftenimpossibleOthertreatmentmodalitieshavetobeconsidered.10/27/202253SecondaryTumorsNoexperienceAlternativeofCurrentTherapySurgeryRadiopharmaceuticalsCombinedChemotherapyArterialEmbolization.10/27/202254AlternativeofCurrentTherapy.10/27/202255.10/22/202220131I-MIBGisthetreatmentofchoiceforallunresectable,MIBGpositivetumors58casesofmalignantPCCtreatedby131I-MIBG—therapeuticresultsandadverseevents(ZHURuisenetal.1999).10/27/202256131I-MIBGisthetreatmentofPatientswereclassifiedinto3groupsaccordingtotheirtumorsize<8cm3(11cases),8～20cm3(21cases),>20cm3(26cases)Ingroup1,themeanabsorptiondosepergramoftumorwasabove1000cGy.Aftertreatment,tumorsdisappearedorshrinkedinallpatients.10/27/202257PatientswereclassifiedintoIngroup2,theabsorptiondosewassimilartothatofgroup1,butthemeanabsorptiondosepergramwas717.6cGy,andtumormassregressionwas36%;76%reducedurinarycatecholamineIngroup3,theabsorptiondosepergramtumortissuewas277cGy,and30%tumorenlargement,20%died;theremaining50%symptomaticimprovementwithoutanychangeintumorsize.10/27/202258Ingroup2,theabsorptiondo131I-MIBGisofcertaintherapeuticeffectivenessofsymptomaticimprovementCompletetumormassdisappearancehasonlybeenfoundinsmalltumorsTreatmentwith131I-MIBGshouldbeinstitutedimmediatelyaftersurgicalresectiontoeradicatetheresidualtumorcellsandtopreventrecurrencesBonemarrowsuppressionistemporaryandnotdosagerelated.10/27/202259131I-MIBGisofcertaintheraIn1997,Lohetal.publishedareviewoftheworldwideexperienceinvolving116patientstreatedwith131I-MIBGformalignantpheochromocytoma.Overall,therewasasymptomaticresponsein76%,ahormonalresponsein45%,andtumorregressionin30%.Theactivityof131I-MIBGpersingledosewas96–300mCi,andthemeancumulativeactivitywas490±350mCi.OnlyfiveCRsto131I-MIBGwerereported..10/27/202260In1997,Lohetal.publishedLimitationsNotallpatientswithmultiplemetastasesofmalignantpheochromocytomashavesufficientuptakeofMIBGtoallowMIBGtherapyMIBGnegativelesionscoexistwithMIBGpostivelesions,requiringcombinedtreatment.10/27/202261LimitationsNotallpatientswiAsasingleagent,131I-MIBGhaslimitedefficacyintreatingmalignantpheochromocytoma.Itsuseincombinationwithothercytotoxicagents,asiscurrentlybeingstudiedinpatientswithneuroblastoma,mayresultinadditionalbenefit(Sissoneta